搜索结果：Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology

India is generally regarded as a traditional ‘dry’ or ‘abstaining’ culture [1]. A recent National Household Survey of Drug Use in the country [2], the only systematic effort to document the nation-wide prevalence of drug use, recorded alcohol use in the past year in only 21% of adult males. Expectedly, this figure cannot mirror accurately the wide variation that obtains in a large and complex country such as India. The prevalence of current use of alcohol ranged from a low of 7% in the western state of Gujarat (officially under Prohibition) to 75% in the North-eastern state of Arunachal Pradesh. There is also an extreme gender difference. Prevalence among women has consistently been estimated at less than 5%[3–5] but is much higher in the North-eastern states. Significantly higher use has been recorded among tribal, rural and lower socio-economic urban sections [6,7,25]. The per capita consumption is 2 l/adult/year (calculated from official 2003 sales and population figures). After adjusting for undocumented consumption (illicit beverages as well as tax-evaded products), which accounts for 45–50% of total consumption [8,9], this is likely to be around 4 l, but still low compared to that in wet nations. Spirits, i.e. government-licensed country liquor (rectified spirit mixed with water at 33.3% v/v), Indian-made foreign liquors such as whisky, rum, vodka and gin (42.8% v/v) and illicitly distilled spirits (of indeterminate composition) constitute more than 95% of the beverages drunk by both men and women. Beer accounts for less than 5% of consumption (70% of beer sales is dominated by strong beers at strengths over 8% v/v). Wine is a nascent but growing market. This apparent tradition of abstinence may, however, be a construct of relatively recent origin. The extensive records of diverse fermented and distilled beverages produced from fruits, grains and flowers [10], archaeological evidence of distillation in ancient India [c. 200 BCE][11], the elaborate sets of rules governing production, sales, taxation and public intoxication [12], lyrical descriptions of ritual fiesta drinking by both sexes in secular literature [13], the early recognition of the medical consequences of excess [14] and the frequent admonitions against the use of alcohol by the priestly elite [15] do not support the notion of a long-standing dry culture. The period of rapid social change during the colonial era transformed a society which, barring a segment of the brahminical (priestly class) elite, had until then what appears to be a relatively relaxed attitude to drink [16,17]. The emergence of an urban middle class, participating in the rapid industrial development of the 19th century, led to socio-economic empowerment of the lower rungs of the caste hierarchy. Changes in dietary practices were one of the means adopted by the lower strata to acquire higher social status. As a result of this phenomenon of Sanskritization [18], the growing middle classes embraced upper-caste norms of vegetarianism and abstinence from alcohol [19]. In parallel, the abkari (excise) policies of the colonial government, restricting manufacture of alcoholic beverages to licensed government distilleries, led to the rapid replacement of traditional alcoholic beverages by mass-produced factory-made products, with greater alcohol content and less variety, which were progressively more expensive due to ever-increasing taxation [20]. The enormous increase in the number of distilleries and the practice of auctioning rights to distill and sell unlimited amounts of beverage alcohol led to increased consumption, drunkenness and crime [21]. This was increasingly viewed as an unpopular imposition of English rule and drinking acquired the stature of a peculiarly English vice [22,23]. Alcohol use came to be regarded by the power elite as an atavistic trait of the primitive and the poor (tribals and socially backward drinking to transcend their miserable existence) or a licentious affectation of the upper classes [7,24–27]. Side by side, Gandhi and the nationalist movement harnessed the temperance aspirations of the middle classes into mass movements against drinking as a symbol of colonial oppression. Fired by the belief that the Indian nation should be ritually pure, they evolved a demand for total prohibition. The Constituent Assembly of independent India included prohibition as one of the Directive Principles of state policy [28]. In practice, alcohol policy devolved to individual states to formulate their own regulations and levy their own taxes. Most states derive 15–20% of their revenue from taxation on alcohol, which is the second largest source of the states’ exchequers after sales tax [29]. This has created an ‘ambivalent’ drinking culture—neither dry nor wet. Alcohol use attracts social opprobrium at the same time that governments and alcohol manufacturers promote alcohol sales in pursuit of profit [30]. In several states renewal of retail licenses are contingent upon meeting stiff sales quotas which are revised upwardly from time to time. The alcoholic beverage industry visibly influences the political process [31], with contributions to political parties and in the form of inducements to voters during elections. A few years ago, the Prime Minister designate of the country flew in for his investiture ceremony in the private aeroplane of a prominent liquor manufacturer. Nevertheless, alcohol use for the majority is still stigmatized [24]. Expectedly, in such a situation where traditional social regulation of drinking has been supplanted by centuries of temperance or prohibitionist controls, no prescribed patterns of behavior exist to regulate drinking behaviours. This is known to predispose to deviant, unacceptable and asocial behaviour, as well as chronic disabling alcoholism [32]. Repeated observations have documented that more than 50% of all drinkers satisfy criteria for hazardous drinking. The signature pattern is one of heavy drinking, typically more than five standard drinks on a typical occasions [31,33,34]. There is surprisingly little difference between amounts drunk by men and women. Although a large proportion of drinkers of both genders drink daily or almost daily, the frequency is significantly higher in men. Under-socialized, solitary drinking of mainly spirits, drinking to intoxication and expectancies of drink-related disinhibition and violence add to the hazardous patterns [35,36]. Needless to say, this translates into significant alcohol-related morbidity. Alcohol-related problems account for over a fifth of hospital admissions [37,38] but are under-recognized by primary care physicians. Alcohol misuse has been implicated in over 20% of traumatic brain injuries [39] and 60% of all injuries reporting to emergency rooms [40]. It has a disproportionately high association with deliberate self-harm [41], high-risk sexual behaviour, HIV infection [42], tuberculosis [43], oesophageal cancer [44], liver disease and duodenal ulcer [45,46]. Alcohol misuse wreaks a high social cost [47,48]. A study from the state of Karnataka in South India estimated that monetizable direct and indirect costs attributable to people with alcohol dependence alone was more than three times the profits from alcohol taxation and several times more than the annual health budget of that state [49]. All these studies on morbidity are regional estimates, but given the ubiquitous presence of hazardous drinking patterns [50] should be generalizable across the country. However, there is inadequate recognition that alcohol misuse is a major public health problem in India. Indian society is currently undergoing another tectonic shift in its socio-economic fabric. The impact of globalization and economic liberalization (exposure to satellite television, rapid socio-economic transition and growing disposable incomes) appears to have influenced a widespread attitudinal shift to greater normalization of alcohol use. There has been a significant lowering of age at initiation of drinking. Data from Karnataka showed a drop from a mean of 28 years to 20 years between the birth cohorts of 1920–30 and 1980–90 [8]. Alcohol sales have registered a steady growth rate of 7–8% in the past 3 years. The largest expansion is seen in southern India, which has been driving most of this economic growth. It is visibly focused on the non-traditional segment of urban women [5] and young people, with a noticeable upward shift in rates of drinking among urban middle and upper socio-economic sections. The country liquor and whisky segment that earlier accounted for over 95% of documented consumption [51] has seen stagnation; the growth is in the non-traditional sectors of beer, white spirits and wine. A new segment of consumers is forming and a novel, convivial pattern is supplanting older drinking norms. The local alcohol industry, quick to seize upon this emerging market, has introduced new products such as flavoured and mild alcoholic products, aimed to recruit non-drinkers, targeted primarily at women and young men [52]. The industry circumvents bans on advertising by surrogate advertising, and the subject of alcohol advertising (surrogate and point-of-purchase) has changed from voluptuous pin-ups (targeting the