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Brain and Protective Equipment
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Chapter One: Management Today The challenges of working in the new economy recognize: 1.1 Working Today Talent Talented people- What they know, what they learn and what they can achive The source of organisational performance Develop skills and improve What is intellectual capital The combined brain power and shared knowledge of an organization's employees TO orginzations: Intellectual capital resents a strategic asset as human creativity, insight and decision making can be converted into superior performance To individuals: Intellectual capital is a personal asset, one to be nurtured and continually updated Things evolve, make sure we keep updated Intellectual capital: The package on intellect skills and capabilities that set us apart making us valable to potential employers Maintaining your talent: There is no escaping the fact that your career success will require a lot of initiative, self awareness and continuous learning Technology Tech is in our everyday lives Latest developments Smart phone, smart apparel, smart cars, smart homes We struggle to keep up with social media ana staying connected with messaging, full of email and voicemail What happenings as younger workers advance into management Flexibility Work ethic It is critical to build and maintain a high Tech IQ! What is Tech IQ: The ability to use current technologies at work and in your personal life, combined with the commitment to keep yourself updated as technology continues to evolve Intellectual capi5la is a combination of: Commitment x Competency = Intellectual capital How to make the world a better place Globalisation The worldwide interdependence of resources flows, product markets and business competition Under the influence, government leaders worry and about the competitiveness of nations just as corporate leaders worry about business competitiveness Emerging markets will power global growth over the next 20 years. By 2025 overall global consumption is forecast to reach $62 trillion, twice its 2013 level and fully half of this increase will come from the emerging world Consequence: Going to fast in uses resources, inflation, corporate greed It's cheaper to have things made in different countries (wages are low and going down) Shamrock organization 1 leaf - full time employees- standard career paths 2 leaf - âfreelancersâ 3 leaf - Part times without benefits (first to lose their jobs when employers face economic difficulties) The rising of emerging markets Now account for 60% of all low and medium technology manufacturing worldwide Total value add in high tech manufacturing from a low 26% in the 1970s to 48% at present China strategy to upgrade its industries and move the manufacturing value ching by prioritising 10 sectors Information technology, robotic, aerospace, maritime equipment, modern railway equipment, alternative energy vehicles, power equipment, agriculture equipment, advanced materials, biopharma and medical products Ethics A code of moral principa;s that sets standards for conduct that is âgoodâ and ârightâ as well as âbadâ and âwrongâ Enron company huge corruption even in elections same thing happened with The Mechanism 1.2 - Organizations Organizational Purpose An orgnizations is a collection of people working together to achieve a common purpose Unique social phenomenon that enables its members to perform tasks far beyond the reach of individual accomplishment (synergy) The broad purpose of any orginzation is to provide goods or services of value to customers and clients A clear sense of purpose tied to: Quality of products and services Customer satisfaction Social responsibility Can be an important source of organisational strength and performance advantage All organisations are open systems (Systems that interact with its environment for renewal and growth) Organizations as systems All organizations are open systems that interact with their environment Continual process of obtaining resource inputs-people, information, resources and capital- and transforming them into outputs in the form of finished goods and services for customers One simple way to assess the impact of any organisation is to ask the question: How is the world different because it existed Value Creation: Organisations create value when they use resources well to produce good products and take care of their customers One simple way to assess the impact of any organization is to ask the questions: How is the world different because it existed? The 3 Ps of organizational performance Profit - is the decision economically sound? People - Does the decision treat people with respect and dignity? Planet - Is the decision good for the environment? Productivity: An overall measure of the quantity and quality of work performance with recourse utilisation taken into account Performance effectiveness: An output measure of task or goal accomplishment Performance efficiency: An input measure of the resource costs associated with goal accomplishment. Workplace changes that impact management Focus on valuing human capital Demise of âCommand and controlâ Emphasis on teamwork Pre-eminence of technology New workforce expectations Importance of networking Concern for sustainability 1.3 Managers Importance of human resources and manger People are not âcosts to be controlledâ High performing organizations treat people as valuable strategic assets Three takeaways 1. Give leaders broad authority 2. Encourage them to think like CEO 3. Challenge strong performers ealy with big opportunities Direct support, supervise and help activate the work efforts of others The people who managers help are the ones whose contributions represent the real work of the organisation Types of managers Line managers are responsible for work activities that directly affect organizationâs output Staff managers use technical expertise to advise and support the efforts of line workers Functional managers are responsible for a single area of activity Quality of work life (QWL) An indicator of the overall quality of human experiences in the workplace QWL Indicators Respect Fair pay Safe working conditions Opportunities to learn and use new skills Room to grow and progress in a career Protection of individuals rights The organization as an upside-down pyramid A managerâs job is to support workerâs efforts The best managers are known for helping and supporting Customers at the top served by worker who are supported by managers 1.4 The management Process Managers achieve high performance for their organizations by best utilizing its humans and material resources Management is the process of planning, organizing, leading and controlling the use of resources to accomplish performance goals All managers are responsible for the four functions The functions are carried on continually Characteristics of managerial work Long hours Intense pace Fragmented and varied tasks Many communication media Filled with interpersonal relationships Managerial agendas and networks Agenda setting Develops action priorities for accomplishing goals and plans Networking Process of building and maintaining positive relationships with people who can help advance agendas Social Capital Capacity to attract support and help from others Learning The change in a behaviour that results from experience Lifelong learning The process of continuously learning from daily experiences and opportunities The challenges of working in the new economy recognize: 1.1 Working Today Talent Talented people- What they know, what they learn and what they can achive The source of organisational performance Develop skills and improve What is intellectual capital The combined brain power and shared knowledge of an organization's employees TO orginzations: Intellectual capital resents a strategic asset as human creativity, insight and decision making can be converted into superior performance To individuals: Intellectual capital is a personal asset, one to be nurtured and continually updated Things evolve, make sure we keep updated Intellectual capital: The package on intellect skills and capabilities that set us apart making us valable to potential employers Maintaining your talent: There is no escaping the fact that your career success will require a lot of initiative, self awareness and continuous learning Technology Tech is in our everyday lives Latest developments Smart phone, smart apparel, smart cars, smart homes We struggle to keep up with social media ana staying connected with