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By L. Trompok. University of the Ozarks. 2019.

There are surprisingly few studies in this area buy levitra oral jelly 20mg low cost, however order 20mg levitra oral jelly free shipping. For example purchase 20 mg levitra oral jelly with visa, if you stances purchase levitra oral jelly 20 mg amex, only the sleep/wake cycle appeared to be entrained (103–105). We estimate that there are at least 100,000 totally blind people in the United States who have periodic insomnia. We have recently discovered a way to entrain most of these people (101,106). A dose of 10 mg given within an hour of preferred bedtime should in all likelihood eventually entrain most of them. Once the free-running clock of the blind person has been 'captured,' the maintenance dose can be decreased to as low as. Ongoing work in our labora- tory is investigating the possibility of moving the melatonin dose earlier, to 7 to 13 hours after habitual wake time, so as to provide a typical phase angle of entrainment. Therefore, it may be possible to entrain people initially with. Indeed, the only person who failed to entrain to the 10-mg dose had the longest free-running period of our group (24. Proposed times for when bright light exposure should occur and when bright light exposure should be avoided light response, such as the melatonin suppression test, which the first fewdays after transmeridional flight. For example, after we developed in sighted people (23,110–114)and has also a 2-hour west-to-east trip, bright light exposure should begin at been recommended for blind people (107). However, until dawn and should be (optimally) 2 hours in duration. In another example, after a 10-hour west-to-east trip, however, bright light we have ruled out entrainment by ocularly mediated light exposure should be avoided until 4 hours after sunrise and should in what are thought to be totally blind people, we do not occur (optimally) for 6 hours. Scheduled recommend the use of the melatonin suppression test, exposure to daylight: a potential strategy to reduce 'jet lag' fol- lowing transmeridian flight. Psychopharmacol Bull 1984;20: which we recently have come to think may risk desensitizing 566–568, with permission. The intrinsic period of one of these subjects was stud- ied in temporal isolation and was found to be 23. This should be of interest to those interested in else (24). We do not think that bright light has the same phenotyping sighted people for clock gene studies. Whether or not correcting the phase distur- The melatonin fad of a few years ago has stimulated a num- bance improves the remaining symptoms is not known at ber of scientists to make skeptical comments. There is no clinical evidence that melatonin is useful for anything other than phase shifting Melatonin in Young and Elderly People and sleep; however, some investigators have expressed skep- ticism even for these well-documented uses. However, we Although we might want to use lower doses of melatonin view this as a strength of the methodology: because the in young and elderly people, melatonin appears to be rea- subjects lived mainly at home, the findings can be more sonably safe in these populations as long as a physician is directly applied to real-life situations. Moreover, it is difficult to millions of people have been doing so for the past several imagine a systematic confound in the study owing to mela- years. However, we do not expect this to be a very up at night to take a placebo capsule causes phase shifts, if common effect of melatonin, given the fact that melatonin any, opposite to those of melatonin (Lewy, in preparation). Claustrat used a 3-hour and the fact that there is only a very slight seasonal rhythm intravenous infusion of melatonin, whereas our. This might explain why the intrave- Syndromes nous dose given in the evening produced more of a phase Appropriately timed bright light exposure and melatonin advance than the one given in the afternoon, in that the administration can be used to treat other circadian phase afternoon dose did not overlap with the endogenous melato- disorders. These include advanced sleep phase syndrome nin profile. Light ing effects increase as it is given earlier in the afternoon: treatment of these disorders has already been summarized even at this time, the. This issue is now moot, given the definitive findings of two independent groups (102,106). We agree with Czeisler that light is the most powerful phase-resetting