Summary Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.

Type 1 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

The genetic architecture of type 2 diabetes

Do men die young and sick, or do women live long and healthy? By trying to explain the sexual dimorphism in life expectancy, both biological and environmental aspects are presently being addressed. Besides age-related changes, both the immune and the endocrine system exhibit significant sex-specific differences. This review deals with the aging immune system and its interplay with sex steroid hormones. Together, they impact on the etiopathology of many infectious diseases, which are still the major causes of morbidity and mortality in people at old age. Among men, susceptibilities toward many infectious diseases and the corresponding mortality rates are higher. Responses to various types of vaccination are often higher among women thereby also mounting stronger humoral responses. Women appear immune-privileged. The major sex steroid hormones exhibit opposing effects on cells of both the adaptive and the innate immune system: estradiol being mainly enhancing, testosterone by and large suppressive. However, levels of sex hormones change with age. At menopause transition, dropping estradiol potentially enhances immunosenescence effects posing postmenopausal women at additional, yet specific risks. Conclusively during aging, interventions, which distinctively consider the changing level of individual hormones, shall provide potent options in maintaining optimal immune functions.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.12326

How sex and age affect immune responses, susceptibility to infections, and response to vaccination

Hepatitis C virus (HCV) infection is a major source of morbidity and mortality in the United States. HCV is transmitted primarily through parenteral exposures to infectious blood or body fluids that contain blood, most commonly through injection drug use. No vaccine against hepatitis C exists and no effective pre- or postexposure prophylaxis is available. More than half of persons who become infected with HCV will develop chronic infection. Direct-acting antiviral treatment can result in a virologic cure in most persons with 8-12 weeks of all-oral medication regimens. This report augments (i.e., updates and summarizes) previously published recommendations from CDC regarding testing for HCV infection in the United States (Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rec 2012;61[No. RR-4]). CDC is augmenting previous guidance with two new recommendations: 1) hepatitis C screening at least once in a lifetime for all adults aged ≥18 years, except in settings where the prevalence of HCV infection is <0.1% and 2) hepatitis C screening for all pregnant women during each pregnancy, except in settings where the prevalence of HCV infection is <0.1%. The recommendation for HCV testing that remains unchanged is regardless of age or setting prevalence, all persons with risk factors should be tested for hepatitis C, with periodic testing while risk factors persist. Any person who requests hepatitis C testing should receive it, regardless of disclosure of risk, because many persons might be reluctant to disclose stigmatizing risks.

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CDC Recommendations for Hepatitis C Screening Among Adults - United States, 2020.

Objective:Polymorphisms in the obesity-associated gene, FTO, have been linked with sensitivity to satiety in children, indicating FTO may be influencing one of the regulatory drivers underlying food intake. In this study, we tested the hypothesis that food intake in a standard eating behaviour paradigm in which palatable food is offered under conditions of satiety would be associated with FTO genotype status, after controlling for differences in body mass index (BMI).Methods:Participants were 131 children aged 4–5 years, taking part in a behavioural study of food intake for whom DNA was available for genotyping. The phenotypic indicator of intake was the child's consumption of palatable food presented after having eaten a meal. We also assessed physical activity using parental reports of the child's enjoyment of active games, their level of activity relative to other children and a standard measure of fidgetiness. Associations between polymorphisms of the intronic FTO single nucleotide polymorphism (rs9939609) and behaviour (food intake and activity) were assessed by analysis of variance controlling for sex, age and BMI s.d. scores.Results:The distribution of AA (homogenous for A allele), AT (heterogeneous T and A alleles) and TT (homogenous for T allele) genotypes was 18, 50 and 32%, respectively. As predicted, TT homozygotes ate significantly less than heterozygotes (P=0.03) or AA homozygotes (P=0.02). The effect was not diminished by controlling for BMI s.d. scores. There were no significant associations between FTO genotype and any marker of physical activity.Conclusions:We showed that children with two copies of the lower-risk FTO alleles ate less than those with one or two higher-risk alleles. We conclude that the T allele is protective against overeating by promoting responsiveness to internal signals of satiety.

Variations in the FTO gene and measured food intake in children

Background
As the hepatitis B genotyping is important for assessing its clinical implications and geographical distribution, the sub-genotypes have been found useful for determination of specific genomic markers related to hepatocarcinogenesis. In Pakistan, there is no reported data on molecular evolutionary analysis of HBV. A study was, therefore, much needed to evaluate the spectra of mutations present in the strains prevalent here.