messaging, full of email and voicemail What happenings as younger workers advance into management Flexibility Work ethic It is critical to build and maintain a high Tech IQ! What is Tech IQ: The ability to use current technologies at work and in your personal life, combined with the commitment to keep yourself updated as technology continues to evolve Intellectual capi5la is a combination of: Commitment x Competency = Intellectual capital How to make the world a better place Globalisation The worldwide interdependence of resources flows, product markets and business competition Under the influence, government leaders worry and about the competitiveness of nations just as corporate leaders worry about business competitiveness Emerging markets will power global growth over the next 20 years. By 2025 overall global consumption is forecast to reach $62 trillion, twice its 2013 level and fully half of this increase will come from the emerging world Consequence: Going to fast in uses resources, inflation, corporate greed It's cheaper to have things made in different countries (wages are low and going down) Shamrock organization 1 leaf - full time employees- standard career paths 2 leaf - âfreelancersâ 3 leaf - Part times without benefits (first to lose their jobs when employers face economic difficulties) The rising of emerging markets Now account for 60% of all low and medium technology manufacturing worldwide Total value add in high tech manufacturing from a low 26% in the 1970s to 48% at present China strategy to upgrade its industries and move the manufacturing value ching by prioritising 10 sectors Information technology, robotic, aerospace, maritime equipment, modern railway equipment, alternative energy vehicles, power equipment, agriculture equipment, advanced materials, biopharma and medical products Ethics A code of moral principa;s that sets standards for conduct that is âgoodâ and ârightâ as well as âbadâ and âwrongâ Enron company huge corruption even in elections same thing happened with The Mechanism 1.2 - Organizations Organizational Purpose An orgnizations is a collection of people working together to achieve a common purpose Unique social phenomenon that enables its members to perform tasks far beyond the reach of individual accomplishment (synergy) The broad purpose of any orginzation is to provide goods or services of value to customers and clients A clear sense of purpose tied to: Quality of products and services Customer satisfaction Social responsibility Can be an important source of organisational strength and performance advantage All organisations are open systems (Systems that interact with its environment for renewal and growth) Organizations as systems All organizations are open systems that interact with their environment Continual process of obtaining resource inputs-people, information, resources and capital- and transforming them into outputs in the form of finished goods and services for customers One simple way to assess the impact of any organisation is to ask the question: How is the world different because it existed Michal Porter - Value Chain Value Creation: Organisations create value when they use resources well to produce good products and take care of their customers One simple way to assess the impact of any organization is to ask the questions: How is the world different because it existed? Triple Bottom Line The 3 Ps of organizational performance Profit - is the decision economically sound? People - Does the decision treat people with respect and dignity? Planet - Is the decision good for the environment? Organizational Performance Productivity: An overall measure of the quantity and quality of work performance with recourse utilisation taken into account Performance effectiveness: An output measure of task or goal accomplishment Performance efficiency: An input measure of the resource costs associated with goal accomplishment. Workplace changes that impact management Focus on valuing human capital Demise of âCommand and controlâ Emphasis on teamwork Pre-eminence of technology New workforce expectations Importance of networking Concern for sustainability 1.3 Managers Importance of human resources and manger People are not âcosts to be controlledâ High performing organizations treat people as valuable strategic assets Three takeaways 1. Give leaders broad authority 2. Encourage them to think like CEO 3. Challenge strong performers easily with big opportunities Direct support, supervise and help activate the work efforts of others The people who managers help are the ones whose contributions represent the real work of the organisation Levels of management Types of managers Line managers are responsible for work activities that directly affect organizationâs output Staff managers use technical expertise to advise and support the efforts of line workers Functional managers are responsible for a single area of activity Quality of work life (QWL) An indicator of the overall quality of human experiences in the workplace QWL Indicators Respect Fair pay Safe working conditions Opportunities to learn and use new skills Room to grow and progress in a career Protection of individuals rights The organization as an upside-down pyramid A managerâs job is to support workerâs efforts The best managers are known for helping and supporting Customers at the top served by worker who are supported by managers 1.4 The management Process Managers achieve high performance for their organizations by best utilizing its humans and material resources Management is the process of planning, organizing, leading and controlling the use of resources to accomplish performance goals All managers are responsible for the four functions The functions are carried on continually Four functions: Planning,organizing, leading and controlling Mintzbergâs 10 Managerial Roles Characteristics of managerial work Long hours Intense pace Fragmented and varied tasks Many communication media Filled with interpersonal relationships Managerial agendas and networks Agenda setting Develops action priorities for accomplishing goals and plans Networking Process of building and maintaining positive relationships with people who can help advance agendas Social Capital Capacity to attract support and help from others Learning The change in a behaviour that results from experience Lifelong learning The process of continuously learning from daily experiences and opportunities Katzâ Essential Managerial Skills Chapter 22 Antihypertensive Drugs Hypertension Defined (JNC-8) Pharmacology Overview 7 main categories of drugs to treat HTN Adrenergic drugs (old friend) Angiotensin-converting enzyme (ACE) inhibitors Angiotensin II receptor blockers (ARBs) Calcium channel blockers (CCBs) Diuretics Vasodilators Direct renin inhibitors A. Adrenergic Drugs: 5 Subcategories and where they act A1. Adrenergic neuron blockers (central and peripheral)- we wonât talk about this A2. Alpha1 receptor blockers (peripheral) A3. Alpha2 receptor agonists (central) A4. Beta receptor blockers (peripheral) A5. Combined α and ÎČ receptor blockers (peripheral) A2. Peripherally Acting Adrenergic Drug Alpha1 Blockers (weâve met these) Doxazosin, prazosin, alfuzosin Block alpha1-receptors which causes BP to decrease Reduces peripheral vascular resistance and BP by dilating both arterial and venous blood vessels Main Use: benign prostatic hyperplasia (BPH) Alpha1 Blockers REMEMBER Tamsulosin (Flomax)* is an α1 blocker BUT *Tamsulosin is not used to control BP, just for BPH. A3. Centrally Acting Adrenergic Drugs Alpha 2 agonist Clonidine and methyldopa 1- Stimulate alpha2-adrenergic receptors. in the brain Decreases sympathetic outflow from the CNS which decreases NE production 2. Stimulate alpha2-adrenergic receptors in kidneys remember alpha 2 opposes alpha 1 Dilates peripheral blood vessels â lowers peripheral resistance â Results in decreased BP So âŠ.Clonidine (Catapres) Used primarily for its ability to decrease blood pressure in an urgent setting Also use in opioid withdrawal as previously discussed Oral (multiple times a day), and topical patch formulations Do not stop abruptly as it may lead to rebound hypertension In reality, Clonidine and methyldopa Not prescribed as first-line home antiHTN drugs High incidence of unwanted adverse effects: orthostatic hypotension, fatigue, and dizziness MIGHT be uses as adjunct drugs after other drugs have failed, in conjunction with other antiHTN such as diuretics A4. Adrenergic Drugs Selective Beta 1 Blockers Metoprolol, Atenolol Reduction of HR through ÎČ1 receptor blockade (remember adrenergic