traditional market of middle-aged male consumers) to life-style advertisements promoting the connection with good times, aimed clearly at women and youth. Multi-national alcohol beverage companies redeploying from shrinking markets in the developed world have identified India, with its growing consumer base, vast unexploited markets and commitments to the World Trade Organization to reduce quantitative restrictions on alcohol imports, as one of the most attractive markets for investment [51]. In recent times the trade papers have reported a spate of buy-outs of local beverage companies by multi-national corporations. The revenue aims of state governments are at odds with their health and welfare aims as they push sales by imposing annually incremental quotas on production and sales. As the rising prevalence converges on the signature pattern of frequent heavy drinking, the burden of health attributable to alcohol will mount dramatically. It is often assumed that non-communicable diseases affect higher social classes disproportionately, as mortality levels fall and national incomes increase. In low-income countries such as India the prevalence of alcohol and tobacco use is higher among the poor, which increases the risk of cardiovascular disease, cancer, liver disease and injuries among the poor relative to the better-off [53]. There is also a strong association between use of tobacco and alcohol, and impoverishment through borrowing and distress-selling of assets due to costs of hospitalization [54]. Unfortunately, the official response remains focused on the visible tip of the alcohol problem—people with alcohol dependence (around 4% of the adult male population)—instead of on the emerging crisis due to hazardous drinking in more than 20% of the adult population. This is reflected in the approach to alcohol control policies at federal and state levels. The focus is exclusively on supply reduction (prohibition-centric) and tertiary prevention. Every attempt by individual state governments to prevent misuse through prohibition has been hastily reversed in the face of mounting revenue deficits, costs of policing smuggling from neighboring states and resulting underground alcohol economies, notwithstanding evidence of decreased consumption [3,36] and improved indices of economic wellbeing (personal communication, Excise Commissioner, Andhra Pradesh). In fact, most state governments have publicly recanted the official commitment to prohibition, although it remains enshrined in the constitution. Increased taxation has been used in other countries, to reduce consumption. In India, the impact of such measures is weak as consumers have easy access to undocumented (illicit and excise-evaded) alcohol, beyond the purview of taxation. There is also concern that alcohol as a commodity is relatively price-inelastic and therefore an increase in its price would simply increase the expense of alcohol consumers aggravating the economic hardship of their family members, without necessarily reducing any of the other negative impacts [26,30]. Regulatory laws pertaining to hours of sale, sale to minors and drunken driving are observed in the breach. The Indian Motor Vehicles Act specifies a blood alcohol cut-off of 30 mg% for drivers, which is arguably one of the strictest in the world. However, a recent study in Bangalore city across a calendar month found that 40% of drivers were over the legal limit [55]. The Government of India has funded 483 detoxification and 90 counselling centres country-wide under the auspices of the National Drug Deaddiction Programme to treat people with substance abuse disorders; 45% of people seeking treatment in these centres are for alcohol dependence. Most of these centres are defunct as they received a one-time grant. Paradoxically, the rates of help-seeking in these centres are the lowest in states with the highest prevalence of alcohol use [2], and the overall efficacy of treatment programmes provided is low [56]. The evidence from India is substantial that the direction for policy is to focus on macro-environments and make them more conducive to promoting health behaviours than bank on individual behavioural change [57]. Nevertheless, that is hardly likely as state governments publicly recant their beliefs in prohibition and alcohol control, and try to extricate themselves from public funding of health care. Private expenditure already accounts for 82% of the total expenditure on health. The popular media favour lurid descriptions of alcohol related violence and heroic accounts of sporadic, short-lived anti-alcohol agitations by women's groups [58]. These, paradoxically, serve to marginalize the issue further and detract from a balanced public discourse. Because the subject is of low priority funding for research is low; there is little by way of a body of published literature, which can inform public policy, by projecting the socio-economic impact of alcohol misuse on a national scale. Social aspect organizations of the major liquor companies advocating safe drinking and sections of the mainstream English language media extolling the health benefits of alcohol have invaded that space. In the absence of evidence that the sensible or safe drinking paradigms can be universally applicable, there is apprehension that such moves may be counter-productive or even be interpreted as invitations to drink among an abstinent population [59]. Hopefully, the impetus for a rational public health approach to alcohol policy will stem from the efforts of non-governmental organizations, which are waking up to the sizeable negative impact that harmful alcohol use has on the delivery of their health and development programmes. A combination of (a) a population-based approach reducing overall consumption and (b) a high-risk approach targeting high-risk behaviours is essential to reduce the impact of the signature pattern of hazardous alcohol use in the country. This requires an urgent shift to a public health paradigm in the approach to alcohol use. Health systems, especially at primary care levels, must be geared to play a greater role in the early detection and prevention of alcohol-related harm, perhaps through brief, cost-effective interventions that have been demonstrated to be useful [38]. The social welfare system and the criminal justice system, often the first to come into contact with alcohol-related problems, can be sensitized in identifying and assisting individuals and families at risk from heavy drinking and acting as early referral systems. Extensive opportunities exist to lessen alcohol problems through community education and the prevention of drink driving, domestic violence, public disorder, unintentional injuries and criminal damage [55]. Community programmes supporting healthier life-styles, mass media campaigns that present the advantages of reduced consumption rather than the dangers of heavy alcohol and community development in general (job creation, skills development and upgrading infrastructure or recreational facilities in communities with high levels of alcohol abuse) should be utilized to encourage alternatives to drinking among the young and disadvantaged. Community action can also serve to shape attitudes, values and norms about drinking. Recently, several effective temperance campaigns have been led by heads of certain Hindu religious orders, although the impact has been limited to their immediate followers. Existing legislation relating to controls on availability and marketing, restrictions on advertising, and especially minimum drinking age, need to be enforced rigorously. Simulations have demonstrated that implementing a nation-wide legal drinking age of 21 years can achieve about 50–60% of the alcohol consumption reducing effects of prohibition [29]. Each year that drinking is delayed significantly reduces the likelihood of developing alcoholism and the life-time risk of alcohol abuse [60]. Dialogue and a degree of consensus between the health and revenue arms of government (i.e. federal and state agencies who are virtually opposing players) are crucial to reduce the mutually antagonistic directions of profit and welfare. A proportion of the considerable revenue from alcohol should be ploughed back into treatment and research. The priority for alcohol researchers in India is surely to focus on the public health dimensions of alcohol misuse and to focus on appropriate interventions. It is equally important for research findings to be published and publicized. Hopefully, the imminent centralized system of value-added taxation will reduce the inequities in alcohol taxes between states, and thus diminish interstate smuggling, which nullifies the potential benefits of increasing alcohol prices to reduce consumption. Volume-based taxation (wherein a litre of beer is taxed equally as a litre of spirits) that promotes excess consumption of spirits requires rationalization and control on the of alcoholic beverages into is There is also a need to public health in relating to trade in alcohol production and by companies in India and the of is likely to increase availability and consumption and limit the of prevention programmes. all this to a first is for health and other to and an and rational alcohol policy appropriate for India as it into the of the

