Sex matters: the frequently overlooked importance of considering sex in computational models.

Personalised medicine and the development of a virtual human or a digital twin comprises visions of the future of medicine. To realise these innovations, an understanding of the biology and physiology of all people are required if we wish to apply these technologies at a population level. Sex differences in health and biology is one aspect that has frequently been overlooked, with young white males being seen as the "average" human being. This has not been helped by the lack of inclusion of female cells and animals in biomedical research and preclinical studies or the historic exclusion, and still low in proportion, of women in clinical trials. However, there are many known differences in health between the sexes across all scales of biology which can manifest in differences in susceptibility to diseases, symptoms in a given disease, and outcomes to a given treatment. Neglecting these important differences in the development of any health technologies could lead to adverse outcomes for both males and females. Here we highlight just some of the sex differences in the cardio-respiratory systems with the goal of raising awareness that these differences exist. We discuss modelling studies that have considered sex differences and touch on how and when to create sex-specific models. Scientific studies should ensure sex differences are included right from the study planning phase and results reported using sex as a biological variable. Computational models must have sex-specific versions to ensure a movement towards personalised medicine is realised.

Changes in swine ammonia emissions associated with improved production management.

Swine manure management and storage have been implicated as major sources of increasing agricultural ammonia (NH3 ) emissions resulting in increased ammonium deposition in North Carolina. This study was conducted to establish how improvements in manure and animal management have affected lagoon nutrient loading and subsequent NH3 emissions determined from measured lagoon chemistry and climate data. Archived lagoon chemistry analyses from 182 farm lagoons (106,000 sample analyses) were used to evaluate trends in lagoon chemical properties. Process and empirical (statistical) NH3 volatilization models were used with the data to calculate changes in NH3 emissions from 2001 through 2018. Lagoon nutrient trends for finisher and sow farms showed that annual averages of nutrients had decreases ranging from 18 to 93%, except for a 41% increase in copper for finisher primary lagoons. Because of reduced nitrogen and pH in the lagoons, a process model of NH3 emissions suggested decreases from primary lagoons of 49 and 25% from finisher and sow farm lagoons, respectively. Empirical (statistical) models predicted even larger relative NH3 decreases (up to 54%).

The effect of biogas ebullition on ammonia emissions from animal manure-processing lagoons.

Various models have been developed to determine ammonia (NH3 ) emissions from animal manure-processing lagoons to enable relatively simple estimations of emissions. These models allow estimation of actual emissions without intensive field measurements or "one-size-fits-all" emission factors. Two mechanisms for lagoon NH3 emissions exist: (a) diffusive gas exchange from the water surface and (b) mass-flow (bubble transport) from NH3 contained within the ebullition gas bubble (as it rises to the surface) produced from anaerobic decomposition of organic matter. The purpose of this research is to determine whether gas ebullition appreciably affects NH3 emissions and therefore should be considered in emissions models. Specifically, NH3 mass-flow emissions were calculated and compared with calculated diffusive NH3 emissions. Mass-flow NH3 emissions were evaluated based on a two-film model, in connection with the acid dissociation constant of ammonium, to predict the degree of NH3 gas saturation within the bubbles. Average daily ammoniacal nitrogen concentration, pH, and measured biological gas production (ebullition) in conjunction with literature values for Henry's law constant were used to calculate emissions from NH3 saturation of ebullition gases. Ebullition enhancement of NH3 surface emissions due to increased turbulence was estimated from average lagoon ebullition rates and literature values of turbulence enhancement. Ebullition enhancement of NH3 surface emissions and ebullition mass-flow NH3 emissions was determined to be <10% and <0.052%, respectively, of total NH3 emissions. Therefore, because ebullition effects are small, they may be neglected when developing process models to estimate NH3 emissions from water surfaces of swine manure processing lagoons.

Ammonia emissions and dispersion from broiler production.

Ammonia (NH3 ) has been used as a target gas for nuisance complaints to restrict or close poultry operations near encroaching rural development. There are conflicting data on NH3 emissions from broiler production across the United States. The purpose of this research is to compare emission rates from a Georgia broiler operation across seasons and with other geographical areas in the United States. Comparison of seasonal and geographical emission rates showed large seasonal variation in NH3 emissions for eastern U.S. sites but little seasonal variation in the semi-arid region of the United States. Differences in production management practices, ambient temperature, and animal density did not appear to explain differences in emissions between regions; however, the climatic influence of ambient humidity and litter management practices are thought to be key factors in the generation of emissions.