blocking of this receptor???) HR results in BP Cause reduced secretion of renin = BP A4. Adrenergic Drugs Selective Beta1 Blockers Nebivolol (Bystolic) Uses: hypertension and HF Action: blocks ÎČ1 receptors and produces vasodilatation, which results in a decrease in SVR High doses loses selectivity and blocks both ÎČ1 and ÎČ2 Less sexual dysfunction All BB- Do not stop abruptly; must be tapered over 1 to 2 weeks A4. Adrenergic Drugs NONSelective Beta Blockers Propranolol Acts equally on ÎČ1 and ÎČ2 Other uses include situational anxiety associated with public speaking, test taking As mentioned on previous slide, nebivolol at high doses becomes beta nonselective A5. Dual-Action Adrenergic Drugs α1 and ÎČ Receptor Blockers Dual antihypertensive effects of reduction in heart rate (beta1 receptor blockade) and vasodilation (alpha1 receptor blockade) Examples are carvedilol (common) and labetalol (not as common) A5. Dual-Action Adrenergic Drugs α1 and ÎČ Receptor Blockers Carvedilol (Coreg) Widely used drug that is well tolerated Uses: HTN, mild to moderate HF in conjunction with digoxin, diuretics, and ACE inhibitors Contraindications: severe bradycardia or unstable HF, bronchospastic conditions such as asthma, and various cardiac conduction problems Adrenergic Drugs Indications - HTN But also for Glaucoma (topical) BPH: doxazosin, prazosin, and terazosin (2 for 1) Management of severe HF when used with cardiac glycosides and diuretics Contraindications Acute HF- have to stabilize first MOAIs- yeah doesnât everything interact with MAOIs? Peptic ulcers Severe liver/kidney disease Asthma (with beta blockers) Adrenergic Drugs: Adverse Effects Orthostatic hypotension 1st-dose syncope Rebound hypertension with abrupt discontinuation Most common: Dry mouth, drowsiness, constipation, sedation Interactions- always check for specific drug interactions Can cause additive CNS depression with alcohol, benzodiazepines, opioids Question #1 When administering an alpha-adrenergic drug for hypertension, it is most important for the nurse to assess the patient for the development of what response? Hypotension Hyperkalemia Oliguria Respiratory distress Answer A Hypotension This is a key point in patient education These drugs have strong vasodilating properties and may cause severe hypotension, especially at the beginning of therapy. B. Angiotensin-Converting Enzyme Inhibitors aka ACE Inhibitors or ACEi Large group of safe and effective drugs Currently are 10 ACEi Often used as first-line drugs for HF and hypertension May be combined with a thiazide diuretic, loop diuretic, or Calcium Channel Blocker (CCB) You need to understand the basics ACE Inhibitors: Review RAAS ACE converts angiotensin I, formed through the action of renin, to angiotensin II Angiotensin 2 is a potent vasoconstrictor and also induces aldosterone secretion by the adrenal glands Aldosterone stimulates sodium resorption (H20 follows Na Both act to raise BP which causes kidneys to reduce renin production ACEi= Great drug to treat HTN BUT contraindicated in pregnancy (2nd,3rd trimester due to fetal renal damage) and breastfeeding first few weeks after birth B. ACE Inhibitors - PRIL Lisinopril (Prinivil) super common, often the 1st drug Enalapril (Vasotec) also common Captopril (Capoten) great if liver disease present Benazepril (Lotensin) Fosinopril (Monopril) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Primary Effects of the ACE Inhibitors Prevent Na (and H2O) resorption by inhibiting aldosterone secretion (volume reduction) (GO BACK TO RAAS DIAGRAM) blood volume decreases work of the heart preload, or the left ventricular end-diastolic volume which is important in HF ACE SUMMARY OF ACTIVITY 1) Prevent vasoconstriction caused by angiotensin 2 (2) Prevent aldosterone secretion ïš less sodium and water resorption Cardioprotective Effects of ACEi They slow progression of left ventricular hypertrophy (ventricular remodeling) after MI so considered cardioprotective ACE inhibitors have been shown to decrease morbidity and mortality in patients with HF Renal Protective Effects of ACEi ACE inhibitors: reduce glomerular filtration pressure by volume reduction Cardiovascular drug of choice for patients with diabetes since it helps protect kidneys by reducing pressure. Sometimes used low dose for kidney protection with DM without HTN B. ACEi Enalapril (Vasotec) Only ACEi available in both oral and IV Enalapril IV does not require cardiac monitoring Oral enalapril: prodrug (metabolized in liver) Improves patientâs chances of survival after an MI Reduces the incidence of HF B. ACEi Captopril (Capoten) Uses: prevention of ventricular remodeling after MI; reduce the risk of HF after MI Shortest half-lifeïš Must be administered multiple times throughout the day so this limits its use Not a prodrug so good for patient with liver disease Question #2 A patient with diabetes has a new prescription for the ACE inhibitor lisinopril. She questions this order because her provider has never told her that she has hypertension. What is the best explanation for this order? The doctor knows best The patient is confused This medication has cardioprotective properties This medication has a protective effect on the kidneys for patients with diabetes Answer D ACE inhibitors have been shown to have a protective effect on the kidneys because they reduce glomerular filtration pressure. This property makes them the cardiovascular drug of choice for patients with diabetes. Question #3 A patient with a history of pancreatitis and cirrhosis is also being treated for hypertension. Which drug will most likely be ordered for this patient? Clonidine Prazosin Diltiazem Captopril Answer D Captopril Captopril is not a prodrug; therefore, it does not need to be metabolized by the liver to be effective. This is an advantage in patients with liver disease. ACE Inhibitors: Adverse Effects *Dry, nonproductive cough, which reverses when therapy is stopped. This is a class effect Dizziness- Note: First-dose hypotensive effect may occur Headache & Fatigue Possible hyperkalemia ** Angioedema: rare but potentially fatal Not safe in pregnancy-are contraindicated during the second and third trimesters of pregnancy because of increased risk of fetal renal damage C. Angiotensin II Receptor Blockers (ARB) Considered an alternative to ACEi Less likely to cause a dry cough and hyper K+ that is common with ACE inhibitors Angiotensin II Receptor Blockers: Mechanism of Action Go back to RAAS diagram! ARBs affect primarily 2 places 1. Vascular smooth muscle - blocks vasoconstriction 2. Adrenal gland -Selectively blocks the binding of Ang 2 to certain Ang 2 receptors inhibiting secretion of aldosterone Lowers volume retention and BP Angiotensin II Receptor Blockers -ARTAN Losartan (Cozaar)- very common Eprosartan (Teveten) Valsartan (Diovan) Irbesartan (Avapro) Candesartan (Atacand) Olmesartan (Benicar) Telmisartan (Micardis) Azilsartan (Edarbi) C. ARB Losartan (Cozaar) Beneficial in patients with HTN and HF Used with caution in patients with kidney or liver dysfunction and in patients with renal artery stenosis ***Not safe for breastfeeding women and should not be used in pregnancy (Cat C 1st trimester, Cat D 2nd-3rd trimester), potential fetal toxicity Appear to be equally effective for the treatment of hypertension and well tolerated ARBs less likely to cause cough and hyperK+ but can still happen Evidence that ARBs are associated with lower mortality after MI than ACE inhibitors Never take ACEi and ARBs at the same time* 5. Calcium Channel Blockers (CCB) Primary use: HTN, angina, some dysrhythmias Cause smooth muscle relaxation by blocking the binding of calcium to its receptors, preventing muscle contraction Results in: Relaxed blood vessels to the heart Decreased peripheral smooth muscle tone Decreased SVResistance Decreased BP E. Diuretics First-line antiHTN in JNC 8 guidelines Decreases fluid volume The results from diuresis: preload, Peripheral resistance Overall effect ï Decreased workload of the heart and decreased BP Thiazide diuretics are the most commonly used diuretics for HTN Ie hydrochlorothiazide (HCTZ), chlorthalidone We will discuss diuretics further in the chapter on diuretics F. Vasodilators Directly relax arterial or venous smooth muscle (or both) Results in: Decreased SVR Decreased afterload Peripheral vasodilation Indicated for treatment of HTN May be used in combination with other drugs F. Vasodilators Hydralazine (Apresoline) Orally: routine cases of essential hypertension Injectable: hypertensive emergencies BiDil: specifically indicated as an adjunct for treatment