An overview of systematic reviews on the public health consequences of social isolation and loneliness.

OBJECTIVES: Social isolation and loneliness have been associated with ill health and are common in the developed world. A clear understanding of their implications for morbidity and mortality is needed to gauge the extent of the associated public health challenge and the potential benefit of intervention. STUDY DESIGN: A systematic review of systematic reviews (systematic overview) was undertaken to determine the wider consequences of social isolation and loneliness, identify any differences between the two, determine differences from findings of non-systematic reviews and to clarify the direction of causality. METHODS: Eight databases were searched from 1950 to 2016 for English language reviews covering social isolation and loneliness but not solely social support. Suitability for inclusion was determined by two or more reviewers, the methodological quality of included systematic reviews assessed using the a measurement tool to assess systematic reviews (AMSTAR) checklist and the quality of evidence within these reviews using the grading of recommendations, assessment, development and evaluations (GRADE) approach. Non-systematic reviews were sought for a comparison of findings but not included in the primary narrative synthesis. RESULTS: Forty systematic reviews of mainly observational studies were identified, largely from the developed world. Meta-analyses have identified a significant association between social isolation and loneliness with increased all-cause mortality and social isolation with cardiovascular disease. Narrative systematic reviews suggest associations with poorer mental health outcomes, with less strong evidence for behavioural and other physical health outcomes. No reviews were identified for wider socio-economic or developmental outcomes. CONCLUSIONS: This systematic overview highlights that there is consistent evidence linking social isolation and loneliness to worse cardiovascular and mental health outcomes. The role of social isolation and loneliness in other conditions and their socio-economic consequences is less clear. More research is needed on associations with cancer, health behaviours, and the impact across the life course and wider socio-economic consequences. Policy makers and health and local government commissioners should consider social isolation and loneliness as important upstream factors impacting on morbidity and mortality due to their effects on cardiovascular and mental health. Prevention strategies should therefore be developed across the public and voluntary sectors, using an asset-based approach.

16(th) IHIW: immunogenomic data-management methods. report from the immunogenomic data analysis working group (IDAWG).

SUMMARY: The goal of the immunogenomic data analysis working group (IDAWG) is to facilitate the consistent analysis of HLA and KIR data, and the sharing of those data among the immunogenomic and larger genomic communities. However, the data management approaches currently applied by immunogenomic researchers are not widely discussed or reported in the literature, and the effect of different approaches on data analyses is not known. With ASHI's support, the IDAWG developed a 45 question survey on HLA and KIR data generation, data management and data analysis practices. Survey questions detailed the loci genotyped, typing systems used, nomenclature versions reported, computer operating systems and software used to manage and transmit data, the approaches applied to resolve HLA ambiguity and the methods used for basic population-level analyses. Respondents were invited to demonstrate their HLA ambiguity resolution approaches in simulated data sets. By May 2012, 156 respondents from 35 nations had completed the survey. These survey respondents represent a broad sampling of the Immunogenomic community; 52% were European, 30% North American, 10% Asian, 4% South American and 4% from the Pacific. The project will continue in conjunction with the 17th Workshop, with the aim of developing community data sharing standards, ambiguity resolution documentation formats, single-task data Management tools and novel data analysis methods and applications. While additional project details and plans for the 17th IHIW will be forthcoming, we welcome the input and participation in these projects from the histocompatibility and immunogenetics community.

16(th) IHIW: global distribution of extended HLA haplotypes.

This report describes the project to identify the global distribution of extended HLA haplotypes, a component of 16th International HLA and Immunogenetics Workshop (IHIW), and summarizes the initial analyses of data collected. The project aims to investigate extended HLA haplotypes, compare their distribution among different populations, assess their frequency in hematopoietic stem cell unrelated donor registries and initiate an international family studies database and DNA repository to be made publicly available. HLA haplotypes compiled in immunogenetics laboratories during the evaluation of transplant candidates and related potential donors were analysed. Haplotypes were determined using the pedigree analysis tool publicly available from the National Marrow Donor Program (NMDP) website. Nineteen laboratories from 10 countries (11 laboratories from North America, five from Asia, two from Latin America and one from Australia) contributed data on a total of 1719 families comprised of 7474 individuals. We identified 10393 HLA haplotypes, of which 1682 haplotypes included high-resolution typing at HLA-A, B, C, DRB1 and DQB1 loci. We also present haplotypes containing MICA and other HLA loci and haplotypes containing rare alleles seen in these families. The project will be extended through the 17th IHIW, and investigators interested in joining the project may communicate with the first author.