Introduction The availability of combination antiretroviral therapy (cART) has led to substantial reduction in morbidity and mortality in HIV-infected patients; however, life expectancy remains reduced especially in HIV-infected patients who initiate cART with CD4 T-cell counts less than 200 cells/μl [1]. Increased immune activation in patients on long-term suppressive cART [2–4] has been associated with increased mortality [5,6] and both AIDS and non-AIDS-defining illnesses [7–10], suggesting that chronic immune activation may have a potential role in driving increased morbidity and mortality. Causes of HIV-associated immune activation The mechanisms driving systemic immune activation in chronic HIV infection are multifactorial (reviewed in [11], Fig. 1) [12] and include the translocation of microbial products from the gastrointestinal tract [13,14], low-level HIV viremia [15,16], and coinfections with other persistent viral pathogens including cytomegalovirus (CMV) and hepatitis C virus (HCV) [17]. A recent study in simian immunodeficiency virus-infected macaques demonstrated a significant increase in immune activation and coagulation markers, including D-dimers, following exogenous administration of lipopolysaccharide (LPS) [18]. The excessive production of interferon alpha (IFN-α) [19–22] and pro-inflammatory cytokines leading to upregulation of pro-apoptotic molecules [23–26], lymph node fibrosis [27], dysfunction of CD4 T-regulatory cells (T-regs) [28,29], and depletion of CD161++/(mucosal-associated invariant T cells, MAIT) [30,31] are likely to also contribute.Fig. 1: Schematic representation of the potential causes of chronic immune activation in HIV-infected patients, its impact on clinical end-points, and strategies of interventions tested in recently completed and ongoing clinical trials.Potential drivers of immune activation include microbial translocation which occurs due to persistent dysfunction in the gut-associated lymphoid tissue (GALT), persistent HIV infection, coinfections with cytomegalovirus (CMV) and hepatitis C virus (HCV), aberrant activation of plasmacytoid dendritic cells (pDC), and altered ratio of Tregs and Th17 cells. Immune activation, though significantly reduced, persists even in patients receiving suppressive combination antiretroviral therapy (cART) and leads to increased lymph node fibrosis and T-cell exhaustion, which affects CD4 T-cell recovery. Chronic immune activation also activates monocytes, which drives local inflammation in tissues and leads to the development of various end-organ damage and non-AIDS-defining illnesses including cardiovascular disease (CVD). Various treatment strategies to attenuate immune activation or its effects have recently been trialed and are labeled A to F. These strategies include (A) agents that promote mucosal repair in the GALT (bovine serum colostrum, micronutrient supplementation, probiotics and prebiotics); (B) cART treatment intensification (maraviroc and raltegravir); (C) treatment of coinfections (valgancyclovir, interferon-α, and ribavirin); (D) agents that reduce pDC activation (chloroquine and hydroxychloroquine); (E) agents that reduce transforming growth factor-β1 (TGF-β1)-mediated lymph node fibrosis (pirfenidone); and (F) immunomodulators [HMG CoA reductase inhibitors, minocycline, selective cyclooxygenase-2 inhibitors, leflunomide, and intravenous immunoglobulin (IVIG)]. Modified from [12].Strategies to reduce persistent immune activation in HIV-infected patients Pharmacological agents Multiple clinical trials have been completed (Table 1) [32–76], or are in development (Table 2) [27,77–86], to reduce immune activation in HIV-infected patients and have also been recently reviewed in [87].Table 1-a: Therapeutic agents/biologicals that have been evaluated in HIV-infected patients for their effects on immune activation and associated morbidities.Table 1-b: Therapeutic agents/biologicals that have been evaluated in HIV-infected patients for their effects on immune activation and associated morbidities.Table 2: Therapeutic agents currently in or being considered for clinical trial to reduce immune activation levels in HIV.Statins The use of statins in HIV-infected patients on and off cART has reported variable changes in T-cell activation and highly sensitive C-reactive protein (hsCRP) levels [32–35] but no effect on CD4 T-cell counts [32,33,36]. However, in two large observational studies of cART-treated patients, the use of statins was associated with reduced mortality [37] and reduced incidence of non-Hodgkin lymphoma (NHL) [38]. No immunological correlates were assessed in these two studies and a greater understanding of the mechanisms underlying the benefits of statins is needed. Chloroquine and hydroxychloroquine Chloroquine and hydroxychloroquine inhibit endosomal acidification in plasmacytoid dendritic cells (pDCs) and Toll-like receptor 7 (TLR-7) signaling by HIV-1 single stranded (ss)RNA and also inhibit IFN-α production [88,89]. In vitro, chloroquine inhibited pDC activation and maturation, reduced IFN-α-mediated CD8 T-cell activation, and downmodulated indolamine 2–3 dioxygenase (IDO) and PD-L1 expression on pDCs, which are negative regulators of T-cell responses [90]. A recent randomized controlled trial (RCT) in cART-naive patients (n = 13) found chloroquine was associated with decreased memory CD8 T-cell activation, CD4 and CD8 T-cell proliferation, and LPS levels compared to baseline but there were no changes in plasma HIV RNA [39]. In contrast, a RCT of hydroxychloroquine in cART-naive patients demonstrated no change in CD8 and CD4 T-cell activation and proliferation, an increase in HIV RNA, and decrease in CD4 T-cell counts [40]. In a small nonrandomized study (n = 20), administration of hydroxychoroquine to patients receiving suppressive cART was associated with a reduction in multiple markers of immune activation but no significant increase in CD4 T-cell recovery [41]. Given these promising findings, numerous clinical trials are currently being conducted with choloroquine (NCT00819390) and hydroxychloroquine (NCT01232660). Selective cyclooxygenase-2 inhibitors Selective cyclooxygenase-2 (COX-2) inhibitors are anti-inflammatory agents that modulate T-cell activation via inhibition of prostaglandin E2 and the cyclic adenosine 3′,5′-monophosphate (cAMP)-protein kinase A pathway ([91,92], reviewed in [93]). In cART-treated patients, selective COX-2 inhibitors were associated with increased T-cell proliferation [94], a nonsignificant reduction in T-cell activation, and increased perforin-containing CD8 T cells [42]. A recent RCT of high-dose celecoxib in untreated HIV-infected patients (n = 31) reported a significant reduction in immune activation levels [43]. Leflunomide A77 1726, the active metabolite of the antirheumatoid arthritis agent leflunomide, has anti-HIV activity [95,96], inhibits pyrimidine synthesis [96,97], and reduces proliferation of activated T cells in vitro[98]. A small RCT in cART-naive patients (ALETHIA, A Study of Leflunomide to Target Immune Activation in HIV; n = 16), found no significant change in CD4 and CD8 T-cell counts or HIV RNA levels in patients treated with leflunomide compared to placebo [44]. Furthermore, more grade 1 and 2 adverse events were reported with leflunomide. However, short-term leflunomide use was associated with reduced T-cell cycling and activation. It is currently unclear whether similar immunological effects will be seen in patients receiving cART. Biological agents Bovine colostrum, micronutrients, and prebiotics/probiotics Multiple approaches are now being taken to directly reduce microbial load and translocation in HIV patients. These include supplementation with micronutrients, bovine colostrum, probiotics, and prebiotics, all of which have previously been shown to reduce HIV-associated diarrhea [99–101,45,46]. These strategies may also alter the composition of gut microflora, which may be important in modulating microbial translocation-driven immune activation [102,103]. Most of these studies have been in cART-naive patients and some have reported increases in CD4 T-cell counts [45,46,47–51] (Table 1). In a RCT of orally administered hyperimmune bovine colostrum (that contains antibodies to LPS), there was no effect on immune activation or CD4 T-cell recovery in patients receiving suppressive cART [52]. Antiretroviral intensification Chronic immune activation in patients receiving cART may also be driven by low-level HIV viremia [15,16,104,105]. In multiple observational and RCT studies, the addition of raltegravir to suppressive cART resulted in no significant immune activation reduction in plasma, cerebrospinal fluid, or tissue [52,53–58] nor any change in endothelial function, a surrogate marker of cardiovascular disease [106]. There have, however, been two studies that have shown that the addition of raltegravir led to a significant reduction in T-cell activation markers in a subset of patients and a reduction in reservoir size [59,60]. Further larger randomized studies are still needed to definitively determine the impact of raltegravir intensification on immune activation. Several studies of maraviroc intensification have shown a reduction in immune activation [61–63]; however, one study reported an unexpected increase in immune activation [64] (Table 1). CCR5 antagonists inhibit the binding and signaling of CCR5 ligands (including CCL3, CCL4, and CCL5) leading to an increase in their plasma concentration. This increase could potentially activate monocytes/macrophages via CCR1 [62] and/or increase antigen-specific T-cell and antibody responses, which has been observed in some [107] but not all studies [108]. Further studies are needed to better characterize the immunological changes associated with maraviroc use. The timing of cART initiation may be an important parameter that influences immune activation. Studies of patients treated during chronic infection have demonstrated persistently elevated immune activation levels post-cART compared to uninfected controls [2–4]. A recent prospective study of cART initiated during acute infection demonstrated reduced immune activation to normal levels after 48 weeks [109]. Prospective or randomized trials need to be performed to determine the effect of early versus delayed cART on immune activation in patients with chronic infection. Treatment of coinfections Anti-cytomegalovirus treatment: valgancyclovir Increased CMV-specific antibodies and/or T cells have been associated with atherosclerosis [110,111] and impaired CD4 T-cell reconstitution [112] in HIV-infected patients on cART, suggesting that CMV coinfection may be a driver of persistent immune activation. A RCT with valgancyclovir in CMV-seropositive cART-treated patients (n = 30) found that both CMV DNA and expression of CD38+HLA DR+ on T cells declined significantly during valgancyclovir therapy [65]. It is currently unclear whether this approach will translate to clinical benefits and the feasibility of prolonged administration of valgancyclovir may be limited by significant toxicities of the drug. Anti-hepatitis C virus treatment: interferon alpha and ribavirin HCV-specific treatment with IFN-α and ribavirin in HIV/HCV coinfected patients receiving cART has been associated with a significant reduction in markers of T-cell activation [66] and endothelial dysfunction [113]; however, its impact on clinical end-points is currently unknown. Other strategies including treatment with intravenous immunoglobulin (IVIG) and minocycline have also been trialed in small studies but have yielded negative results (see Table 1). Challenges in designing clinical trials to reduce immune activation There are multiple challenges in designing clinical trials to reduce chronic immune activation in patients receiving suppressive cART. First, these studies will require patients who are otherwise clinically well to take an additional drug(s) that may be associated with toxicities. Therefore, the risks and benefits need to be carefully assessed. Second, there are multiple markers of immune activation and inflammation that have been studied and it is currently unclear which best predicts AIDS and non-AIDS-related morbidities in patients receiving suppressive cART. Biomarkers such as IL-6, D-dimer, and sCD14 show promise as they are relatively easy to standardize from measurements in plasma but whether they are indeed robust markers for predicting clinical outcomes following specific interventions needs further evaluation. Finally, given that clinical events are rare in patients on suppressive cART, relatively large samples sizes will be required to demonstrate a clinically relevant impact of any intervention to reduce immune activation. Conclusion To date, most studies aimed at reducing immune activation have only included a small number of patients and/or shown an effect on biomarkers of immune activation and have not had the power to assess any effects on clinical outcomes. Given that there are several candidate approaches that have shown promise in small proof-of-concept trials, these compounds warrant evaluation in larger randomized clinical trials that systematically evaluate both immune activation biomarkers and clinical outcomes. Acknowledgements R.R. and S.L. wrote the article. G.K., A.K., M.F., and P.U.C. provided helpful comments and edited the article. R.R. and A.K. receive funding from the HIR/MOHE grant (UM.C/625/1/HIR/MOHE/MED01), R.R. from UMRG (RG377/11HTM) and S.R.L. from the National Institutes of Health (U19 AI096109 and 1R56AI095073-01A1. S.R.L. is an Australian National Health and Medical Research Council (NHMRC) Practitioner Fellow. G.K. is a recipient of a NHMRC postgraduate scholarship. Conflicts of interest There are no conflicts of interest.