An Amygdala-Hippocampus Subnetwork that Encodes Variation in Human Mood.

Human brain networks that encode variation in mood on naturalistic timescales remain largely unexplored. Here we combine multi-site, semi-chronic, intracranial electroencephalography recordings from the human limbic system with machine learning methods to discover a brain subnetwork that correlates with variation in individual subjects' self-reported mood over days. First we defined the subnetworks that influence intrinsic brain dynamics by identifying regions that showed coordinated changes in spectral coherence. The most common subnetwork, found in 13 of 21 subjects, was characterized by ß-frequency coherence (13-30 Hz) between the amygdala and hippocampus. Increased variability of this subnetwork correlated with worsening mood across these 13 subjects. Moreover, these subjects had significantly higher trait anxiety than the 8 of 21 for whom this amygdala-hippocampus subnetwork was absent. These results demonstrate an approach for extracting network-behavior relationships from complex datasets, and they reveal a conserved subnetwork associated with a psychological trait that significantly influences intrinsic brain dynamics and encodes fluctuations in mood.

Propofol for Treatment-Resistant Depression: A Pilot Study.

Background: We hypothesized that propofol, a unique general anesthetic that engages N-methyl-D-aspartate and gamma-aminobutyric acid receptors, has antidepressant properties. This open-label trial was designed to collect preliminary data regarding the feasibility, tolerability, and efficacy of deep propofol anesthesia for treatment-resistant depression. Methods: Ten participants with moderate-to-severe medication-resistant depression (age 18-45 years and otherwise healthy) each received a series of 10 propofol infusions. Propofol was dosed to strongly suppress electroencephalographic activity for 15 minutes. The primary depression outcome was the 24-item Hamilton Depression Rating Scale. Self-rated depression scores were compared with a group of 20 patients who received electroconvulsive therapy. Results: Propofol treatments were well tolerated by all subjects. No serious adverse events occurred. Montreal Cognitive Assessment scores remained stable. Hamilton scores decreased by a mean of 20 points (range 0-45 points), corresponding to a mean 58% improvement from baseline (range 0-100%). Six of the 10 subjects met the criteria for response (>50% improvement). Self-rated depression improved similarly in the propofol group and electroconvulsive therapy group. Five of the 6 propofol responders remained well for at least 3 months. In posthoc analyses, electroencephalographic measures predicted clinical response to propofol. Conclusions: These findings demonstrate that high-dose propofol treatment is feasible and well tolerated by individuals with treatment-resistant depression who are otherwise healthy. Propofol may trigger rapid, durable antidepressant effects similar to electroconvulsive therapy but with fewer side effects. Controlled studies are warranted to further evaluate propofol's antidepressant efficacy and mechanisms of action. ClinicalTrials.gov: NCT02935647.

Stressing out the Social Network.

In this issue of Neuron, Hultman et al. (2016) find that stress-induced abnormal social behavior reflects aberrant prefrontal regulation of downstream limbic networks. This illustrates how linking aberrant network dynamics to neuropsychiatric disorders may lead to new circuit-based therapeutic interventions.

Retinal Waves Modulate an Intraretinal Circuit of Intrinsically Photosensitive Retinal Ganglion Cells.