of HF in African-American patients F. Vasodilators Sodium Nitroprusside (Nitropress) *Sodium nitroprusside and IV diazoxide are reserved for the management of hypertensive emergencies. Contraindications: severe HF, known inadequate cerebral perfusion (especially during neurosurgical procedures) F. Vasodilators Adverse Effects Hydralazine: dizziness, headache, tachycardia, edema, dyspnea, N/V/D, vitamin B6 deficiency, rash Sodium nitroprusside: hypotension, bradycardia, decreased platelet aggregation, rash G. Direct Renin Inhibitors Aliskirin (Tekturna) Blocks the RAS pathway at the point of activation. Inhibiting renin production prevents the downstream production of Ang II (potent vasoconstrictor) Adverse effects: N/V, severe hypotension, hyponatremia, hyperkalemia⊠Contraindicated in patients with DM taking ACEi or ARB Miscellaneous Antihypertensives Eplerenone (Inspra) Newer class of drugs called selective aldosterone blockers (remember RAAS?) Reduces BP by blocking the actions of aldosterone at its corresponding receptors in the kidney, heart, blood vessels, and brain Indications: routine treatment of hypertension and for post-MI HF Contraindicated if serum potassium levels are high (above 5.6 mEq/L) A Special Form of HTN Treatment of Pulmonary Hypertension Sildenafil and Tadalafil Commonly used for erectile dysfunction Used for pulmonary hypertension but with different trade names Sildenafil: Revatio* (Viagra for ED) Tadalafil: Adcirca* (Cialis for ED) Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty DesirĂ©e Nieuwenhuis | NatĂ lia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including âonset of puberty and adiposity/obesityâ, âonset of pubertyâ, âchildren with obesityâ, âadipose tissueâ, âchildhood obesityâ, âadiposityâ, âobesityâ, âadipokine(s)â, âHPG axisâ, âadipokines ovary/ova- riesâ, or âadipokines testesâ, either alone or in combination. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are goverMemory Adventure: From Learning to Forgetting Imagine Alex is preparing for a school science fair. Storing Memories (2.5) Alex studies a science experiment. The semantic memory (facts and knowledge, like âwater boils at 100°Câ) is stored in the brain, while episodic memory (personal experiences, like âI mixed vinegar and baking soda yesterdayâ) records the event. The hippocampus (the brainâs âsave buttonâ) helps transfer these memories into long-term memory. During sleep, memory consolidation (making memories stable and long-lasting) happens, and Alex vividly remembers the fun surprise when the mixture fizzesâa flashbulb memory (emotionally strong, vivid memory). Alex also learns the skill of carefully pouring liquids, a procedural memory stored in the basal ganglia, and how to react when the mixture splashes, a conditioned response stored in the cerebellum. Emotions make the memory even stronger, thanks to the amygdala. Retrieving Memories (2.6) The next day, Alex goes to the science fair. Seeing the experiment table triggers priming (unconscious memory activationâseeing the table makes Alex remember steps). Being in the same classroom helps context-dependent memory (better recall in the same place as learning). Alex is also in the same excited mood as while practicing, so mood-congruent memory helps remember details of the experiment. When listing the steps, Alex remembers the first step clearly and the last step best, thanks to the serial position effect. Using strategies like quizzing himself earlier (testing effect) and spacing study sessions (spacing effect) improves retrieval. Forgetting & Memory Errors (2.7) During the fair, Alex tries to remember an old trick learned last year, but some details are fuzzy. This is retroactive interference (new memories block old ones). At the same time, old steps from last year sometimes confuse him, an example of proactive interference (old memories block new info). Alexâs friend jokingly says he added glitter to the experiment last week. Alex later misremembers seeing glitterâthis is the misinformation effect. He even forgets where he first learned the correct steps, a case of source amnesia, and feels a strange sense of dĂ©jĂ vu when looking at a similar experiment table. Unfortunately, Alexâs cousin has anterograde amnesia (cannot form new memories) and can only remember things from before last year, while his neighbor has retrograde amnesia (loses past memories) and cannot recall last weekâs fair prep. Luckily, Alexâs strong study habits, sleep, and emotional engagement helped protect his memories from being forgotten too quickly. âOn this night, we share a roof protecting us from fleets of inequity. Our unification promises a better tomorrow. Those larger than myself, sitting on their marble thrones, sipping blood from cups composed of human skin and singing songs of so-called virtue, grow weaker each moment. Their caravans are revolting. There is hope yet. There is progress! Though tonight may mark a countdown, it is still a celebration. Look at all we have done, not just for Trials but for Palatium Infra as a whole. In four years, when Iâm no longer Sovereignty, the Spoiled Purity and his people will continue to strive. So drink! Smoke! Crush up those exotic plants and snort them! We will not falter, weaken, or wane. Our influence is expanding, and somebody new opens their eyes every day. Even the Silbys of Aculeus have reached alarming potentials despite their embittered minds. So long as you relish in tonight, dance, and pray to your âdeadâ Gods, our revolution shall rise beyond the bounds of class, and when Iâm only a commoner, we shall rise again beyond our brainwashed adversaries! Cheers, my people. Cheers!â Followers raised their cups. Some clinked theirs together. Others stood still and screamed breathlessly in agreement. I smiled with courtesy, then stepped off my platform. My voice still rang across the cellar. Speeches before were grander. Those displays were supposed to be emptying, and yet this one left me bloated, swollen tight. I watched as they popped the corks of their bottles and chanted in the name of Purity. Maybe the quality of my words wasnât what mattered to them anyway, so long as I screamed loud enough. Thereâs no merit in attacking your people, a voice corrected me. âThatâs right,â I said aloud. âKnox, my-my Sovereign!â squealed a nearby devotee, jittering as he stuffed his face with catered pastries. He was one Iâd never seen before or had failed to remember. âLook what Iâve found! Itâs wine, and not the shoddy Infran kind, either. Earth-made with good fruit! I donât know how anyone managed to get their hands on this. Maybe some space travel mischief.â He giggled and held up a small glass bottle. âHow neat.â âI want you to have it, Sir.â I nodded my head. âYes, of course. Thank you.â Backing off into the midst of rowdy disciples, I clutched the bottle. What a waste of grapes. It could have been jam instead. Earthly food had a superior taste, ripe with delicate intricacies and nostalgia, but Palatium Infra had mastered the art of alcohol. Why waste your time with a drunkenness so sad and sickening? The booze of trash. Not many more followers approached me. The barren peroration must have upset them. My hands itched to submerge into my suit pockets, and my legs stood suddenly numb, wobbling. Four more years until Iâm nothing. But tonight, you are nothing. âShut up,â I told myself. Tightly packed together in the corner of the dwelling sat the Sibyls. A mound of writhing fabric and tones of skin made up their unified silhouette. I snapped the strap of the nearest gown, balancing on my hands and knees, waving the bottle before them. In their almost rodent nature, narrow noses prodded my way. Their dresses wrinkled and fell to their ankles. Knees dropped, and eyes widened. Many grumbled at me like hungry she-beasts. Those newer ones with faded curtains for hair, sunken eyes, and dirtied nails looked, hid their face, then sobbed. I imagined them in a pack together, fighting wildly against the Spoiled Purity in their rat decorumâbiting down with square teeth laced with rabies. âIâve got you all something,â I said. âGo back off to your pedestal and yap some more. We donât want it.â A woman rose from the pile and spat. âYou donât even know what it is yet. It's Earth hooch, or more likely a near-flawless replica. I figured you girls would also like a chance to enjoy yourselves tonight.â âYour playmates have been harassing us since the moment you hung the banners and opened the cellar door.