Optimization of residential green space for environmental sustainability and property appreciation in metropolitan Phoenix, Arizona.

Cities in arid and semi-arid regions have been exploring urban sustainability policies, such as lowering the vegetation coverage to reduce residential outdoor water use. Meanwhile, urban residents express concerns that such policies could potentially impact home prices regardless of the reduced water costs because studies have shown that there is a positive correlation between vegetation coverage and home values. On the other hand, lower vegetation coverage in arid and semi-arid desert regions could increase surface temperatures, and consequently increases energy costs. The question is therefore where the point in which residential outdoor water use can be minimized without overly increasing surface temperatures and negatively impacting home values. This study examines the impacts of spatial composition of different vegetation types on land surface temperature (LST), outdoor water use (OWU), and property sales value (PSV) in 302 local residential communities in the Phoenix metropolitan area, Arizona using remotely sensed data and regression analysis. In addition, the spatial composition of vegetation cover was optimized to achieve a relatively lower LST and OWU and maintain a relatively higher PSV at the same time. We found that drought-tolerant landscaping that is composed of mostly shrubs and trees adapted to the desert environment is the most water efficient way to reduce LST, but grass contributes to a higher PSV. Research findings suggest that different residential landscaping strategies may be better suited for different neighborhoods and goal sets can be used by urban planners and city managers to better design urban residential landscaping for more efficient water conservation and urban heat mitigation for desert cities.

Comparison of genome sequencing and clinical genotyping for pharmacogenes.

We compared whole exome sequencing (WES, n = 176 patients) and whole genome sequencing (WGS, n = 68) and clinical genotyping (DMET array-based approach) for interrogating 13 genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. We focused on 127 CPIC important variants: 103 single nucleotide variations (SNV), 21 insertion/deletions (Indel), HLA-B alleles, and two CYP2D6 structural variations. WES and WGS provided interrogation of nonoverlapping sets of 115 SNV/Indels with call rate >98%. Among 68 loci interrogated by both WES and DMET, 64 loci (94.1%, confidence interval [CI]: 85.6-98.4%) showed no discrepant genotyping calls. Among 66 loci interrogated by both WGS and DMET, 63 loci (95.5%, CI: 87.2-99.0%) showed no discrepant genotyping calls. In conclusion, even without optimization to interrogate pharmacogenetic variants, WES and WGS displayed potential to provide reliable interrogation of most pharmacogenes and further validation of genome sequencing in a clinical lab setting is warranted.

Effect of HLA class I or class II incompatibility in pediatric marrow transplantation from unrelated and related donors.

The degree of histoincompatibility that can be tolerated, and the relative importance of matching at individual HLA class I and class II locus in bone marrow transplantation (BMT) has not been established. We hypothesized that matching for HLA-DR may not be more important than matching for HLA-A or HLA-B in selection of a donor for successful BMT. We retrospectively analyzed the outcomes of 248 consecutive pediatric patients who received allogeneic BMT from related donors (RD, n = 119) or unrelated donors (URD, n = 129). HLA-A and HLA-B were serologically matched, and HLA-DRB1 were identical by DNA typing in 69% of donor-recipient pairs. Most patients (89%) had hematologic malignancies; the rest had aplastic anemia or a congenital disorder. One HLA-A antigen mismatch was associated with a decrease in survival (p = 0.003) and a delay in granulocyte engraftment (p = 0.02) in recipients of RD marrow; as well as a decrease in survival (p = 0.02) and the development of severe acute graft-versus-host disease (GVHD) (p = 0.03) in recipients of URD marrow. One HLA-B antigen mismatch was associated with a decrease in the survival (p = 0.05) and the development of severe GVHD (p = 0.0007) in recipients of RD marrow. One HLA-DRB1 allele mismatch was associated only with a decrease in the survival (p = 0.0003) of recipients of RD marrow. Results of this study suggest that disparity in HLA-A and HLA-B antigens may not be better tolerated than disparity in HLA-DR allele in allogeneic BMT. Further studies are warranted to confirm our results.