BACKGROUND: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. METHODS: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. FINDINGS: Global DALYs increased from 2·63 billion (95% UI 2·44-2·85) in 2010 to 2·88 billion (2·64-3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7-17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8-6·3) in 2020 and 7·2% (4·7-10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0-234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7-198·3]), neonatal disorders (186·3 million [162·3-214·9]), and stroke (160·4 million [148·0-171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3-51·7) and for diarrhoeal diseases decreased by 47·0% (39·9-52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54-1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5-9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0-19·8]), depressive disorders (16·4% [11·9-21·3]), and diabetes (14·0% [10·0-17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7-27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6-63·6) in 2010 to 62·2 years (59·4-64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6-2·9) between 2019 and 2021. INTERPRETATION: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. METHODS: Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. FINDINGS: Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2·2% (95% uncertainty interval [UI] 1·5-3·0) of age-standardised female deaths and 6·8% (5·8-8·0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3·8% (95% UI 3·2-4·3) of female deaths and 12·2% (10·8-13·6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2·3% (95% UI 2·0-2·6) and male attributable DALYs were 8·9% (7·8-9·9). The three leading causes of attributable deaths in this age group were tuberculosis (1·4% [95% UI 1·0-1·7] of total deaths), road injuries (1·2% [0·7-1·9]), and self-harm (1·1% [0·6-1·5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27·1% (95% UI 21·2-33·3) of total alcohol-attributable female deaths and 18·9% (15·3-22·6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0·0-0·8) standard drinks per week. INTERPRETATION: Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption. FUNDING: Bill & Melinda Gates Foundation.