UNLABELLED: Before the maturation of rod and cone photoreceptors, the developing retina relies on light detection by intrinsically photosensitive retinal ganglion cells (ipRGCs) to drive early light-dependent behaviors. ipRGCs are output neurons of the retina; however, they also form functional microcircuits within the retina itself. Whether ipRGC microcircuits exist during development and whether they influence early light detection remain unknown. Here, we investigate the neural circuit that underlies the ipRGC-driven light response in developing mice. We use a combination of calcium imaging, tracer coupling, and electrophysiology experiments to show that ipRGCs form extensive gap junction networks that strongly contribute to the overall light response of the developing retina. Interestingly, we found that gap junction coupling was modulated by spontaneous retinal waves, such that acute blockade of waves dramatically increased the extent of coupling and hence increased the number of light-responsive neurons. Moreover, using an optical sensor, we found that this wave-dependent modulation of coupling is driven by dopamine that is phasically released by retinal waves. Our results demonstrate that ipRGCs form gap junction microcircuits during development that are modulated by retinal waves; these circuits determine the extent of the light response and thus potentially impact the processing of early visual information and light-dependent developmental functions. SIGNIFICANCE STATEMENT: Light-dependent functions in early development are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). Here we show that ipRGCs form an extensive gap junction network with other retinal neurons, including other ipRGCs, which shapes the retina's overall light response. Blocking cholinergic retinal waves, which are the primary source of neural activity before maturation of photoreceptors, increased the extent of ipRGC gap junction networks, thus increasing the number of light-responsive cells. We determined that this modulation of ipRGC gap junction networks occurs via dopamine released by waves. These results demonstrate that retinal waves mediate dopaminergic modulation of gap junction networks to regulate pre-vision light responses.

Synapse elimination and learning rules co-regulated by MHC class I H2-Db.

The formation of precise connections between retina and lateral geniculate nucleus (LGN) involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the major histocompatibility complex (MHC) class I molecule H2-D(b) is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-K(b) and H2-D(b) (K(b)D(b)(-/-)), despite intact retinal activity and basal synaptic transmission, the developmentally regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-D(b) in K(b)D(b)(-/-) mice rescues both synapse elimination and eye-specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, long-term potentiation (LTP) is intact but long-term depression (LTD) is impaired in K(b)D(b)(-/-) mice. This change is due to an increase in Ca(2+)-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-D(b) to K(b)D(b)(-/-) neurons renders AMPA receptors Ca(2+) impermeable and rescues LTD. These observations reveal an MHC-class-I-mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-D(b) in functional and structural synapse pruning in CNS neurons.

A role for correlated spontaneous activity in the assembly of neural circuits.

Before the onset of sensory transduction, developing neural circuits spontaneously generate correlated activity in distinct spatial and temporal patterns. During this period of patterned activity, sensory maps develop and initial coarse connections are refined, which are critical steps in the establishment of adult neural circuits. Over the last decade, there has been substantial evidence that altering the pattern of spontaneous activity disrupts refinement, but the mechanistic understanding of this process remains incomplete. In this review, we discuss recent experimental and theoretical progress toward the process of activity-dependent refinement, focusing on circuits in the visual, auditory, and motor systems. Although many outstanding questions remain, the combination of several novel approaches has brought us closer to a comprehensive understanding of how complex neural circuits are established by patterned spontaneous activity during development.

Intrinsically photosensitive ganglion cells contribute to plasticity in retinal wave circuits.

Correlated spontaneous activity in the developing nervous system is robust to perturbations in the circuits that generate it, suggesting that mechanisms exist to ensure its maintenance. We examine this phenomenon in the developing retina, where blockade of cholinergic circuits that mediate retinal waves during the first postnatal week leads to the generation of "recovered" waves through a distinct, gap junction-mediated circuit. Unlike cholinergic waves, these recovered waves were modulated by dopaminergic and glutamatergic signaling, and required the presence of the gap junction protein connexin 36. Moreover, in contrast to cholinergic waves, recovered waves were stimulated by ambient light via activation of melanopsin-expressing intrinsically photosensitive retinal ganglion cells. The involvement of intrinsically photosensitive retinal ganglion cells in this reconfiguration of wave-generating circuits offers an avenue of retinal circuit plasticity during development that was previously unknown.

Frequency and outcomes of painful physical symptoms in a naturalistic population with major depressive disorder: an analysis of pooled observational studies focusing on subjects aged 65 years and over.