agent. However, Czeisler thinks that light is an order of magnitude more powerful than light, whereas as indicated in the preceding (Table 129. In any event, melatonin is much more convenient than using light as a phase-resetting agent. Schematic diagram of some of the relationships zeitgeber. The jury is out as to the strength of the activity/ between nighttime melatonin production by the pineal gland, the light/dark cycle and the endogenous circadian pacemaker rest zeitgeber in humans. This second pathway duction appears to be critically involved in the regulation for entrainment by light is particularly significant during shifts of seasonal rhythms. However, this does not appear to be of the light/dark cycle. This function for melatonin is critically conveying the time of the year (primarily for seasonal breed- dependent on suppression of melatonin by bright light. The acute suppressant effect of light (23) regulates all overt circadian rhythms, including the nightly is important in truncating the endogenous melatonin pro- increase in pineal melatonin production. As mentioned in file, and humans have retained the suppressant effect of light the beginning of this chapter, melatonin feeds back onto but are not really seasonal breeders. Sufficiently bright light at ing, and that this difference might distinguish humans from the twilight transitions suppresses melatonin production, nonhuman primates. In other words, perhaps primates use causing the endogenous melatonin onset to occur later and melatonin either for telling the time of the year or the time the endogenous melatonin offset to occur earlier. In this way, the phase-shifting effect of Interestingly, activity is an effective zeitgeber in at least one light is augmented by an indirect effect of light acting on species of primates, which has a seasonal breeding cycle suppressing melatonin production. Simultaneously, the melatonin offset will occur 2 melatonin as one. The same thinking can be applied to geber, depending on whether or not melatonin is used for changes in bright exposure in the evening. Clearly, light is the major zeitgeber for entraining circa- Once again, there is no question that light is the primary dian rhythms. Does light have a specific antidepressant effect other than Optimal dosing of melatonin will depend on minimizing phase shifting? This may entail using a low-dose sustained-release other affective disorders? We have also speculated that placing a person rently not licensed to any company. Loss of circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. A retinohypothalamic projection in the sleep at destination (most subjects expected to be an active rat. The development, topographical relations and ¨ In some people, melatonin may be used as a mild sleep- innervation of the epiphysis cerebri in the albino rat. The prospects for using melatonin and forsch Mikrosk Anat 1960;52:163–215. Melatonin in rat pineal gland and serum; rapid parallel decline after light exposure at night. Neurosci Lett 1978: Most circadian phase disorders are relatively straightfor- 189–193. Indole metabolism in the pineal gland: the disorder most often treated with portable bright light a circadian rhythm in N-acetyltransferase. The -adrenergic receptor and the regulation phase advanced (these people often report a history of get- of circadian rhythms in the pineal gland. Chapter 129: Circadian Sleep and Mood Disorders 1891 11. Clonidine reduces plasma chronobiologic sleep and mood disorders. Understanding circadian clocks: from c-Fos to 1987:181–206. Treating chronobiologic sleep and mood disorders 13.

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Regional gray matter reductions are associated with genetic liability for anxiety and depression: an MRI twin study purchase levitra oral jelly 20 mg line. A meta-analysis of the efficacy of acceptance and commitment therapy for clinically relevant mental and physical health problems discount 20mg levitra oral jelly. Bienvenu O levitra oral jelly 20 mg generic, Onyike C purchase levitra oral jelly 20mg without prescription, Stein M, Chen L, Samuels J, Nestadt G, Eaton W. Agoraphobia in adults: incidents and longitudinal relationship with panic. In Psychiatric disorders in America: the Epidemiologic Catchment Area Study (ed. Current and lifetime comorbidity of the DSM-IV anxiety and mood disorders in a large clinical sample. Canadian Journal of Psychiatry 2006; 51 (Suppl 2): 1S-90S. The development of anxiety: the role of control in the early environment. Epigenetic signature of panic disorder: a role of glutamate decarboxylase 1 (GAD1) DNA hypomethylation? Prog Newuropsychopharmacol Biol Psychiatry 2013; 46: 189-196. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory newtwork in generalized anxiety disorder. Functional neuroimaging in anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder and specific phobia. Cortical thickness alterations in social anxiety disorder. British Journal of Psychological Medicine 1959; 32:50-55. A meta-analytic study of self-help interventions for anxiety problems. MicroRNA has-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety related traits. American Journal Medical Genetics B Neuropsychiatry Genetics 2015; 168B: 296-306. Panic syndromes in a population-based sample of male and female twins. Major depression and generalized anxiety disorder: same genes (partly) different environments? The genetic epidemiology of phobias in women: the interrelationship of agoraphobia, social phobia, situational phobia, and simple phobia. The relationship between the genetic and environmental influences on common internalizing psychiatric disorders and mental well-being. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Study. The association of BDNF Val66Met with trait anxiety in panic disorder. J Neuropsychiatry Clin Neuroscience 2014; 26: 344-351. Altered gray matter morphometry and resting-state functional and structural connectivity in social anxiety disorder. Brain Research 2011 March 12 [Epub ahead of print] Liebowitz M, Ninan P, Schneier F, Blanco C. Integrating neurobiology and psychopathology into evidence-based treatment of social phobia. Paternal care in a fish: epigenetics and fitness enhancing effects on offspring anxiety. Proceedings of the Royal Society B 2014; 281:20141146. A twin study of lifetime generalized anxiety disorder (GAD) in older adults: genetic and environmental influences shared by neuroticism and GAD. Delineating the boundary of social phobia: its relationship to panic disorder and agoraphobia. Journal of the American Medical Association 1997; 227:742-746. Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatric Disease and Treatment 2015: 11; 165-175. Applied tension, exposure in vivo, and tension only in the treatment of blood phobia. Palomero-Gallagher N, Eickhoff S, Hoffstaedter F, et al. Functional organization of human subgenual cortical areas: relationship between architectonical segregation and connectional heterogeneity. CRHR1 genotype, neural circuits and the diathesis for anxiety and depression. Prevalence of personality disorder in patients with anxiety disorders. Generalized anxiety disorder: psychopharmacotherapy update on a common and commonly overlooked condition. A neuro-evolutionary approach to the anxiety disorders. Setting diagnostic thresholds for social phobia: considerations from a community survey of social anxiety. Anxiety states: a review of conceptual and treatment issues. Tromp do P, Grupe D, Oathes D et al, Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder. The relation of strength of stimulus to rapidity to habit- formation. Journal of Comparative Neurology and Psychology 1908; 18:459-482. Phenomenology and course of generalized anxiety disorder. Zvolensky M, Bernstein A, Sachs-Ericsson N, Schmidt N, Buckner J, Bonn-Miller M. Lifetime associations between cannabis, use, abuse, and dependence and panic attacks in a representative sample. SENESCENCE AND DEMENTIA “An old man is twice a child” Shakespeare (Hamlet) SENESCENCE/AGING Senescence (Latin, senex: “old man” or “old age”) is the combination of processes which follow the period of development of an organism. Aging is generally characterized by declining ability to respond to stress and increased risk of disease. Accordingly, death may be seen as the inevitable consequence of aging. A controversial view is that aging is itself a “disease” which may be curable. A related and interesting definition: Aging represents a state of complex multifactorial pathways that involve and ongoing molecular, cellular, and organ damage causing functional loss, disease vulnerability and eventual death (Fontana et al, 2010). Memory loss is a less prominent feature of normal ageing than has sometimes been supposed. Healthy older people do not perform quite as well on objective memory tests as healthy younger people. However, normal aging does not cause functional decline, and ability to perform the normal activities of daily living is maintained.