â The youngest, with a striking cyan mop upon her head, uncoiled from the mass. What was she now? 20, 21? We celebrated a birthday recently, I thought as she spun around me. âI remember something about a promise. Multiple promises, actually. Are you trying to bribe us into just shutting up and taking it? Because if another sticky, 40-year-old, Earth-born virgin gropes my shoulder, Iâm going to have an aneurysm!â the girl continued. âWhy not an Infran follower? Do you like it when they touch you?â I returned her accusing tone. âIâm sorry, sweet prophets, that you feel Iâve neglected my duties. Iâll keep a better eye out. Remember, you can always just holler if somebody is bothering you. And Anwen, friend, if Iâve ever tried to bribe you with anything, it was certainly the hair dye. I mean, look at you! Such handsomeness!â I exclaimed. The other Siblys began to encircle her, uttering compliments or even announcements of their envy. Anwen disappeared in a wink with flushed cheeks back into the mound. âIâll just leave this here.â Smiling, I set down the bottle. ** â141, 143. . .â I counted each step as I trekked the staircase. There was no doubt I lost track somewhere. The ledges kept spawning under my feet, infinitely multiplying until I wasnât moving at allâswallowing me up in a whirlpool of stone. My tie still hung around my neck, and my blazer remained tied around my hips as a skirt. Streaks of red dribbled off from the cavity in my chest. It was a gorgeous marking, sensual to my fingertips as I traced its edges. Purity, oh, Purity. Purity and his wings of burnt skin. Purity and his many faces. Purity the spoiled. Purity the mutilated. The Silbys did not bother waiting for me. On bare feet, they stormed up the stairs to their room. A trail of red, though in paint unlike mine, streamed after them. None looked remotely near me as they squeaked and gossiped intangibly. I saved them, those Infran broads, enlightened them. As much as they liked to deny it, spit at me, and bask in the thought of their victimhood, in this home, they stood empowered. Youâve done well, my thoughts affirmed, though in the manner of an insincere commentator rather than a hype man. Teeth grace in tile violin goes laundry paper when. It dissolved into an intruding drivel. I rubbed my head and sniveled. âDo you need help, Knox?â called a Silby. Fattened by my coddling, her shadow fell upon me from the doorway steps ahead. I attempted counting again. There mustâve been at least another hundred between me and her. âIâm hallucinating some,â I said, breathing deeply to suppress a burp as I struggled to recall her name. Two syllables. Typically Latin, though sometimes English. Drops of slobber leaked from my mouth. âIâm hallucinating some, Tybal. Do you like your name, Tybal? I would have named you something better. Ty-Tyballinia. No, weâd have to eliminate the âballâ aspect. It sounds too crude.â âOne foot in front of the other,â she said. So I walked. Mess greeted me at the doorway. Dirtied culinary obscured the dark wooden countertops, and the sink lay running. I approached the kitchen table, sat, and set my face down upon its cool wooden surface. Assaulting my nose was the smell of neglected flowers, like soil mixed with the kind of sweet cough medicine that would have left me gagging as a child. Open windows whispered songs of the twilight hour through the vessels of busy trolleys and shooting guns. My mouth strained to vomit, but there was nothing in my stomach to regurgitate except the petals of Stultoâs bloom, which came out effortlessly in little sputters. Teetering, I stood up and brushed disgorged plant parts off the tabletop. âLove,â I said as I slogged up yet another staircase. âAre you awake?â She said sheâd wait. Somebodyâs gotten her. No, she always misses movie night. That sleepyhead, I assured myself. There was a stirring amidst the manorâs cloak of dusk. Portraits of myself, my wife, and my daughter turned to face me as the hallway lights flickered, escaping their quartz frames to penetrate my ears with nonsense. The taxidermied heads of Infran creatures bared their teeth. I stopped to stare at my favorite, an adabactor with daunting spiked tusks poking out from its forehead. Its nose remained black and sharp, and its eyes wide with malice. âWhere is my Spes, Adaba-boy? Is she sleepy?â Thereâs someone in the house. The sounds of the stirring rose along with my blood pressure. Footsteps orbited around me, drawing near and far and then near again, little dancers in the dark. The carpet immersed me in its mass of purples and blues, leaving my skin stained indigo and my vision abstracted. I toiled to reach the master bedroom across the aisle as it stretched out to me with bright lights and celestial howling, like a dove struggling in a pool of oil. Never again with Stultoâs bloom. Never again on what was already a bad night. My hand brushed the doorknob, and the high abruptly faded into only a persistent hum-buzz twirling around my brain. The portraits returned to their typical depressionâSpes posing with her ax, Ariâs school photo, and myself in the cap I wore when addressing the military with the Verbis emblem embroidered in its center. All lifeless shots. Who were they for when they captured not the subjectâs essence but only some fragment of their identity? They used to feel personal, not advertisements of some supposed characters. Servants, babysitters, and likewise civilian guests, I reminded myself, mustnât forget whose home theyâre in. Yet my body moved independently, taking Ariâs from its hook and laying it backward against the wall to hide her distant grin and tamed posture. It was time for new pictures. Sweet ones, real ones; time was ticking. I approached my own when the stirring began again. Groans and squeals erupted from the vents as if someone had set a pen of pigs loose in my crawlspace. No, not the crawlspace, my bedroom door. I turned the ruby knob. Underneath a blanket wrestled my two squealing piglets, their skins melting together beneath the layer of duvet. Fishnet leggings and manicured nails outstretched and scraped at the sheet beneath them. One raised its head, a salmon-colored man with sweat running down his forehead. Through the crack in the door, we met eyes, his Infran Dr. Sesuss nose flaring its narrow nostrils. No mark of the Spoiled Purity existed carved onto his naked body. My chest felt tight. I stepped back. I was suffocating. Spes emerged from the linens, her hair flowing down her back and her dark skin glistening in front of the bedroom window. She giggled and held the man, the blanket falling and revealing inches of her body I had not seen in months. âDarling,â whispered the rosy-faced man, âlook.â He was unfathomably ugly and grotesquely young, with beady, lifeless pupils that dilated when he faced me. The excess flesh on his face sagged while he bit down on his thin lips. My wife faced me, gasped, and strained to cover herself. Suddenly, I was a stranger. A small child who had walked into his parents having sex. I unfurled the door completely. âGet out of my house,â I said. The man stayed in place. âGet out of my house,â I repeated. âKnox,â Spes began. Tears ran down her round cheeks. âShut up!â I turned to the man, picking up a marble trophy from on top of my dresser. âGet out of my house! Iâll kill you!â âKnox!â Spes sobbed. âGod damn it! I hate you! You barely look at me. Every day, thereâs less passion. God, God, God, I donât want to fuck a dead man!â she screamed, âYou get out! Get! Get!â My hands wrapped tighter around the statue. That pig of a man was attached to her at the side, his face equipped with a scowl that challenged mine. He thought I was weak; frail like a decaying dementia-ridden senior. I imagined his skull bashed in, his scowl gone, and the feist and confidence in his face beaten into numbness. A new portrait was in order of such brutality, him as a splintered slab of wood, rashed and beaten, a carcass licking my boot. The churning in my brain had come back. Every wall shook. Clock faces came to life and rang in alarm. Indescribable noises caressed my eardrum before breaking into sorrowful weeps. Was it my own? I stared at Spes in motionless frenzy, clenched my teeth, and screamed like a siren. Passionless. What a lie! An excuse, more like. One that erased all my ventures, reducing me to a nobody. But I was not a nobody. I thought of my sect, my campaigns, my endurance through the political brutality of my empty hive-mind worldâeven my collection of literature, maps, and artifacts. I thought of daring nights alone with Spes when we were young, ravaging each other, two sardonic eggheads suddenly overcome with desire. The veins in my neck throbbed as I gasped for air. It was all I had. I threw the figurine at the manâs head. Eye shut, I heard the thud. A million singing voices of victory flooded out of the cracks in the floorboard. Proving myself a man to the woman I loved in a display of fervent violence was passion. I strained my ears for his cries, though I did not look yet. There had to be a pause, a moment of relief, where I stood tall as a skyscraper and seemingly fought to stay contained in front of my wife and her wounded, quivering paramour. Frantic footsteps rushed off the bed and past my side. I turned and grappled against myself to seize my wifeâs shoulder. âSpes!