AIMS: To estimate the frequency of painful physical symptoms (PPS) in elderly subjects (≥ 65 years) with major depressive disorder (MDD) in real-world clinical conditions and to establish whether PPS are associated with poor depression outcomes, including more severe depression and worse health-related quality of life (HRQoL). METHODS: Observational studies of MDD that included assessment of PPS and elderly subjects were screened. Measures of PPS were based on the Somatic Symptom Inventory (SSI) or Visual Analogue Scale (VAS). Data from a variety of depressive symptom severity and HRQoL scales were used. Analysis cohorts were based on age [aged ≥ 65 years (elderly) or < 65 years (younger)] and/or PPS status (presence or absence); five subsets were used to examine specific outcomes in matched elderly subjects. RESULTS: Data from seven studies (representing 26 countries) were collated. Of the 11,477 subjects, 14% were aged ≥ 65 years and 71% were classified as having PPS (PPS+). PPS were more frequent in elderly subjects (74% vs. 70% of younger subjects) and were positively associated with being female and Hispanic, and negatively associated with being East Asian in the elderly. The presence of PPS was associated with more severe clinical symptomatology and comparatively poorer HRQoL in elderly subjects. CONCLUSIONS: PPS, although frequent in younger MDD patients, were slightly more frequent in elderly MDD patients and associated with comparatively poorer clinical and functional outcomes. As elderly patients report somatic symptoms more readily than emotional symptoms, physicians should consider depression in addition to physical causes when PPS are present.

Effects on carbon and nitrogen emissions due to swine manure removal for biofuel production.

Methane (CH) and ammonia (NH) are emitted from swine-manure processing lagoons, contributing to global climate change and reducing air quality. Manure diverted to biofuel production is proposed as a means to reduce CH emissions. At a swine confined animal feeding operation in the U.S. Central Great Basin, animal manure was diverted from 12 farms to a biofuel facility and converted to methanol. Ammonia emissions were determined using the De Visscher Model from measured data of dissolved lagoon ammoniacal N concentrations, pH, temperature, and wind speed at the lagoon sites. Other lagoon gas emissions were measured with subsurface gas collection devices and gas chromatography analysis. During 2 yr of study, CO and CH emissions from the primary lagoons decreased 11 and 12%, respectfully, as a result of the biofuel process, compared with concurrently measured control lagoon emissions. Ammonia emissions increased 47% compared with control lagoons. The reduction of CH and increase in NH emissions agrees with a short-term study measured at this location by Lagrangian inverse dispersion analysis. The increase in NH emissions was primarily due to an increase in lagoon solution pH attributable to decreased methanogenesis. Also observed due to biofuel production was a 20% decrease in conversion of total ammoniacal N to N, a secondary process for the removal of N in anaerobic waste lagoons. The increase in NH emissions can be partially attributed to the decrease in N production by a proposed NH conversion to N mechanism. This mechanism predicts that a decrease in NH conversion to N increases ammoniacal N pH. Both effects increase NH emissions. It is unknown whether the decrease in NH conversion to N is a direct or physical result of the decrease in methanogenesis. Procedures and practices intended to reduce emissions of one pollutant can have an unintended consequence on the emissions of another pollutant.

Gender and health lifestyle: an in-depth exploration of self-care activities in later life.

UNLABELLED: OBJECTIVE. Evaluate similarities and differences in the self-care domain of health lifestyle among older, rural-dwelling women and men. METHOD: Qualitative analysis of in-depth interview data from 62 community-dwelling older (M = 74.3 years) African and European American women and men. RESULTS: Both older women and men rely heavily on over-the-counter medications and home remedies for self-care; professional health care is typically sought when self-care is not effective. However, relative to men, women were more knowledgeable about different approaches to self-care, especially home remedies; they used a wider range of self-care activities; and they placed greater priority on self-care over professional health care. DISCUSSION: The structure of older women's and men's self-care domain of health lifestyle is similar. However, there are subtle differences in health lifestyle that are likely embedded in gendered role behavior and may contribute to women's greater health complaints.

Obesity and bariatric surgery: a systematic review of associations with defecatory dysfunction.