In recent years, there have been reports suggesting a high prevalence of low vitamin D intakes and vitamin D deficiency or inadequate vitamin D status in Europe. Coupled with growing concern about the health risks associated with low vitamin D status, this has resulted in increased interest in the topic of vitamin D from healthcare professionals, the media and the public. Adequate vitamin D status has a key role in skeletal health. Prevention of the well-described vitamin D deficiency disorders of rickets and osteomalacia are clearly important, but there may also be an implication of low vitamin D status in bone loss, muscle weakness and falls and fragility fractures in older people, and these are highly significant public health issues in terms of morbidity, quality of life and costs to health services in Europe. Although there is no agreement on optimal plasma levels of vitamin D, it is apparent that blood 25-hydroxyvitamin D [25(OH)D] levels are often below recommended ranges for the general population and are particularly low in some subgroups of the population, such as those in institutions or who are housebound and non-Western immigrants. Reported estimates of vitamin D status within different European countries show large variation. However, comparison of studies across Europe is limited by their use of different methodologies. The prevalence of vitamin D deficiency [often defined as plasma 25(OH)D <25 nmol/l] may be more common in populations with a higher proportion of at-risk groups, and/or that have low consumption of foods rich in vitamin D (naturally rich or fortified) and low use of vitamin D supplements. The definition of an adequate or optimal vitamin D status is key in determining recommendations for a vitamin D intake that will enable satisfactory status to be maintained all year round, including the winter months. In most European countries, there seems to be a shortfall in achieving current vitamin D recommendations. An exception is Finland, where dietary survey data indicate that recent national policies that include fortification and supplementation, coupled with a high habitual intake of oil-rich fish, have resulted in an increase in vitamin D intakes, but this may not be a suitable strategy for all European populations. The ongoing standardisation of measurements in vitamin D research will facilitate a stronger evidence base on which policies can be determined. These policies may include promotion of dietary recommendations, food fortification, vitamin D supplementation and judicious sun exposure, but should take into account national, cultural and dietary habits. For European nations with supplementation policies, it is important that relevant parties ensure satisfactory uptake of these particularly in the most vulnerable groups of the population.