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Hepatitis B virus subgenotypes D1 and D3 are prevalent in Pakistan

Gender differences prevail in the infections caused by the Hepatitis B virus. Four hundred and seventy two patients with HBV infection were selected for the study. The frequency of hepatic infection in males was 79.5% (n=375) and in females 20.5% (n=97), with a male to female ratio of 3.8:1. Out of 472 patients, 49% had acute hepatitis, 26% were carriers, 18% had chronic hepatitis, 6% had cirrhosis and 3% patients had hepatocellular carcinoma. Male dominance was found to be consistent in all categories of patients. When the patients were divided into groups according to age, the male to female ratio increased during the reproductive years. There may be an influence of estrogen in the protection and defense of hepatic cells against the development of chronic liver disease.

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Gender disparity in infections of Hepatitis B virus.

Genotyping of HBV is generally used for determining the epidemiological relationship between various virus strains and origin of infection mostly in research studies. The utility of genotyping for clinical applications is only beginning to gain importance. Whether HBV genotyping will constitute part of the clinical evaluation of Hepatitis B patients depends largely on the availability of the relevance of the evidence based information. Since Pakistan has a HBV genotype distribution which has been considered less virulent as investigated by earlier studies from south East Asian countries, a study on correlation between HBV genotypes and risk of progression to further complex hepatic infection was much needed A total of 295 patients with HBsAg positive were selected from the Pakistan Medical Research Council's (PMRC) out patient clinics. Two hundred and twenty six (77%) were males, sixty nine (23%) were females (M to F ratio 3.3:1). Out of 295 patients, 156 (53.2%) had Acute(CAH), 71 (24.2%) were HBV Carriers, 54 (18.4%) had Chronic liver disease (CLD) Hepatitis. 14 (4.7%) were Cirrhosis and HCC patients. Genotype D was the most prevalent genotype in all categories of HBV patients, Acute (108), Chronic (39), and Carrier (53). Cirrhosis/HCC (7) were HBV/D positive. Genotype A was the second most prevalent with 28 (13%) in acute cases, 12 (22.2%) in chronics, 14 (19.7%) in carriers and 5 (41.7) in Cirrhosis/HCC patients. Mixed genotype (A/D) was found in 20 (12.8%) of Acute patients, 3 (5.6%) of Chronic and 4 (5.6%) of carriers, none in case of severe liver conditions. Mixed HBV genotypes A, D and A/D combination were present in all categories of patients except that no A/D combination was detected in severe conditions. Genotype D was the dominant genotype. However, genotype A was found to be more strongly associated with severe liver disease. Mixed genotype (A/D) did not significantly appear to influence the clinical outcome.

The association of complex liver disorders with HBV genotypes prevalent in Pakistan

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The association of complex liver disorders with HBV genotypes prevalent in Pakistan.

Hepatitis B Virus (HBV) leads to a number of hepatic complications, from acute to chronic hepatitis, cirrhosis and hepatocellular carcinoma, is a well-established fact. Upcoming clinical research, over the years, associates numerous extrahepatic manifestations during the acute and chronic episodes of hepatitis B with significant morbidity and mortality. A causal relationship between HBV and serious autoimmune disorders has also been observed among certain susceptible vaccine recipients in a defined temporal period following immunization. The cause of these extrahepatic manifestations is generally believed to be immune mediated. The most commonly described include skin rash, arthritis, arthralgia, glomerulonephritis, polyarteritis nodosa, and papular acrodermatitis etc. The serum-sickness like "arthritis-dermatitis" prodrome has also been observed in approximately one-third of patients acquiring HBV infections. Skin manifestations of HBV infection typically present as palpable purpura reported to be caused by chronic HBV, although this association remains controversial. To consider the relationship between HBV and other clinically significant disorders as well as serious autoimmune disorders among certain vaccine recipients is the topic of this review. Variable factors that influence extrahepatic manifestation are discussed, including possible synergy between hepatitis B virus and the immune system.

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Saeeda Baig

Papers

Hepatitis B virus subgenotypes D1 and D3 are prevalent in Pakistan

Gender disparity in infections of Hepatitis B virus.

The association of complex liver disorders with HBV genotypes prevalent in Pakistan

The association of complex liver disorders with HBV genotypes prevalent in Pakistan.

The extrahepatic manifestations of hepatitis B virus.