Parental and healthcare provider attitudes towards the Healthy Child Programme in England: a qualitative analysis.

BACKGROUND: The Healthy Child Programme (HCP) in England, delivered by Health Visitors (HV) and Nursery Nurses (NN), aims to assess growth and development in pre-school age children. This qualitative analysis aimed to evaluate the perceptions and experiences of HCP providers and parents located in a London borough. METHODS: This qualitative analysis is part of a larger study piloting an automated growth screening algorithm in a London borough. We conducted three focus group discussions; two with parents of pre-school children participating in the pilot study, one in English (n = 6) and one in Sylheti (n = 5), and one with HVs and NNs (n = 11). Sampling was purposeful, and written informed consent was obtained. Groups were facilitated by the same bilingual researcher using semi-structured topic guides. Data were analysed using reflexive thematic analysis and assessed for intercoder reliability. RESULTS: Three broad themes were identified in the data: (1) lack of clarity around the role of the HV and NN; (2) a lack of resources; and (3) a desire for a preventative service. Underlying these themes was a sense of disempowerment shown by HVs/NNs and parents, as well as systemic issues in terms of the accessibility and practicality of the service. Nevertheless, parents and HVs/NNs all stressed the importance of the service in providing information, reassurance and advice. CONCLUSIONS: Various challenges prevent the HCP from providing equitable and effective care to every child. However, the service was recognised as very valuable by users and providers despite systemic difficulties.

Characterizing asset-based studies in public health: development of a framework.

Asset-based approaches are becoming more common within public health interventions; however, due to variations in terminology, it can be difficult to identify asset-based approaches. The study aimed to develop and test a framework that could distinguish between asset-based and deficit-based community studies, whilst acknowledging there is a continuum of approaches. Literature about asset-based and deficit-based approaches were reviewed and a framework was developed based on the Theory of Change model. A scoring system was developed for each of the five elements in the framework based on this model. Measurement of community engagement was built in, and a way of capturing how much the study involved an asset approach. The framework was tested on 13 studies examining community-based interventions to investigate whether it could characterize asset-based versus deficit-based studies. The framework demonstrated how much the principles underpinning asset-based approaches were present and distinguished between studies where the approach was deficit-based to those that had some elements of an asset-based approach. This framework is useful for researchers and policymakers when determining how much of an intervention is asset-based and identifying which elements of asset-based approaches lead to an intervention working.

Deficit-based approaches are a common approach to addressing public health issues within a community and involve identifying a health problem or need and finding a way to solve these. However, asset-based approaches, those that involve the community using its assets, or strengths, to enable community members to have more control over their health and wellbeing, are increasingly common. The terminology used to describe these methods varies greatly so it can be difficult to identify whether an approach is more deficit-based or asset-based. To address this a framework was developed to identify and score elements of asset-based studies. We did this by reviewing academic information describing asset-based approaches and built into this a scoring system. This framework was used to assess and measure the degree to which 13 community-based studies took an asset-based approach. The framework was able to identify studies which were more asset-based in their approach compared to those which were more deficit-focused, acknowledging that some studies may have elements of each approach. This framework will be useful for people working in health policy and research who want a resource to help identify asset-based approaches in practice and which aspects of the approach were important for its success in the community.

Short stature and language development in the United Kingdom: a longitudinal analysis of children from the Millennium Cohort Study.

BACKGROUND: In low- and middle-income countries, poverty and impaired growth prevent children from meeting their cognitive developmental potential. There are few studies investigating these relationships in high-income settings. METHODS: Participants were 12,536 children born between 2000 and 2002 in the UK and participating in the Millennium Cohort Study (MCS). Short stature was defined as having a height-for-age 2 or more standard deviations below the median (≤ - 2 SDS) at age 3 years. Standardized British Abilities Scales II (BAS II) language measures, used to assess language development at ages 3, 5, 7 and 11 years, were the main outcome assessed. RESULTS: Children with short stature at age 3 years (4.1%) had language development scores that were consistently lower from ages 3 to 11 years (- 0.26 standard deviations (SD) (95% CI - 0.37, - 0.15)). This effect was attenuated but remained significant after adjustment for covariates. Trajectory analysis produced four distinct patterns of language development scores (low-declining, low-improving, average and high). Multinomial logistic regression models showed that children with short stature had a higher risk of being in the low-declining group, relative to the average group (relative risk ratio (RRR) = 2.11 (95% CI 1.51, 2.95)). They were also less likely to be in the high-scoring group (RRR = 0.65 (0.52, 0.82)). Children with short stature at age 3 years who had 'caught up' by age 5 years (height-for-age ≥ 2 SDS) did not have significantly different scores from children with persistent short stature, but had a higher probability of being in the high-performing group than children without catch-up growth (RRR = 1.84 (1.11, 3.07)). CONCLUSIONS: Short stature at age 3 years was associated with lower language development scores at ages 3 to 11 years in UK children. These associations remained significant after adjustment for socioeconomic, child and parental factors.

STOP- a training intervention to optimise treatment for smoking cessation in community pharmacies: cluster randomised controlled trial.