Abstract Polyols are hydrogenated carbohydrates used as sugar replacers. Interest now arises because of their multiple potential health benefits. They are non-cariogenic (sugar-free tooth-friendly), low-glycaemic (potentially helpful in diabetes and cardiovascular disease), low-energy and low-insulinaemic (potentially helpful in obesity), low-digestible (potentially helpful in the colon), osmotic (colon-hydrating, laxative and purifying) carbohydrates. Such potential health benefits are reviewed. A major focus here is the glycaemic index (GI) of polyols as regards the health implications of low-GI foods. The literature on glycaemia and insulinaemia after polyol ingestion was analysed and expressed in the GI and insulinaemic index (II) modes, which yielded the values: erythritol 0, 2; xylitol 13, 11; sorbitol 9, 11; mannitol 0, 0; maltitol 35, 27; isomalt 9, 6; lactitol 6, 4; polyglycitol 39, 23. These values are all much lower than sucrose 65, 43 or glucose 100, 100. GI values on replacing sucrose were independent of both intake (up to 50 g) and the state of carbohydrate metabolism (normal, type 1 with artificial pancreas and type 2 diabetes mellitus). The assignment of foods and polyols to GI bands is considered, these being: high (> 70), intermediate (> 55-70), low (> 40-55), and very low (< 40) including non-glycaemic; the last aims to target particularly low-GI-carbohydrate-based foods. Polyols ranged from low to very low GI. An examination was made of the dietary factors affecting the GI of polyols and foods. Polyol and other food GI values could be used to estimate the GI of food mixtures containing polyols without underestimation. Among foods and polyols a departure of II from GI was observed due to fat elevating II and reducing GI. Fat exerted an additional negative influence on GI, presumed due to reduced rates of gastric emptying. Among the foods examined, the interaction was prominent with snack foods; this potentially damaging insulinaemia could be reduced using polyols. Improved glycated haemoglobin as a marker of glycaemic control was found in a 12-week study of type 2 diabetes mellitus patients consuming polyol, adding to other studies showing improved glucose control on ingestion of low-GI carbohydrate. In general some improvement in long-term glycaemic control was discernible on reducing the glycaemic load via GI by as little as 15-20 g daily. Similar amounts of polyols are normally acceptable. Although polyols are not essential nutrients, they contribute to clinically recognised maintenance of a healthy colonic environment and function. A role for polyols and polyol foods to hydrate the colonic contents and aid laxation is now recognised by physicians. Polyols favour saccharolytic anaerobes and aciduric organisms in the colon, purifying the colon of endotoxic, putrefying and pathological organisms, which has clinical relevance. Polyols also contribute towards short-chain organic acid formation for a healthy colonic epithelium. Polyol tooth-friendliness and reduced energy values are affirmed and add to the potential benefits. In regard to gastrointestinal tolerance, food scientists and nutritionists, physicians, and dentists have in their independent professional capacities each now described sensible approaches to the use and consumption of polyols.

ESGE suggests endoscopic therapy and/or extracorporeal shockwave lithotripsy (ESWL) as the first-line therapy for painful uncomplicated chronic pancreatitis (CP) with an obstructed main pancreatic duct (MPD) in the head/body of the pancreas. The clinical response should be evaluated at 6 - 8 weeks; if it appears unsatisfactory, the patient's case should be discussed again in a multidisciplinary team and surgical options should be considered.Weak recommendation, low quality evidence.ESGE suggests, for the selection of patients for initial or continued endoscopic therapy and/or ESWL, taking into consideration predictive factors associated with a good long-term outcome. These include, at initial work-up, absence of MPD stricture, a short disease duration, non-severe pain, absence or cessation of cigarette smoking and of alcohol intake, and, after initial treatment, complete removal of obstructive pancreatic stones and resolution of pancreatic duct stricture with stenting.Weak recommendation, low quality evidence.ESGE recommends ESWL for the clearance of radiopaque obstructive MPD stones larger than 5 mm located in the head/body of the pancreas and endoscopic retrograde cholangiopancreatography (ERCP) for MPD stones that are radiolucent or smaller than 5 mm. Strong recommendation, moderate quality evidence.ESGE suggests restricting the use of endoscopic therapy after ESWL to patients with no spontaneous clearance of pancreatic stones after adequate fragmentation by ESWL.Weak recommendation, moderate quality evidence.ESGE suggests treating painful dominant MPD strictures with a single 10-Fr plastic stent for one uninterrupted year if symptoms improve after initial successful MPD drainage. The stent should be exchanged if necessary, based on symptoms or signs of stent dysfunction at regular pancreas imaging at least every 6 months. ESGE suggests consideration of surgery or multiple side-by-side plastic stents for symptomatic MPD strictures persisting beyond 1 year after the initial single plastic stenting, following multidisciplinary discussion. Weak recommendation, low quality evidence.ESGE recommends endoscopic drainage over percutaneous or surgical treatment for uncomplicated chronic pancreatitis (CP)-related pseudocysts that are within endoscopic reach.Strong recommendation, moderate quality evidence.ESGE recommends retrieval of transmural plastic stents at least 6 weeks after pancreatic pseudocyst regression if MPD disruption has been excluded, and long-term indwelling of transmural double-pigtail plastic stents in patients with disconnected pancreatic duct syndrome.Strong recommendation, low quality evidence.ESGE suggests the temporary insertion of multiple side-by-side plastic stents or of a fully covered self-expandable metal stent (FCSEMS) for treating CP-related benign biliary strictures.Weak recommendation, moderate quality evidence.ESGE recommends maintaining a registry of patients with biliary stents and recalling them for stent removal or exchange.Strong recommendation, low quality evidence.