â My eyelids lifted. Escaping was the man with that same numb expression in which I had imagined him. âYouâre insane,â he said. I swiveled back towards the bed. With her curly locks flowing over her breasts and her limbs bent at her sides, Spes sat limp pressed against the headboard, her forehead bludgeoned and the statue resting on her stomach. Lips pursed and sweet, my Renaissance beauty reclined there in the guise of a squashed bug. But she was not dead. The desk ornament I flung was only the size of my shoe. Spes, that dramatist, may have been slightly hurt but was far from dead. She only wanted me to think she was to observe me at my most distraught, like a leech feeding on misery. âGet up.â Staggering toward the bed, I said. âYou wanted passion? I showed you passion. âShoved it right into your head. Of course, we both know who that gesture was meant for. . .â I fumbled to find my wit. Cold skin met my hands as I stroked her face, unable to resist checking her pulse, even though she was not dead. âI love you, Spes,â I said. Rain pelted against a nearby window. âSpes, please. Please.â No vibration answered my plea. I lifted my hand, sitting next to her now. Tears did not come. There was not any blood on the trophy, but when I picked it up, it felt to be now only a cruel instrument. It depicted a younger me in white marble, with my glasses and collared shirt being the only things painted. Both were in pink. It was a favorable color. I scrambled from the bed to vomit pure digestive bile on the rug. My stomach heaved. I ran my nails along every piece of myself I saw, a dog chasing my tail. As I slammed myself against walls and convulsed, my own heart grew ever louder in my chest. âDad? I heardââ Ariâs slippered feet hammered across the floor. âMom? Mom?â I kept my eyes on the storm. Silence fell. âShe-She isnâtâyourâ.â Gasps interrupted every syllable she spoke. âYouâre a murderer. Bad. Like they said,â she breathed, â You beat her!â The words became mush, alphabet soup. Ari ran back down the hall. âMy-My mom is dead. . . .Yes. . . Manor of the Trials Sovereignty. . .Ari Sorkin. . . Iâm afraid heâs going to hurt me,â she said, presumably over the phone. It was all too fast. I crawled onto the windowsill, opened the glass, and let myself plummet into the alley below. Gusts of wind howled. The lack of motion or sensation informed me I had passed and again lived. Another Palatium Infra, another strange planet in which the celestial endowed rotting men with the opportunity to inhabit. Was this it? Was it all just an impossible limbo of galactic traveling? My surroundings were overwhelmingly gray, an abyss of clouds. Perhaps I had now met the real coming world, and my family and old friends lived here, ready to rush to my sides, lift me up, and jump for joy. Spes would be there. She would be enraged, but at least sheâd be there. You are a bad man. You are a bad man. My eyelashes fluttered. There was a tugging sensation in my leg. The fog was wavering along with my ascendance. âNo,â I yearned, trying to grip the clouds and stick them in place. âStay with me.â But the peace was fleeting. I felt the cement under me and the moist garments clinging to my figure. My leg burned. Carefully, I craned my neck, only to observe the promenade as my surroundings. The most underwhelming of filth and danger, individually Infran. Forever my coming world. What a fool I was, having forgotten my blessing. Those idiot Gods could not tell the difference between assassination and self-infliction; a faulty insurance plan. The urge to cry at last set over me, and so I sat and wailed hot salvia into my palm, shielding my mouth to muffle the noise. Thunder echoed my hushed howling. Raindrops turned to pebbles. Under the ambiance of the stormy night, I could have sworn I heard troops stomping, guns cocking, and the chanting of my name. They had all been waiting for this. Billboards came to life, and I could only sit and spectate as the scenery flashed red. I inhaled fear and sobriety through runny nostrils. âTrials Sovereign Vsevolod âKnoxâ Sorkin is currently at large for the suspected homicide of Spes Sorkin, breaking the first term of the Sovereignty Charter. We now instruct you to report any sightings of the Earth-born, caucasian, roughly 195 centimeters tall, brown-haired, and brown-eyed man to your local Guard post. One can identify the suspected convict specifically by an occult tattoo of Purityâs Coronet on his lower back. No attempted execution or elongated punishment will take place until our Guards conduct an autopsy proving his guilt, per Lifeâs 1238 commandment. We cannot be sure when or if the Gods will revoke his blessing. Remember, when Gods frown upon strife, opt for a peaceful life. We permit all grieving festivities until Cagidus 4th. Good year!â towering buildings sang out in broadcast, repeating that same convoluted message quicker the instant it ended. Sometimes, the announcer spoke in Latin for the Infran children, other times in Chinese, Hindi, or Spanish to cater to those of irrelevant tongues. You arenât a bad man. You are a stupid boy. Puddles sloshed. Somebody was approaching. I didnât dare waste any remaining energy avoiding the Guards and their prodding blades. How did that phrase go? You dug your grave. Now lie in it. And so I embraced the cement. âKnox?â said the Guard. No, her tone was too sincere, and no authority would proceed in such a manner. There wasnât confirmation on whether or not I was armed, and it wasnât as if she could shoot me first. She was a partygoer, having just left from the cellarâs backdoor. I shooed her away with my hand. She hovered, and I discerned her shadow hesitating over my body. A man could not rot in peace. âCome on, get up! Theyâre after you!â Hands reached around my torso, struggling to handle my weight as they urged me onto my feet. That leg, the burning one, my right, trembled and bent unnaturally upon impact with the ground. The partygoer slung my arm over her shoulder, balancing me. My eyes caught a glimpse of a cyan mop. âAnwen?â I rasped, âhu-who let you out?â Keys jangled in her handsâmy keys. âI escaped,â she said casually, coercing me to walk beside her. âQuicken your pace. I just heard somebody on your front porch. âYou see that compost bin down the alley? Weâre gonna burrow right down into the depth of that. If they open it and uncover us, Iâll be on top, and I can hide you and act like Iâm just a homeless amica trying to take a nap.â With a tightening grip, she led me like livestock to the stinking crate. âI donât understand, Anwen,â I said. âTheyâre going to torture and kill you, stupid. You know theyâve been wanting to, and you just handed the opportunity to them!â âI understand that.â It was becoming increasingly challenging to hide the fragility emerging in my voice. âYou said you were escaping. Why stop and help your captor?â âWhat else could I do? Leave you there?â Attempts to shove my wounded body inside its mass of discarded fruits and vegetables began. She yanked down upon my head and submerged me in the fertilizer sea. The evidence grows indisputable, I thought as I stared at the abruptly humane Infran girl, diving in after me, that I belong here. âDamn me to hell! Iâve killed her! My love is dead!â an uncontrollable cry leaped from my mouth. âShut up! Soon youâll be, too, if you donât quiet down.â The actual noise of the Guards darted past us: disorientated marching, guns clanking against each other, cluttered belts rattling, the Latin squawking. One paused to open the binâs lid, though only rummaged through the surface layer of peat before carrying on. âWhat are they talking about? I struggle with my Latin,â I whispered. âThe search, mainly.