BACKGROUND: Community pharmacies serve people with high levels of tobacco-related illness, but throughput in NHS Stop Smoking Services in pharmacies remains relatively low. We investigated the effectiveness of a complex intervention to increase service uptake and retention. METHODS: We randomised 60 pharmacies in England and Wales to the STOP intervention or usual practice in a pragmatic, parallel-group, controlled trial over 11 months. Smokers were blind to the allocation. The intervention was theory-based consultation skills training for pharmacy staff with environmental prompts (badges, calendars and behavioural cues). The primary outcome was the number of smokers attending an initial consultation and setting a quit date. RESULTS: The intervention made no significant difference in setting a quit date, retention or quit rate. A total of 631 adult smokers (service users) enrolled and set a quit date in intervention pharmacies compared to 641 in usual practice pharmacies, a rate ratio of 0.75 (95% CI 0.46 to 1.23) adjusted for site and number of prescriptions. A total of 432 (68%) service users were retained at 4 weeks in intervention and 500 (78%) in usual practice pharmacies (odds ratio 0.80, 0.41 to 1.55). A total of 265 (42%) service users quit smoking at 4 weeks in intervention and 276 (43%) in usual practice pharmacies (0.96, 0.65 to 1.43). The pharmacy staff were positive about the intervention with 90% (56/62) stating that it had improved their skills. Sixty-eight per cent would strongly recommend the training to others although there was no difference in self-efficacy for service delivery between arms. Seventy of 131 (53%) service users did not complete the 6-month follow-up assessment. However, 55/61 (90%) service users who completed follow-up were satisfied or very satisfied with the service. All usual practice arm service users (n = 33) and all but one in the intervention arm (n = 27) would recommend the service to smokers. CONCLUSIONS: We found high levels of retention and acceptable quit rates in the NHS pharmacy stop smoking service. Despite pharmacy staff providing positive feedback on the STOP intervention, it made no difference to service throughput. Thus, other factors may currently limit service capacity to help smokers to quit. TRIAL REGISTRATION: ISRCTN, ISRCTN16351033 . Retrospectively registered.

Acellular Dermal Matrix Mimicking a New Retroareolar Mass After Central Pillar Neonipple Reconstruction.

ABSTRACT: Acellular dermal matrix (ADM) is an increasingly popular alloplastic cadaveric dermis used to enhance postmastectomy reconstruction. Acellular dermal matrix can be used as a nipple-shaped cylinder in central pillar nipple reconstruction to help maintain long-term projection. We report a unique presentation of ADM mimicking a retroareolar mass after central pillar neonipple reconstruction. A 49-year-old woman with a history of invasive ductal carcinoma underwent delayed nipple reconstruction after lumpectomy and oncoplastic closure using an inframammary V-Y advancement flap.The nipple reconstruction was performed using pretattoo and articulated tab flaps. A rolled tube of acellular dermal matrix was placed in the central aspect of the neonipple reconstruction for projection. At 4 months postoperative, a screening mammogram and ultrasound noted a new retroareolar mass classified as BIRADS 4 necessitating a breast biopsy. Biopsy revealed portions of fibrous connective tissue consistent with partially incorporated acellular dermal matrix allograft. There was no evidence of malignancy. To mitigate the risk of future radiographic or clinical misinterpretation of ADM in nipple reconstruction, the placement of radiopaque markers such as microclips on the ADM implant could be a useful adjunct. Radiologists and surgeons should include ADM artifact in their differential diagnosis of radiologic imaging when evaluating a new mass in the proximity of prior ADM placement in neonipple reconstruction of the breast.

Regional differences in short stature in England between 2006 and 2019: A cross-sectional analysis from the National Child Measurement Programme.

BACKGROUND: Short stature, defined as height for age more than 2 standard deviations (SDs) below the population median, is an important indicator of child health. Short stature (often termed stunting) has been widely researched in low- and middle-income countries (LMICs), but less is known about the extent and burden in high-income settings. We aimed to map the prevalence of short stature in children aged 4-5 years in England between 2006 and 2019. METHODS AND FINDINGS: We used data from the National Child Measurement Programme (NCMP) for the school years 2006-2007 to 2018-2019. All children attending state-maintained primary schools in England are invited to participate in the NCMP, and heights from a total of 7,062,071 children aged 4-5 years were analysed. We assessed short stature, defined as a height-for-age standard deviation score (SDS) below -2 using the United Kingdom WHO references, by sex, index of multiple deprivation (IMD), ethnicity, and region. Geographic clustering of short stature was analysed using spatial analysis in SaTScan. The prevalence of short stature in England was 1.93% (95% confidence interval (CI) 1.92-1.94). Ethnicity adjusted spatial analyses showed geographic heterogeneity of short stature, with high prevalence clusters more likely in the North and Midlands, leading to 4-fold variation between local authorities (LAs) with highest and lowest prevalence of short stature. Short stature was linearly associated with IMD, with almost 2-fold higher prevalence in the most compared with least deprived decile (2.56% (2.53-2.59) vs. 1.38% (1.35-1.41)). There was ethnic heterogeneity: Short stature prevalence was lowest in Black children (0.64% (0.61-0.67)) and highest in Indian children (2.52% (2.45-2.60)) and children in other ethnic categories (2.57% (2.51-2.64)). Girls were more likely to have short stature than boys (2.09% (2.07-2.10) vs. 1.77% (1.76-1.78), respectively). Short stature prevalence declined over time, from 2.03% (2.01-2.05) in 2006-2010 to 1.82% (1.80-1.84) in 2016-2019. Short stature declined at all levels of area deprivation, with faster declines in more deprived areas, but disparities by IMD quintile were persistent. This study was conducted cross-sectionally at an area level, and, therefore, we cannot make any inferences about the individual causes of short stature. CONCLUSIONS: In this study, we observed a clear social gradient and striking regional variation in short stature across England, including a North-South divide. These findings provide impetus for further investigation into potential socioeconomic influences on height and the factors underlying regional variation.