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

In the United States, there is a largely hidden burden of diseases caused by a group of chronic and debilitating parasitic, bacterial, and congenital infections known as the neglected infections of poverty. Like their neglected tropical disease counterparts in developing countries, the neglected infections of poverty in the US disproportionately affect impoverished and under-represented minority populations. The major neglected infections include the helminth infections, toxocariasis, strongyloidiasis, ascariasis, and cysticercosis; the intestinal protozoan infection trichomoniasis; some zoonotic bacterial infections, including leptospirosis; the vector-borne infections Chagas disease, leishmaniasis, trench fever, and dengue fever; and the congenital infections cytomegalovirus (CMV), toxoplasmosis, and syphilis. These diseases occur predominantly in people of color living in the Mississippi Delta and elsewhere in the American South, in disadvantaged urban areas, and in the US-Mexico borderlands, as well as in certain immigrant populations and disadvantaged white populations living in Appalachia. Preliminary disease burden estimates of the neglected infections of poverty indicate that tens of thousands, or in some cases, hundreds of thousands of poor Americans harbor these chronic infections, which represent some of the greatest health disparities in the United States. Specific policy recommendations include active surveillance (including newborn screening) to ascertain accurate population-based estimates of disease burden; epidemiological studies to determine the extent of autochthonous transmission of Chagas disease and other infections; mass or targeted treatments; vector control; and research and development for new control tools including improved diagnostics and accelerated development of a vaccine to prevent congenital CMV infection and congenital toxoplasmosis.

More than a half of the world's population are infected with one or more species of intestinal worms of which the nematodes Ascaris lumbricoides, Trichuris trichiura and the hookworms are the most common and important in terms of child health. This paper: (1) introduces the main species of intestinal worms with particular attention to intestinal nematodes; (2) examines how such worms may affect child growth and nutrition; (3) reviews the biological and epidemiological factors that influence the effects that worms can have on the growth and nutrition of children; (4) considers the many factors that can affect the impact of treatment with anthelmintic drugs; (5) presents the results of a meta-analysis of studies of the effect of treating worm infections on child growth and nutrition; (6) discusses the results in terms of what is reasonable to expect that deworming alone can achieve; (7) describes some important characteristics of an ideal study of the effects of deworming; and (8) comments on the implications for programmes of recommendations concerning mass deworming.

In recent years, increasing numbers of people have been choosing herbal medicines or products to improve their health conditions, either alone or in combination with others. Herbs are staging a comeback and herbal “renaissance” occurs all over the world. According to the World Health Organization, 75% of the world’s populations are using herbs for basic healthcare needs. Since the dawn of mankind, in fact, the use of herbs/plants has offered an effective medicine for the treatment of illnesses. Moreover, many conventional/pharmaceutical drugs are derived directly from both nature and traditional remedies distributed around the world. Up to now, the practice of herbal medicine entails the use of more than 53,000 species, and a number of these are facing the threat of extinction due to overexploitation. This paper aims to provide a review of the history and status quo of Chinese, Indian, and Arabic herbal medicines in terms of their significant contribution to the health promotion in present‐day over‐populated and aging societies. Attention will be focused on the depletion of plant resources on earth in meeting the increasing demand for herbs.

OBJECTIVES: Feeding difficulties are frequent in children with neurological impairments and can be associated with undernutrition, growth failure, micronutrients deficiencies, osteopenia, and nutritional comorbidities. Gastrointestinal problems including gastroesophageal reflux disease, constipation, and dysphagia are also frequent in this population and affect quality of life and nutritional status. There is currently a lack of a systematic approach to the care of these patients. With this report, European Society of Gastroenterology, Hepatology and Nutrition aims to develop uniform guidelines for the management of the gastroenterological and nutritional problems in children with neurological impairment. METHODS: Thirty-one clinical questions addressing the diagnosis, treatment, and prognosis of common gastrointestinal and nutritional problems in neurological impaired children were formulated. Questions aimed to assess the nutritional management including nutritional status, identifying undernutrition, monitoring nutritional status, and defining nutritional requirements; to classify gastrointestinal issues including oropharyngeal dysfunctions, motor and sensory function, gastroesophageal reflux disease, and constipation; to evaluate the indications for nutritional rehabilitation including enteral feeding and percutaneous gastrostomy/jejunostomy; to define indications for surgical interventions (eg, Nissen Fundoplication, esophagogastric disconnection); and finally to consider ethical issues related to digestive and nutritional problems in the severely neurologically impaired children. A systematic literature search was performed from 1980 to October 2015 using MEDLINE. The approach of the Grading of Recommendations Assessment, Development, and Evaluation was applied to evaluate the outcomes. During 2 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation using the nominal voting technique. Expert opinion was applied to support the recommendations where no randomized controlled trials were available.

Medicinal plants have been used in healthcare since time immemorial. Studies have been carried out globally to verify their efficacy and some of the findings have led to the production of plant-based medicines. The global market value of medicinal plant products exceeds $100 billion per annum. This paper discusses the role, contributions and usefulness of medicinal plants in tackling the diseases of public health importance, with particular emphasis on the current strategic approaches to disease prevention. A comparison is drawn between the 'whole population' and 'high-risk' strategies. The usefulness of the common-factor approach as a method of engaging other health promoters in propagating the ideals of medicinal plants is highlighted. The place of medicinal plants in preventing common diseases is further examined under the five core principles of the Primary Health Care (PHC) approach. Medicinal plants play vital roles in disease prevention and their promotion and use fit into all existing prevention strategies. However, conscious efforts need to be made to properly identify, recognise and position medicinal plants in the design and implementation of these strategies. These approaches present interesting and emerging perspectives in the field of medicinal plants. Recommendations are proposed for strategising the future role and place for medicinal plants in disease prevention.

The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.

OBJECTIVE: Esophageal cancer is the second commonest cancer in Malawi, and 95% of all cases are esophageal squamous cell carcinoma (ESCC). Very little is known about the epidemiology of ESCC in Malawi including risk factors. The main objective of the study was to evaluate and describe risk factors of ESCC in Malawi. METHODS: We conducted a case-control study from 2017 to 2020 at two hospitals in Lilongwe, Malawi and consenting adults were eligible for inclusion. Endoscopy was conducted on all cases and biopsies were obtained for histological confirmation. Controls were selected from patients or their guardians in orthopedic, dental and ophthalmology wards and they were frequency matched by sex, age, and region of origin to cases. An electronic structured questionnaire was delivered by a trained interviewer. Multivariate conditional logistic regression models were used to assess the associations between subject characteristics, habits, and medical history and risk of ESCC. RESULTS: During the study period, 300 cases and 300 controls were enrolled into the study. Median age of cases and controls was 56 years and 62% of the cases were male. Among cases, 30% were ever cigarette smokers as were 22% of controls. Smoking cigarettes had an adjusted odds ratio of 2.4 (95% CI 1.4-4.2 p = 0.003). HIV+ status was present in 11% of cases and 4% controls, which resulted in an adjusted odds ratio was 4.0 (95% CI 1.8-9.0 p = 0.001). Drinking hot tea was associated with an adjusted odd ratio of 2.9 (95% CI 1.3-6.3 p = 0.007). Mold on stored grain has an adjusted odd ratio of 1.6 (95% CI 1.1-2.5 p = 0.021). CONCLUSION: Reducing smoking cigarettes, consumption of scalding hot tea, and consumption of contaminated grain, could potentially help reduce the burden of ESCC in Malawi. Further investigation of the association between HIV status and ESCC are warranted.