â Aggression remained firey in Anwenâs clenched jaw. Though she sat on top of me, there was a monumental distance between our rain-soaked forms. I curled up into a ball, ducked my head between my knees, and dreamt of Spes, ignoring the stench of spoiled food rising from every crevice of my dwelling. The next coming world was due to adopt me again as I forced sleep. I prayed for a canyon of fluffy haze, where I waltzed with pale memories but found nothing but the petrifying stillness of my mind. Killed and ran. Violent as a Guard just to prove a point and watch it backfire. Why would any heaven want to welcome me? I clung to the picture of Spes in my head like it was the last ember of an extinguished flame. âDid you mean to kill her?â Anwen interrogated. âSomeone like you would immutably believe yes.â âAnd who is someone like me? You canât even treat me like a person for a moment, can you?â grating drama decorated her words. âYou know my opinions. I have not seen much of your or your breedâs faces besides that of cruelty and ignorance.â I retorted. âI just saved you! Does that make me cruel and ignorant?â âIt makes you an idiot, which is another word for somebody ignorant.â âAnd why am I an idiot?â She asked. âBecause you helping me does no good. Thank you anyhow. Now, do yourself a favor and scram.â As she bent her leg in anticipation, preparing to strike me on the forehead, I sensed an invisible withdrawal widening the gap between us. âYou never answered my question,â Anwen took me by the end of my tattered tie suddenly and started her game of shepherd and sheep over again, pulling me back up to the crateâs exit. It appeared as a shining light at the end of a maze of rubbish and mold. âNo. Of course not. Spes was my everything,â I sniffled. âI knew it. You couldnât even bring yourself to hit us, let alone murder your wife. The girls and I always figured you were sensitive.â My heart rate quickened. Today was one of humbling and miseryâone to pray a hail spike would fall from the sky as sharp as a needle, pierce into my eyelid, and lobotomize me. I wished I could have merely died or hit my head hard enough not to have to deal with it all. No, I wished I was Anwen with her snarky, careless glow and lack of depth in her eyes. As we emerged from the compost bin together, I fantasized about strangling her until her face turned purple, her weakening spirit no longer categorizing me as âsensitiveâ, but the thought could only remind me of wielding that trophy and the microscopic traces of my wifeâs tender skin tainting it, which turned my guts inside out. âThatâs why I think you could use a little help,â Anwen said, âIt seems like you canât walk, either. Your leg is all twisted up.â She undid one of her trim pigtails and handed me the band. âTake off your tie and put up your hair. âWill make you less recognizable. Then swallow your pride and stick with me.ââThereâs No Such Thing as Sound Scienceâ by By Christie Aschwanden was a lead science writer for FiveThirtyEight. FiveThirtyEight, Science, Dec. 6, 2017 Science is being turned against itself. For decades, its twin ideals of transparency and rigor have been weaponized by those who disagree with results produced by the scientific method. Under the Trump administration, that fight has ramped up again. In a move ostensibly meant to reduce conflicts of interest, Environmental Protection Agency Administrator Scott Pruitt has removed a number of scientists from advisory panels and replaced some of them with representatives from industries that the agency regulates. Like many in the Trump administration, Pruitt has also cast doubt on the reliability of climate science. For instance, in an interview with CNBC, Pruitt said that âmeasuring with precision human activity on the climate is something very challenging to do.â Similarly, Trumpâs pick to head NASA, an agency that oversees a large portion the nationâs climate research, has insisted that research into human influence on climate lacks certainty, and he falsely claimed that âglobal temperatures stopped rising 10 years ago.â Kathleen Hartnett White, Trumpâs nominee to head the White House Council on Environmental Quality, said in a Senate hearing last month that she thinks we âneed to have more precise explanations of the human role and the natural roleâ in climate change. The same entreaties crop up again and again: We need to root out conflicts. We need more precise evidence. What makes these arguments so powerful is that they sound quite similar to the points raised by proponents of a very different call for change thatâs coming from within science. This other movement strives to produce more robust, reproducible findings. Despite having dissimilar goals, the two forces espouse principles that look surprisingly alike: Science needs to be transparent. Results and methods should be openly shared so that outside researchers can independently reproduce and validate them. The methods used to collect and analyze data should be rigorous and clear, and conclusions must be supported by evidence. These are the arguments underlying an âopen scienceâ reform movement that was created, in part, as a response to a âreproducibility crisisâ that has struck some fields of science.1 But theyâre also used as talking points by politicians who are working to make it more difficult for the EPA and other federal agencies to use science in their regulatory decision-making, under the guise of basing policy on âsound science.â Scienceâs virtues are being wielded against it. What distinguishes the two calls for transparency is intent: Whereas the âopen scienceâ movement aims to make science more reliable, reproducible and robust, proponents of âsound scienceâ have historically worked to amplify uncertainty, create doubt and undermine scientific discoveries that threaten their interests. âOur criticisms are founded in a confidence in science,â said Steven Goodman, co-director of the Meta-Research Innovation Center at Stanford and a proponent of open science. âThatâs a fundamental difference â weâre critiquing science to make it better. Others are critiquing it to devalue the approach itself.â Calls to base public policy on âsound scienceâ seem unassailable if you donât know the termâs history. The phrase was adopted by the tobacco industry in the 1990s to counteract mounting evidence linking secondhand smoke to cancer. A 1992 Environmental Protection Agency report identified secondhand smoke as a human carcinogen, and Philip Morris responded by launching an initiative to promote what it called âsound science.â In an internal memo, Philip Morris vice president of corporate affairs Ellen Merlo wrote that the program was designed to âdiscredit the EPA report,â âprevent states and cities, as well as businesses from passing smoking bansâ and âproactivelyâ pass legislation to help their cause. The sound science tactic exploits a fundamental feature of the scientific process: Science does not produce absolute certainty. Contrary to how itâs sometimes represented to the public, science is not a magic wand that turns everything it touches to truth. Instead, itâs a process of uncertainty reduction, much like a game of 20 Questions. Any given study can rarely answer more than one question at a time, and each study usually raises a bunch of new questions in the process of answering old ones. âScience is a process rather than an answer,â said psychologist Alison Ledgerwood of the University of California, Davis. Every answer is provisional and subject to change in the face of new evidence. Itâs not entirely correct to say that âthis study proves this fact,â Ledgerwood said. âWe should be talking instead about how science increases or decreases our confidence in something.â The tobacco industryâs brilliant tactic was to turn this baked-in uncertainty against the scientific enterprise itself. While insisting that they merely wanted to ensure that public policy was based on sound science, tobacco companies defined the term in a way that ensured that no science could ever be sound enough. The only sound science was certain science, which is an impossible standard to achieve. âDoubt is our product,â wrote one employee of the Brown & Williamson tobacco company in a 1969 internal memo. The note went on to say that doubt âis the best means of competing with the âbody of factââ and âestablishing a controversy.