The epidemiology of trachoma in central Tanzania.

Trachoma is the leading infectious cause of blindness worldwide and data are needed on the epidemiological characteristics of active and residual disease in hyperendemic areas. This study describes the epidemiological characteristics of trachoma in Central Tanzania. Active, inflammatory disease peaks in pre-school children, with 60% showing signs of trachoma. Evidence of past infection, scarring, trichiasis, and corneal opacity, rose with age. In this population, 8% of those over age 55 had trichiasis/entropion. Females of all ages had more trachoma than males, with a fourfold increased risk of trichiasis observed in females. Women who were taking care of children appeared to have more active disease than non-caretakers. Clear evidence of clustering of trachoma by village, and within village, by neighbourhood was found. Clustering persisted even after accounting for differences in distance to water, local religion, and proportion of children with unclean faces. These findings have important implications for a trachoma control strategy.

Risk factors for trichiasis in women in Kongwa, Tanzania: a case-control study.

Women are at a greater risk compared to men for blinding complications from trachoma. In order to evaluate risk factors in women, 205 cases of trichiasis (TT) were selected from 11 villages in rural Tanzania. Each case of trichiasis was matched to two women of the same age and from the same village, who had no clinical signs of trachoma. Factors associated with trichiasis in a conditional logistic regression included history of trichiasis in the women's mother (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 2.0-6.5); sleeping in a room with a cooking fire during childbearing years (OR = 1.8; 95% CI: 1.2-2.8); a home of wood and earth during childbearing years (OR = 2.1; 95% CI: 1.3-3.3); no adult education classes (OR = 2.2; 95% CI: 1.4-3.4); and five or more deaths among her children (OR = 2.6; 95% CI: 1.3-5.1). Detailed measures of prolonged exposure to child care as a young girl and as a mother showed no significant difference between cases and controls. Results from this study characterize women at high risk for severe disease and eventual blindness in a trachoma endemic area.

PIP: Ophthalmologists analyzed data on 205 women with ingrowing eyelashes caused by trachomatous scarring (trichiasis) with data on 410 age- and village-matched controls to determine risk factors for trichiasis in trachoma hyperendemic areas where women face a greater risk of trichiasis than do men. All women lived in the Kongwa subdistrict of Dodoma Region, Tanzania. Cases were 3.6 times more likely to have a mother who also had trichiasis. Family history of fathers or other relatives was not associated with trichiasis, however. Cases tended to have never married (odds ratio [OR] = 3.7), suggesting that in a society that expects marriage women with trichiasis were socially and economically marginalized. Mothers with trichiasis were more apt to experience at least 5 deaths of children than controls (OR = 2.6). The researchers assumed that a factor common to both trichiasis and increased child deaths (e.g., socioeconomic status) accounted for this association. Controls were more likely to have attended adult education classes than cases (OR = 2.2), yet attendance at primary school was not a predictor for trichiasis. Women who had slept in a room with a cooking fire during their reproductive years were more prone to trichiasis than women who did during childhood or as current practice (OR -1.8), indicating a more profound pathogenic response (scarring) to infection with Chlamydia trachomatis during pregnancy. Living in a wood/earth (i.e., traditional) home during childbearing years was also a significant predictor of trichiasis (OR = 2.1). These findings suggest that improving living conditions, educational opportunities, and socioeconomic status during the childbearing years would reduce the risk for trichiasis and blindness.

Reconstitution of the T cell receptor alpha beta repertoire in recipients of allogeneic BMT.