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Agent Mechanism of action Saline and loop diuretics Increase renal excretion of calcium Corticosteroids Block 1 purchase 20 mg levitra oral jelly amex,25-dihydroxy-vitamin D3 synthesis and bone resorption Ketoconazole Blocks P450 system buy generic levitra oral jelly 20mg line, decreases 1 discount levitra oral jelly 20mg visa, 25-dihydroxy-vitamin D3 Oral or intravenous phosphate Complexes calcium Calcitonin Inhibits bone resorption Mithramycin Inhibits bone resorption Bisphosphonates Inhibit bone resorption *Always identify and treat the primary cause of hypercalcemia 20 mg levitra oral jelly amex. Secondary Hyperparathyroidism FIGURE 5-22 Renal failure Pathogenesis of secondary hyperparathyroidism (H PT) in chronic renal failure (CRF). Decreased num bers of proxim al tubular (PT) cells, owing to loss of renal m ass, cause a quantitative decrease in ↓Number of nephrons synthesis of 1,25-dihydroxy-vitam in D (1,25(O H ) D ). Loss of 3 2 3 renal m ass also im pairs renal phosphate (P) and acid (H +) excretion. H ypocalcem ia and hyperphosphatem ia stim ulate PTH release and ↓H+ excretion synthesis and can recruit inactive parathyroid cells into activity and ↓P excretion PTH production. H ypocalcem ia also m ay decrease intracellular degradation of PTH. The lack of 1,25(O H )2D3, which would ordi- 1,25(OH)2D3↓ Hyperphosphatemia narily feed back to inhibit the transcription of prepro-PTH and exert an antiproliferative effect on parathyroid cells, allows the ↓Ca absorption Gastrointestinal increased PTH production to continue. In CRF there m ay be tract decreased expression of the Ca-sensing receptor (CaSR) in parathy- roid cells, m aking them less sensitive to levels of plasm a Ca. Patients with the b allele or the bb genotype vitam in D receptor (VDR) m ay be m ore susceptible to H PT, because the VDR- 1,25(O H )2D3 com plex is less effective at suppressing PTH produc- tion and cell proliferation. The deficiency of 1,25(O H )2D3 m ay also decrease VDR synthesis, m aking parathyroid cells less sensitive to Hypocalcemia ↓Activity 1,25(O H )2D3. Although the PTH receptor in bone cells is downreg- ↓Activity ulated in CRF (ie, for any level of PTH , bone cell activity is lower in CRF patients than in norm al persons), the increased plasm a levels of PTH m ay have harm ful effects on other system s (eg, cardiovascu- VDR CaSR lar system , nervous system , and integum ent) by way of alterations of intracellular Ca. Current therapeutic m ethods used to decrease Increased PTH release in CRF include correction of hyperphosphatem ia, transcription ↓Degradation m aintenance of norm al to high-norm al levels of plasm a Ca, adm in- of PTH istration of 1,25(O H )2D3 orally or intravenously, and adm inistra- Release tion of a Ca-ion sensing receptor (CaSR) agonist [14–16,19–22]. CALCIUM PREPARATIONS Calcium (Ca) salt Tablet size, mg Elemental Ca, mg, % Carbonate 1250 500 (40) Acetate 667 169 (25) Citrate 950 200 (21) Lactate 325 42 (13) Gluconate 500 4. VITAM IN D PREPARATIONS AVAILABLE IN THE UNITED STATES Ergocalciferol Calcifediol Calcitriol (Vitamin D2) (25-hydroxy-vitamin D3) Dihydrotachysterol (1,25-dihydroxy-vitamin D3) Commercial name Calciferol Calderol® (Organon, Inc, DHT Intensol® (Roxane Rocaltrol® (Roche Laboratories, W est Orange, NJ) Laboratories, Columbus, OH) Nutley, NJ) Calcijex® (Abbott Laboratories, Abbott Park, NJ) Oral preparations 50,000 IU tablets 20- and 50-µg capsules 0. Philbrick W M , W ysolm erski JJ, Galbraith S, et al. Louis: of parathyroid horm one-related protein in norm al physiology. Johnson JA, Kum ar R: Renal and intestinal calcium transport: roles of 14. Goodm an W G, Belin TR, Salusky IB: In vivo> assessm ents of vitam in D and vitam in D-dependent calcium binding proteins. Sem in calcium -regulated parathyroid horm one release in secondary N ephrol 1994, 14:119–128. H ebert SC, Brown EM , H arris H W : Role of the Ca2+-sensing receptor 50:1834–1844. Chattopadhyay N , M ithal A, Brown EM : The calcium -sensing 4. Hebert SC, Brown EM : The scent of an ion: calcium-sensing and its roles receptor: a window into the physiology and pathophysiology of in health and disease. Berridge M J: Elem entary and global aspects of calcium signalling. N em eth EF, Steffey M E, Fox J: The parathyroid calcium receptor: a novel therapeutic target for treating hyperparathyroidism. Friedm an PA, Gesek FA: Cellular calcium transport in renal epithelia: N ephrol 1996, 10:275–279. W asserman RH, Fullmer CS: Vitamin D and intestinal calcium transport: 7. Root AW : Recent advances in the genetics of disorders of calcium facts, speculations and hypotheses. Johnson