BACKGROUND: Obesity rates are rapidly growing in the developed world. While upper gastrointestinal disturbances and urinary incontinence are independently associated with obesity, the relationship between obesity and defecatory dysfunction is less well defined. OBJECTIVES: To summarize the literature on faecal incontinence, diarrhoea and constipation in obese patients and its effects of bariatric surgery. SEARCH STRATEGY: A Medline search was carried out on articles published from January 1966 to March 2010. SELECTION CRITERIA: Original articles on adult obese or morbidly obese patients were identified, including results following bariatric surgery that reported faecal incontinence, diarrhoea or constipation. Other forms of pelvic floor dysfunction were excluded. Main outcome measures included faecal incontinence, diarrhoea and constipation rates and their severity in obese patients and following bariatric surgery. RESULTS: Twenty studies reported defecatory outcomes in obese patients (n = 14) and after bariatric surgery (n = 6). While constipation rates were similar, the rates of faecal incontinence and diarrhoea were higher in obese patients compared with non-obese patients. The exact rates of these conditions, and the correlations between body mass index (BMI) and faecal incontinence, diarrhoea and constipation, were not clear. Faecal incontinence improved after Roux-en-Y gastric bypass in studies with preoperative data. The effects of bariatric surgery on diarrhoea were unclear. CONCLUSION: Few studies have assessed the correlations between obesity and defecatory function and the effect of bariatric surgery. Studies were often not well controlled and used non-uniform instruments to assess bowel function. Obesity appears to be correlated with higher rates of faecal incontinence and diarrhoea. The effects of bariatric surgery on these conditions are not well defined. Well-controlled studies correlating outcome with physiological pelvic floor function are needed.

Results of combined medical and surgical treatment of recto-vaginal fistula in Crohn's disease.

AIM: Surgical repair of recto-vaginal fistula (RVF) in Crohn's disease (CD) has been associated with high rates of failure. The aim of this study was to compare the outcome in patients with CD who underwent RVF surgery with or without infliximab infusion. METHOD: A retrospective review was carried out of 51 consecutive patients with CD treated for a symptomatic RVF between March 1998 and December 2004. RESULTS: Fifty-one patients (mean age 39 years) underwent 65 procedures, including seton drainage (n = 35), advancement flap (n = 8), fibrin glue injection (n = 8), transperineal repair (n = 6), collagen plug placement (n = 4) and bulbocavernosus flap (n = 4). All patients were on medical treatment at the time of surgery and 26 patients had received preoperative infliximab treatment (minimum of three infusions, 5 mg/kg). Ten patients underwent preoperative diversion. At a mean follow up of 38.6 months, 27 fistulas (53%) had healed and 24 (47%) had recurred. Fistula healing occurred in 60% of patients treated with preoperative diversion, whereas 51% of nondiverted repairs were successful. Neither active proctitis nor infliximab therapy significantly affected fistula healing. Fourteen (27%) patients eventually required proctectomy. CONCLUSION: RVF in CD is difficult to treat. Failure rates are significant despite repeated surgical interventions and concomitant medical treatment.

Faecal incontinence in men.

AIM: A few studies have specifically addressed faecal incontinence (FI) in men. We sought to describe patterns of male FI, assess treatment outcome and compare some aspects of FI between men and women, including quality of life. METHOD: Prospectively recorded data on 85 consecutive male patients evaluated for FI at our pelvic floor centre in 2004 and 2005 were reviewed and compared with a cohort of 408 female patients. Treatment outcome in men was assessed by questionnaire. RESULTS: The aetiology of FI could be determined in 61 (72%) men and was most commonly related to anal surgery (n = 23), prostate cancer therapy (n = 9) and spinal injury (n = 9). Eight patients had idiopathic soiling only. Mean age, Fecal Incontinence Severity Index (FISI) and quality of life scores were similar between men and women. Maximal mean resting pressure (MRP) and squeeze pressure (MSP) were on average higher in men than in women [MRP 56.9 (26.2) vs 40 (20.4) mmHg; P < 0.0001]; [MSP 98.1 (67.3) vs 39.4 (28.5) mmHg; P < 0.0001]. Sphincter defects involved the external sphincter less often in men (35 vs 70%, P = 0.004). Differences in faecal incontinence quality of life (FIQL) and SF-36 scores between men and women were minimal. After a median follow up of 2 years, complete resolution of symptoms was reported in 17% and improvement of symptoms in another 48% of men. CONCLUSION: Although physiological and anatomical features of FI differ between men and women, its severity and impact on quality of life are similar. External sphincter defects are less common in men; hence, direct sphincter repair is less frequently an option. Evaluation and treatment improves symptoms in more than half of male patients.