This report describes the qualitative analysis of T cell receptor (TCR) repertoire regeneration in recipients of BMT. RNA samples from patient and control peripheral blood lymphocytes were prepared and tested for the presence of multiple V alpha and V beta transcripts by the polymerase chain reaction. TCR V gene expression was highly diverse within the first 6 months post-transplantation in recipients receiving either T cell-depleted or T cell-replete marrow, and in HLA mismatched as well as matched donor-recipient pairs. The sequencing of TCR message from BMT recipients also demonstrated J gene diversity and apparently normal junctional diversity at the V-J alpha join. Thus, T cell pools in BMT recipients are largely heterogeneous, not mono- or oligoclonal.

Hygiene factors and increased risk of trachoma in central Tanzania.

Trachoma remains the major infectious cause of blindness in many developing areas, especially where hygiene is poor. The practices and behaviors associated with an increased risk of trachoma were studied in central Tanzania, where a stratified random cluster sample of 8409 people was examined. Data were collected on family and individual characteristics and behaviors and on trachoma status. Overall, 60% of the children aged 1 to 7 years had active inflammatory trachoma, and 10% of those aged 60 years or older had trichiasis. Regression analysis showed that active inflammatory trachoma in children was associated with the characteristics of the more traditional families and several measures of poor personal hygiene. Two important risk factors for severe inflammatory trachoma were poor facial cleanliness in children (odds ratio of 1.7 [1.17, 2.50]) and household fly density (odds ratio of 1.63 [1.17, 2.29]). Both factors are potentially amenable to intervention. These data suggest that an intervention strategy aimed at these hygiene measures would provide an effective method of controlling trachoma in this region, and a similar approach may be useful in other areas.

The cryopreservation and in vitro cultivation of larval Onchocerca volvulus.

A system developed in our laboratory for the in vitro cultivation of larval Onchocerca volvulus is being employed in a series of morphogenetic, physiologic, chemotherapeutic and immunologic investigations of this parasite. Because of the need for a large and readily available supply of living worms for this work, cryogenic techniques are being used for the long-term preservation of larval parasites collected in various endemic areas of Guatemala, C.A. To date, microfilariae have survived frozen storage in human cutaneous tissues (excised nodules and skin snips) for as long as 504 days, and viable larvae, in all stages of development have been recovered from the black fly vectors (Simulium ochraceum and S. metallicum) kept frozen for 396 days. That cryopreservation does not appear to affect these parasites adversely is indicated by the fact that microfilariae derived from frozen tissues do not differ from those obtained from fresh tissues on the basis of: 1) numbers and vigor of emergent microfilariae; 2) survival and morphogenesis of microfilariae during cultivation in vitro for 24 days; 3) glucose utilization during 72 hours of incubation; and 4) their incorporation of 3H-amino acids as determined after 18 hours of incubation. Details of methodology for cryopreservation and in vitro cultivation, together with resultant data, are presented herein.

HIV antibodies: further questions and a plea for clarification.

The existence of specific antibody/protein reactions is the crucial assumption underlying proof of HIV isolation, proof of HIV infection and the causative role of HIV in AIDS. However, since 1. antibodies which react with the 'HIV' proteins arise following allogenic stimuli in non-HIV-infected animals and humans, as well as in mice and humans with autoimmune disorders; antibodies to antigens from both mycobacteria and yeasts cross-react with HIV env and gag proteins; 2. individuals belonging to the AIDS risk groups are subjected to allogenic stimuli and have high levels of autoimmune antibodies, while the vast majority of patients in the AIDS risk groups are infected with either or both mycobacteria or yeasts; the evidence for the existence of HIV and its putative role in AIDS must be reappraised.

A critical analysis of the pharmacology of AZT and its use in AIDS.