JA, Kum ar R: Vitam in D and renal calcium transport. H olick M F: Defects in the synthesis and m etabolism of vitam in D. Kum ar R: Calcium transport in epithelial cells of the intestine and Practice of N ephrology. W hite CP, M orrison N A, Gardiner EM , Eism an JA: Vitam in D recep- 20. Felsenfeld AJ: Considerations for the treatm ent of secondary hyper- tor alleles and bone physiology. The hyperparathyroidism of chronic renal failure: a receptor gene polym orphism and relative hypoparathyroidism in disorder of growth. Salusky IB, Goodm an W G: Parathyroid gland function in secondary hyperparathyroidism. M ontvale N J: M edical Econom ics Sem Surg O ncol 1997, 13:125–133. Madias aintenance of acid-base homeostasis is a vital function of the living organism. Deviations of systemic acidity in either M direction can impose adverse consequences and when severe can threaten life itself. Acid-base disorders frequently are encountered in the outpatient and especially in the inpatient setting. Effective man- agement of acid-base disturbances, commonly a challenging task, rests with accurate diagnosis, sound understanding of the underlying pathophysiology and impact on organ function, and familiarity with treatment and attendant complications. Clinical acid-base disorders are conventionally defined from the vantage point of their impact on the carbonic acid-bicarbonate buffer system. This approach is justified by the abundance of this buffer pair in body fluids; its physiologic preeminence; and the validity of the iso- hydric principle in the living organism, which specifies that all the other buffer systems are in equilibrium with the carbonic acid-bicar- bonate buffer pair. Thus, as indicated by the H enderson equation, + - [H ] = 24 PaCO2/[H CO3] (the equilibrium relationship of the car- bonic acid-bicarbonate system), the hydrogen ion concentration of blood ([H +], expressed in nEq/L) at any moment is a function of the prevailing ratio of the arterial carbon dioxide tension (PaCO2, expressed in mm H g) and the plasma bicarbonate concentration - ([H CO3], expressed in mEq/L). As a corollary, changes in systemic acidity can occur only through changes in the values of its two deter- minants, PaCO2 and the plasma bicarbonate concentration. Those acid-base disorders initiated by a change in PaCO2 are referred to as C H A P T ER respiratory disorders; those initiated by a change in plasma bicarbon- ate concentration are known as metabolic disorders. There are four cardinal acid-base disturbances: respiratory acidosis, respiratory alka- losis, metabolic acidosis, and metabolic alkalosis. Each can be encountered alone, as a simple disorder, or can be a part of a mixed- disorder, defined as the simultaneous presence of two or more simple 6 6. M ixed acid-base disorders are frequent- illustrated: the underlying pathophysiology, secondary ly observed in hospitalized patients, especially in the critically ill. For each disorder the following are peutic principles. Respiratory Acidosis FIGURE 6-1 Arterial blood [H+], nEq/L Q uantitative aspects of adaptation to respiratory acidosis. H ypercapnia elic- 40 its adaptive increm ents in plasm a bicarbonate concentration that 50 should be viewed as an integral part of respiratory acidosis. An im m ediate increm ent in plasm a bicarbonate occurs in response to hypercapnia. This acute adaptation is com plete within 5 to 10 m in- 40 30 utes from the onset of hypercapnia and originates exclusively from acidic titration of the nonbicarbonate buffers of the body (hem o- globin, intracellular proteins and phosphates, and to a lesser extent 30 plasm a proteins). W hen hypercapnia is sustained, renal adjust- 20 Normal m ents m arkedly am plify the secondary increase in plasm a bicar- bonate, further am eliorating the resulting acidem ia. This chronic 20 adaptation requires 3 to 5 days for com pletion and reflects genera- 10 tion of new bicarbonate by the kidneys as a result of upregulation of renal acidification. Average increases in plasm a bicarbonate 10 and hydrogen ion concentrations per m m H g increase in PaCO 2 after com pletion of the acute or chronic adaptation to respiratory acidosis are shown. The black ellipse near the center of the figure indicates the norm al range for the Steady-state relationships in respiratory acidosis: acid-base param eters. N ote that for the sam e level of PaCO , average increase per mm Hg rise in PaCO 2 2 the degree of acidem ia is considerably lower in chronic respiratory [HCO–] mEq/L [H+] nEq/L acidosis than it is in acute respiratory acidosis. Acid-base values falling outside the areas in color denote the pres- ence of a m ixed acid-base disturbance.