The routine use of post-operative drains in thyroid surgery: an outdated concept.

The use of surgical drains in patients undergoing thyroid surgery is standard surgical teaching. Life-threatening complications, arising from post-operative haematomas, mandates their utilization. There is increasing evidence to suggest that this is an outdated practice. This paper determines whether thyroid surgery can be safely performed without the routine use of drains. A retrospective review of patients undergoing thyroid surgery, over a three year period was performed and post-operative complications documented. One hundred and four thyroidectomies were performed. 63 (60.6%) patients had a partial thyroidectomy, 27 (25.9%) had a total thyroidectomy and 14 (13.5%) had a sub-total thyroidectomy. Suction drains were not inserted in any patient. A cervical haematoma did not develop in any patient in this series and no patient required re-operation. There is no evidence to suggest the routine use of surgical drains following uncomplicated thyroid surgery reduces the rate of haematoma formation or re-operation rates and indeed is now unwarranted.

The effect of biofuel production on swine farm methane and ammonia emissions.

Methane (CH) and ammonia (NH3) are emitted to the atmosphere during anaerobic processing of organic matter, and both gases have detrimental environmental effects. Methane conversion to biofuel production has been suggested to reduce CH4 emissions from animal manure processing systems. The purpose of this research is to evaluate the change in CH4 and NH3 emissions in an animal feeding operation due to biofuel production from the animal manure. Gas emissions were measured from swine farms differing only in their manure-management treatment systems (conventional vs. biofuel). By removing organic matter (i.e., carbon) from the biofuel farms' manure-processing lagoons, average annual CH4 emissions were decreased by 47% compared with the conventional farm. This represents a net 44% decrease in global warming potential (CO2 equivalent) by gases emitted from the biofuel farms compared with conventional farms. However, because of the reduction of methanogenesis and its reduced effect on the chemical conversion of ammonium (NH4+) to dinitrogen (N2) gas, NH3 emissions in the biofuel farms increased by 46% over the conventional farms. These studies show that what is considered an environmentally friendly technology had mixed results and that all components of a system should be studied when making changes to existing systems.

Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO): baseline characteristics of pan-regional observational data from more than 17,000 patients.

OBJECTIVE: To describe the Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO) patient population at study entry, focusing on illness burden and prescribing practices across regions. METHODS: The SOHO study was a 3-year, prospective, observational study designed to assess costs and outcomes associated with antipsychotic use in outpatients initiating or changing antipsychotic (with an emphasis on olanzapine compared with other antipsychotics). SOHO was conducted in 10 European countries and 27 other countries as Intercontinental SOHO (IC-SOHO). Data from all countries have been pooled to produce the W-SOHO dataset. MAIN OUTCOMES MEASURES: Clinical Global Impression-Schizophrenia (CGI-SCH) severity scores, psychotropic medication use, adverse events, social interaction, housing and employment status, self-perceived health state (EuroQoL EQ-5D scale and Visual Analogue Scale, EQ-VAS), and reasons for initiation/change of antipsychotic. RESULTS: The W-SOHO database comprises 17,384 patients from six regions; East Asia (n = 1223), Central and Eastern Europe (n = 2175), Northern Europe (n = 4291), Southern Europe (n = 5788), Latin America (n = 2566), North Africa and the Middle East (n = 1341). Overall, patients were 38 +/- 13 years old (mean +/- SD), moderately ill (mean CGI-SCH overall score of 4.4 +/- 1.0) with a median duration of illness of 7 years (interquartile range 1-16 years); 43% were female, 10% were receiving antipsychotic medication for the first time. Adverse events were prevalent across all regions; on average, 50% (range 41-59%) of patients taking antipsychotics exhibited extrapyramidal symptoms at baseline, and 62% (34-67%) of patients reported sexual dysfunction in the previous month. On average, only 19% (16-23%) of patients were in paid employment and as many as 69% were living in dependent housing. CONCLUSIONS: Despite inherent diversity in these patients and the health care systems supporting them, there are striking cross-regional similarities in baseline characteristics for most measures. Not all countries are represented; regional comparisons may not be valid outside of the countries studied.