â These strategies for undermining inconvenient science were so effective that theyâve served as a sort of playbook for industry interests ever since, said Stanford University science historian Robert Proctor. The sound science push is no longer just Philip Morris sowing doubt about the links between cigarettes and cancer. Itâs also a 1998 action plan by the American Petroleum Institute, Chevron and Exxon Mobil to âinstall uncertaintyâ about the link between greenhouse gas emissions and climate change. Itâs industry-funded groupsâ late-1990s effort to question the science the EPA was using to set fine-particle-pollution air-quality standards that the industry didnât want. And then there was the more recent effort by Dow Chemical to insist on more scientific certainty before banning a pesticide that the EPAâs scientists had deemed risky to children. Now comes a move by the Trump administrationâs EPA to repeal a 2015 rule on wetlands protection by disregarding particular studies. (To name just a few examples.) Doubt merchants arenât pushing for knowledge, theyâre practicing what Proctor has dubbed âagnogenesisâ â the intentional manufacture of ignorance. This ignorance isnât simply the absence of knowing something; itâs a lack of comprehension deliberately created by agents who donât want you to know, Proctor said.2 In the hands of doubt-makers, transparency becomes a rhetorical move. âItâs really difficult as a scientist or policy maker to make a stand against transparency and openness, because well, who would be against it?â said Karen Levy, researcher on information science at Cornell University. But at the same time, âyou can couch everything in the language of transparency and it becomes a powerful weapon.â For instance, when the EPA was preparing to set new limits on particulate pollution in the 1990s, industry groups pushed back against the research and demanded access to primary data (including records that researchers had promised participants would remain confidential) and a reanalysis of the evidence. Their calls succeeded and a new analysis was performed. The reanalysis essentially confirmed the original conclusions, but the process of conducting it delayed the implementation of regulations and cost researchers time and money. Delay is a time-tested strategy. âGridlock is the greatest friend a global warming skeptic has,â said Marc Morano, a prominent critic of global warming research and the executive director of ClimateDepot.com, in the documentary âMerchants of Doubtâ (based on the book by the same name). Moranoâs site is a project of the Committee for a Constructive Tomorrow, which has received funding from the oil and gas industry. âWeâre the negative force. Weâre just trying to stop stuff.â Some of these ploys are getting a fresh boost from Congress. The Data Quality Act (also known as the Information Quality Act) was reportedly written by an industry lobbyist and quietly passed as part of an appropriations bill in 2000. The rule mandates that federal agencies ensure the âquality, objectivity, utility, and integrity of informationâ that they disseminate, though it does little to define what these terms mean. The law also provides a mechanism for citizens and groups to challenge information that they deem inaccurate, including science that they disagree with. âIt was passed in this very quiet way with no explicit debate about it â that should tell you a lot about the real goals,â Levy said. But whatâs most telling about the Data Quality Act is how itâs been used, Levy said. A 2004 Washington Post analysis found that in the 20 months following its implementation, the act was repeatedly used by industry groups to push back against proposed regulations and bog down the decision-making process. Instead of deploying transparency as a fundamental principle that applies to all science, these interests have used transparency as a weapon to attack very particular findings that they would like to eradicate. Now Congress is considering another way to legislate how science is used. The Honest Act, a bill sponsored by Rep. Lamar Smith of Texas,3 is another example of what Levy calls a âTrojan horseâ law that uses the language of transparency as a cover to achieve other political goals. Smithâs legislation would severely limit the kind of evidence the EPA could use for decision-making. Only studies whose raw data and computer codes were publicly available would be allowed for consideration. That might sound perfectly reasonable, and in many cases it is, Goodman said. But sometimes there are good reasons why researchers canât conform to these rules, like when the data contains confidential or sensitive medical information.4 Critics, which include more than a dozen scientific organizations, argue that, in practice, the rules would prevent many studies from being considered in EPA reviews.5 It might seem like an easy task to sort good science from bad, but in reality itâs not so simple. âThereâs a misplaced idea that we can definitively distinguish the good from the not-good science, but itâs all a matter of degree,â said Brian Nosek, executive director of the Center for Open Science. âThere is no perfect study.â Requiring regulators to wait until they have (nonexistent) perfect evidence is essentially âa way of saying, âWe donât want to use evidence for our decision-making,ââ Nosek said. Most scientific controversies arenât about science at all, and once the sides are drawn, more data is unlikely to bring opponents into agreement. Michael Carolan, who researches the sociology of technology and scientific knowledge at Colorado State University, wrote in a 2008 paper about why objective knowledge is not enough to resolve environmental controversies. âWhile these controversies may appear on the surface to rest on disputed questions of fact, beneath often reside differing positions of value; values that can give shape to differing understandings of what âthe factsâ are.â Whatâs needed in these cases isnât more or better science, but mechanisms to bring those hidden values to the forefront of the discussion so that they can be debated transparently. âAs long as we continue down this unabashedly naive road about what science is, and what it is capable of doing, we will continue to fail to reach any sort of meaningful consensus on these matters,â Carolan writes. The dispute over tobacco was never about the science of cigarettesâ link to cancer. It was about whether companies have the right to sell dangerous products and, if so, what obligations they have to the consumers who purchased them. Similarly, the debate over climate change isnât about whether our planet is heating, but about how much responsibility each country and person bears for stopping it. While researching her book âMerchants of Doubt,â science historian Naomi Oreskes found that some of the same people who were defending the tobacco industry as scientific experts were also receiving industry money to deny the role of human activity in global warming. What these issues had in common, she realized, was that they all involved the need for government action. âNone of this is about the science. All of this is a political debate about the role of government,â she said in the documentary. These controversies are really about values, not scientific facts, and acknowledging that would allow us to have more truthful and productive debates. What would that look like in practice? Instead of cherry-picking evidence to support a particular view (and insisting that the science points to a desired action), the various sides could lay out the values they are using to assess the evidence. For instance, in Europe, many decisions are guided by the precautionary principle â a system that values caution in the face of uncertainty and says that when the risks are unclear, it should be up to industries to show that their products and processes are not harmful, rather than requiring the government to prove that they are harmful before they can be regulated. By contrast, U.S. agencies tend to wait for strong evidence of harm before issuing regulations. Both approaches have critics, but the difference between them comes down to priorities: Is it better to exercise caution at the risk of burdening companies and perhaps the economy, or is it more important to avoid potential economic downsides even if it means that sometimes a harmful product or industrial process goes unregulated? In other words, under what circumstances do we agree to act on a risk? How certain do we need to be that the risk is real, and how many people would need to be at risk, and how costly is it to reduce that risk? Those are moral questions, not scientific ones, and openly discussing and identifying these kinds of judgment calls would lead to a more honest debate. Science matters, and we need to do it as rigorously as possible. But science canât tell us how risky is too risky to allow products like cigarettes or potentially harmful pesticides to be sold â those are value judgements that only humans can make.Brain and Consciousness Review