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At the child level cheap 20mg levitra oral jelly otc, the characteristics included gender cheap 20mg levitra oral jelly visa, age at baseline data collection best levitra oral jelly 20 mg, ethnicity cheap levitra oral jelly 20 mg without prescription, individual IMD value, all anthropometric measurements, physical activity and FIQ. The formal statistical comparison at baseline of randomised groups is not good practice46 and, thus, was not undertaken: only summary statistics are presented in Chapter 3. We prespecified that should there be any substantial imbalance between randomised groups at baseline, in terms of any relevant variables not already being adjusted for in the primary analysis, further adjusted sensitivity analyses may be performed, to allow for such variable(s), in addition to the prespecified variables for adjustment, to assess the robustness of the primary analysis. Adjusted analyses included the two school-level stratification variables as covariates, as well as baseline BMI SDS, gender and cohort. The means and SDs are presented for each group, together with the mean difference (intervention minus control) between groups, the 95% CI for the mean difference and the corresponding p-value. The ICC (with 95% CI) from the random-effects regression model for BMI SDS is also reported. Secondary analyses of the primary outcome A small number of sensitivity analyses of the primary outcome were prespecified in the analysis plan to assess how robust the results of the primary analyses were to any biases from missing data or to children in the intervention group who were categorised as non-compliers. These sensitivity analyses were revised following the TSC meeting in July 2016. The proposed amendments were approved by the TSC (chairperson) prior to undertaking the sensitivity analyses outlined below. Amendment 1 Given the low number of missing BMI scores and the low number of data deemed missing at random, a sensitivity analysis was undertaken to look at the effect of missing data using a best-case/worst-case scenario analysis. The first set of these analyses was based on hypothetically driven assumptions. Given the hypothetical preventative nature of the HeLP intervention, the best-case scenario: l assumed no change between baseline and 24 months in BMI SDS for children allocated to the intervention group (i. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 19 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. TRIAL DESIGN AND METHODS The worst-case scenario: l assumed that children allocated to the intervention group who were not obese at baseline were obese at the 24 month follow-up: the 24 month BMI SDS value will be set at the Public Health England threshold for obesity (i. For children allocated to the intervention group who were obese at baseline, the baseline BMI SDS value will be carried forward to replace the missing BMI SDS value l imputed missing 24-month BMI SDS values for children allocated to the control group with their corresponding baseline BMI SDS value plus the (marginal) mean change between baseline and 24 months for the children allocated to the control group with complete baseline and 24-month BMI SDS data. After imputing the missing 24-month BMI SDS scores for both scenarios, the primary analyses model was fitted to the full intention-to-treat data set to allow us to ascertain if the missing primary outcome data significantly influenced the results of the primary effectiveness analysis. In addition to the primary analyses, exploratory analyses of the following possible interactions were undertaken to assess whether any effect of the HeLP intervention was modified by (1) gender, (2) baseline BMI SDS, (3) number of Year 5 classes within school and (4) child-level socioeconomic status. These subgroup analyses were performed by adding the interaction term between allocated group and the subgroup variable into the random-effects regression model. A test of the interaction was also performed to assess whether or not there was evidence that the effect of the intervention differed across the two cohorts. As the study was not powered for these exploratory interaction analyses, the results have been interpreted with caution, based on the corresponding CIs for the subgroups. Finally, a repeated measures model was fitted to all the observed BMI SDS data at baseline, 18 months and 24 months, including effects of time and the interaction term between allocated group and time, to assess whether or not there was evidence that any effect of the intervention differed across time (see Appendix 6). In this model, adjustment was made for gender, a child-level fixed effect, and the school-level factors comprising the two stratification variables. Stepwise comparisons were made between covariance patterns of increasing parsimony up to an exchangeable pattern. The stopping rule for further pattern simplification was a change in the log-likelihood determined to be significant at the 5% level to the next more parsimonious covariance pattern. Analysis of secondary outcomes Secondary outcomes were compared between groups based on the observed data only. Most of the secondary outcomes were of a continuous nature and so comparative analyses followed the approach detailed above for the primary outcome, using random-effects linear regression modelling, allowing