The triphosphorylated form of the nucleoside analogue 3'-azido-3'-deoxythymidine (Zidovudine, AZT) is claimed to interrupt the HIV replication cycle by a selective inhibition of viral reverse transcriptase, thereby preventing the formation of new proviral DNA in permissive, uninfected cells. Given that initial HIV infection of an individual instigates abundant HIV replication from inception until death, and that the life of infected T-cells is only several days, the administration of AZT should lead both in vitro and in vivo (i) to decreased formation of proviral DNA; and thus (ii) to decreased frequencies of 'HIV isolation' (detection of p24 or reverse transcription or both) in stimulated cultures/cocultures of T-cells from seropositive individuals; (iii) to decreased synthesis of HIV p24 and RNA ('antigenaemia', 'plasma viraemia', 'viral load') ultimately resulting in low or absent levels of all three parameters; and (iv) to a perfect and direct correlation between all these parameters. A critical analysis of the presently available data shows that no such evidence exists, an outcome not unexpected given the pharmacological data on AZT. HIV experts all agree that only the triphosphorylated form of AZT (AZTTP) and not the unphosphorylated form administered to patients, nor its mono- or diphosphate, is the active agent. Furthermore, the mechanism of action is the ability of AZTTP to halt the formation of HIV-DNA (chain termination). However, although this claim was posited from the outset, AZT underwent clinical trials and was introduced as a specific anti-HIV drug many years before there were any data proving that the cells of patients are able to triphosphorylate the parent compound to a level considered sufficient for its putative pharmacological action. Notwithstanding, from the evidence published since 1991 it has become apparent that no such phosphorylation takes place and thus AZT cannot possess an anti-HIV effect. However, the scientific literature does elucidate: (i) a number of biochemical mechanisms which predicate the likelihood of widespread, serious toxicity from use of this drug; (ii) in vitro data proving that AZT has significant antibacterial and antiviral properties which confound interpretation of its effects when administered to patients. Based on all these data it is difficult if not impossible to explain why AZT was introduced and still remains the most widely recommended and used anti-HIV drug.

Tissue distribution of indoleamine 2,3-dioxygenase in normal and malaria-infected tissue.

An immunohistochemical method was developed, using a polyclonal antibody, to detect the enzyme indoleamine 2,3-dioxygenase (IDO) in normal and malaria-infected tissue. Plasmodium berghei ANKA, a cerebral malaria (CM) model, and P. berghei K173, a non-cerebral malaria (NCM) model, were used. It was found that vascular endothelial cells were the primary site of IDO expression in both models of malaria infection and that this response was systemic, with the vascular endothelium of brain, heart, lung, spleen and uterus all staining positive. These results suggest that IDO is part of a systemic host response to parasite infection. Although high levels of IDO production alone may not cause pathology, it is possible that when its production is combined with other features of CM, such as breakdown of the blood-brain barrier (BBB), metabolites of the kynurenine pathway may be able to influence the otherwise tightly regulated, immunologically privileged site of the CNS and cause some of the symptoms and pathology observed.

Distribution of 14C-labelled acrylamide and betaine in foetuses of rats, rabbits, beagle dogs and miniature pigs.

[14C]Acrylamide and [14C]betaine hydrochloride were administered in a single iv dose to pregnant rats, rabbits, beagle dogs and miniature pigs late in gestation (1-2 days before expected parturition). Dosages used were 10 mg/kg for rats and 5 mg/kg for the other species. The compounds were allowed to equilibrate in the animal (for 1 hr in rats and for 2 hr in the other species); the dam was then killed and the foetuses were removed by caesarean section. Each foetus was weighed and analysed for radioactivity, either by homogenization of the whole foetus (rat and rabbit) or by determining separately the radioactivity in individual organs and tissues (dog and pig). Foetal uptake of the polar compound betaine hydrochloride was much lower than that of the more lipophilic acrylamide. The sex of the foetus did not appear to affect uptake of either compound. There were no significant differences in total uptake of isotope attributable to the position of the foetus within the uterus in any of the four species given either acrylamide or betaine. Similarly, uterine position did not affect the uptake of acrylamide or betaine by individual tissues of foetal dogs or pigs. Since the distributions of 14C-labelled acrylamide and betaine hydrochloride were essentially uniform throughout a litter, it would not be necessary to sample all of the members of a litter to obtain a representative picture of foetal distribution.

Avidin-ferritin cytochemistry on lectin receptors of uterine epithelial cells in the rat.

Cytochemistry using biotinylated lectins and an avidin-ferritin label has been combined with freeze-fracture to study the relationship between surface carbohydrates and intramembranous particles in uterine epithelial cells. We find no structural relationship between the 2 classes of membrane components and consider the significance of this finding.