Over half of all children with autism spectrum disorders (ASD) have gastrointestinal (GI) co-morbidities including chronic constipation, diarrhea, and irritable bowel syndrome. The severity of these symptoms has been correlated with the degree of GI microbial dysbiosis. The study objective was to assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities. This pilot study is a randomized, double blind, controlled trial of combination treatment (BCP + B. infantis) vs. BCP alone in a cross-over study in children ages 2-11 with ASD and GI co-morbidities (n = 8). This 12-week study included 5 weeks of probiotic-prebiotic supplementation, followed by a two-week washout period, and 5 weeks of prebiotic only supplementation. The primary outcome of tolerability was assessed using validated questionnaires of GI function and atypical behaviors, along with side effects. Results suggest that the combination treatment is well-tolerated in this cohort. The most common side effect was mild gassiness. Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors. Improvement may be explained by a reduction in IL-13 and TNF-α production in some participants. Although limited conclusions can be drawn from this small pilot study, the results support the need for further research into the efficacy of these treatments.

Cerebral palsy (CP) is one of the most frequent causes of motor disability in children. According to the up-to-date definition, CP is a group of permanent disorders of the development of movement and posture, causing activity limitations that are attributed to non-progressive disturbances that occurred in the developing foetal or infant brain. The CP definition has evolved over time; the problem is aetiologically and clinically very heterogeneous. According to European data, the average frequency of CP is 2.08 per 1000 live births, but in the group of children born with a body weight below 1500 g, the frequency is 70 times higher when compared with the group of children with a body weight over 2500 g at birth. The risk factors for CP can be divided into pre-conception, prenatal, perinatal and postnatal ones. CP commonly co-exists with epilepsy, in particular drug-resistant epilepsy, but also with mental retardation, visual and hearing impairment, as well as feeding and behavioral disorders. The degree of motor problem varies from mild to very severe making the child totally dependent on caregivers. Cerebral palsy is divided into forms depending on the type of motor disorders which dominate the clinical presentation; the traditional classifications by Ingram and Hagberg have now been replaced by the Surveillance of Cerebral Palsy in Europe classification which divides CP into spastic, dyskinetic and ataxic forms. Although cerebral palsy is a clinical diagnosis, modern diagnostic imaging provides information that allows the division of the results of magnetic resonance imaging in children with cerebral palsy into five groups according to the magnetic resonance imaging classification system. Just as the clinical presentation and the factors predisposing for CP are very diverse, treatment is also a very complex problem. Modern treatment of spasticity includes both botulinum toxin therapies and surgical techniques, eg, rhizotomy. The authors present current views on definitions, risk factors, diagnostics and treatment of CP as well as comorbid problems, eg, drug-resistant epilepsy.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common gastrointestinal emergency, which is potentially fatal. Proper management of UGIB requires risk-stratification of patients which can guide the type and aggressiveness of management. The aim of this was study was identify the causes of UGIB and factors that increase the risk of mortality in these patients. METHODS: This was a prospective cohort study conducted over a period of seven months at a tertiary hospital. Adults admitted with UGIB were included in the study. Demographic data, laboratory parameters and endoscopic findings were recorded. Patients were then followed up for 60 days to identify the occurrence of mortality. Chi-square tests and cox-regression was used to determine association between risk factors and mortality in the bivariate and multivariate analysis, respectively. RESULTS: A total of 170 patients with UGIB were included. Males accounted for the majority (71.2%). Median age of the study population was 40.0 years. Chronic liver disease was present in 30.6% of study patients. The most common cause of UGIB among the 86 patients who underwent endoscopy was oesophageal varices (57%), followed by peptic ulcer disease (18%) and gastritis (10%). Mortality occurred in 57 patients (33.5%) and was significantly higher in patients with high white blood cell count (HR 2.45, p 0.011), raised serum alanine aminotransferase (HR 4.22, p 0.016), raised serum total bilirubin (HR 5.79, p 0.008) and lack of an endoscopic procedure done (HR 4.40, p <0.001). Rebleeding was reported in 12 patients (7.1%) and readmission due to UGIB in 4 patients (2.4%) CONCLUSIONS: Oesophageal varices was the most common cause of UGIB. One-third of patients admitted with upper gastrointestinal bleeding died within 60 days of admission, signifying a high burden. Rebleeding and readmission rates were low. A high WBC count, raised serum ALT, raised serum total bilirubin and a lack of endoscopy were independent predictors of mortality. These findings can be used to risk-stratify patients who may benefit from early and more aggressive management.

Liver disease accounts for two million deaths annually and is responsible for 4% of all deaths (1 out of every 25 deaths worldwide); approximately two-thirds of all liver-related deaths occur in men. Deaths are largely attributable to complications of cirrhosis and hepatocellular carcinoma, with acute hepatitis accounting for a smaller proportion of deaths. The most common causes of cirrhosis worldwide are related to viral hepatitis, alcohol, and non-alcoholic fatty liver disease. Hepatotropic viruses are the aetiological factor in most cases of acute hepatitis, but drug-induced liver injury increasingly accounts for a significant proportion of cases. This iteration of the global burden of liver disease is an update of the 2019 version and focuses mainly on areas where significant new information is available like alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma. We also devote a separate section to the burden of liver disease in Africa, an area of the world typically neglected in such documents.