for the clustered nature of the data and including the stratification factors, baseline value of the variable under consideration and gender and cohort. Binary outcomes (such as the proportion of children classified as obese at 24 months) were analysed using binary logistic regression, allowing for the clustered nature of the data and including the stratification factors, baseline BMI SDS and cohort. For all models, corresponding distributional assumptions were investigated, as outlined below. Checking distributional and modelling assumptions Initial frequency and normal probability plots helped to inform the selection of models fitted to each outcome and whether transformation or model-based transformation under a generalised linear model might be necessary. When outcomes were discrete, sparse categories were amalgamated to create new levels with a sufficient number of participants in each for subsequent modelling as ordinal outcomes. The tenability of assumptions for modelling outcomes as normally distributed variables was inspected through frequency and normal probability plots of the residuals from the fitted models, as well as box 20 NIHR Journals Library www. Model fit was judged through inspection of these plots along with plots of the observations against the fitted values. The distribution of the random school effect was checked by way of a normal probability plot of the best linear unbiased predictors from each model. Either the applied model was revised or a different model was sought if there were any marked deviations from the assumptions. Model stability and influence of the most extreme values were diagnosed through plotting the dfbetas calculated for each modelled factor and covariate, with careful attention paid to those for the allocated group. Any observations identified with sufficient influence to change the significance of the intervention effect would prompt further investigation, with results presented both with and without any such data points. When the outcomes were deemed ordinal and fitted with an ordinal mixed-effects model, the assumption of proportional odds was tested through application of the generalised ordinal model (clustered on schools) to the data, using the gologit2 package in Stata (version 14, StataCorp LP, College Station, TX, USA). Any significant changes in the coefficients across the levels of the outcome would be identified from significance testing of the Peterson–Harrell parameters. Substantially more children were recruited than the target, given the higher than expected number of recruited schools with more than one Year 5 class: 1371 children were eligible for recruitment, compared with a pre-estimated target of around 950. Various trial processes were put in place to minimise missing data. For example, missing data items, such as age and sex, were queried at the time of data entry and up to three visits were made to the school to take measurements for children who were absent on the first measurement day. For the FIQ, when participants were missing a subset of the items, the total score was extrapolated based on the average scores across the four categories (energy-dense snacks, healthy snack foods, negative food markers and positive food markers). To be included in the physical activity analysis, children needed to comply with the required minimum wear time of ≥ 10 hours per day for at least 3 weekdays and 1 weekend day. Non-wear was determined as outlined previously in Study design, Outcome measures, Accelerometer measurements. Any time window with > 50% non-wear was treated as missing. Missing some but not all of the anthropometric measures could occur if a child did not give their assent/ consent for a particular measure (e. Therefore, the numbers of children with valid data for each of the baseline measurements varied. We explored whether or not the missing data for a particular measure were similar in the two allocated groups. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 21 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. TRIAL DESIGN AND METHODS Analysis populations and missing data Full intention-to-treat analysis (i. It was expected from the outset that a small proportion of children would be lost to follow-up by 24 months. As has been previously noted,49 all statistical methods for handling missing data, including complete-case analysis (i. During the development of the analysis plan, the Trial Management Group considered that the missing at random assumption, necessary for many of the common statistical methods for handling missing data, would be plausible: randomisation was at the school level, opt-out consent was used before baseline measures were collected and it was felt highly unlikely that the delivery of the intervention, or lack of the intervention programme in the control schools, would affect the likelihood of children being absent on days when study data were being collected. Within Devon, it is also known that movement between schools is relatively low. There was, therefore, no strong a priori reason to assume that children who were lost to follow-up would be missing not at random. For the primary analysis, no imputation of missing anthropometric data was undertaken and the primary outcome analysis was based on the complete-case/observed outcomes data set49 (i.

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