The First Dorsal Metacarpal Artery Free Flap for Salvage of Nasal Reconstructions.

ABSTRACT: The first dorsal metacarpal artery free flap is widely known for its use as a pedicled flap in thumb and hand reconstruction; however, its potential for use as a free flap is less well known. We previously described successful use of the first dorsal metacarpal artery free flap for salvage of a subtotal nasal reconstruction. In this retrospective study, we have expanded our experience to 7 consecutive cases in which a FDMFF was utilized to salvage a nasal reconstruction. Single island flaps were used in 6 of 7 cases, in one case a double island configuration was utilized. Sites restored included the columella (5 patients), membranous septum (1 patient), and nasal sidewall (1 patient). Vascular repairs were to the angular artery and vein (2 patients) or the vascular pedicle of a prior free flap (5 patients). There were no flap failures or major complications. The dorsal hand donor sites were uniformly closed using full-thickness skin grafts. All of the salvage nasal reconstructions were brought to a successful completion. Donor site morbidity was minimal with no compromise in hand function noted. Owing to its thinness, consistent anatomy, ease of harvest, and minimal donor site morbidity, the FDMFF has proved to be a very useful flap for restoration of small, but critical, nasal defects arising during the course of nasal reconstruction.

Vitamin D receptor genotype influences risk of upper respiratory infection.

SNP in the vitamin D receptor (VDR) gene is associated with risk of lower respiratory infections. The influence of genetic variation in the vitamin D pathway resulting in susceptibility to upper respiratory infections (URI) has not been investigated. We evaluated the influence of thirty-three SNP in eleven vitamin D pathway genes (DBP, DHCR7, RXRA, CYP2R1, CYP27B1, CYP24A1, CYP3A4, CYP27A1, LRP2, CUBN and VDR) resulting in URI risk in 725 adults in London, UK, using an additive model with adjustment for potential confounders and correction for multiple comparisons. Significant associations in this cohort were investigated in a validation cohort of 737 children in Manchester, UK. In all, three SNP in VDR (rs4334089, rs11568820 and rs7970314) and one SNP in CYP3A4 (rs2740574) were associated with risk of URI in the discovery cohort after adjusting for potential confounders and correcting for multiple comparisons (adjusted incidence rate ratio per additional minor allele ≥1·15, P for trend ≤0·030). This association was replicated for rs4334089 in the validation cohort (P for trend=0·048) but not for rs11568820, rs7970314 or rs2740574. Carriage of the minor allele of the rs4334089 SNP in VDR was associated with increased susceptibility to URI in children and adult cohorts in the United Kingdom.

Current Practices in the Management of Postoperative Arterial Vasospasm in Microsurgery.

BACKGROUND: Postoperative microvascular arterial vasospasm is a rare clinical entity. There are no published management algorithms and also the pathophysiology of this phenomenon has not been elucidated. METHODS: An email survey of American Society for Reconstructive Microsurgery (ASRM) and World Society for Reconstructive Microsurgery (WSRM) members regarding their experiences with postoperative arterial vasospasm was conducted, returning 116 responses. A comprehensive literature search was conducted regarding the current body of knowledge on this entity. RESULTS: Sixty-five percent of respondents encountered cases where postoperative arterial vasospasm was clearly the cause of flap ischemia. The majority (62%) of surgeons believed a damaged segment of the artery was responsible for the spasm, with technical issues cited as the most likely cause. Sixty-two percent and 50% of surgeons used segmental resection of the recipient and donor vessels, respectively.Rated for proclivity to vasospasm, superficial inferior epigastric artery (SIEA) was the flap, superior thyroid artery (STA) the recipient vessel, and the lower limb the anatomic region most frequently mentioned.Most widely used management strategies were: topical vasodilators (91%), adventitial stripping (82%), and dilation of recipient and donor vessels (76%). Over 50% of surgeons used some type of vessel resection technique. CONCLUSIONS: When flap ischemia is encountered without mechanical issues or thrombus, vasospasm can be the root cause. Certain vessels (SIEA, STA) and anatomic regions (lower limb) pose a higher risk for this phenomenon. When a vessel is affected, it is common practice to excise the questionable segment and use a graft as needed. Vessel resection as part of a multimodal approach can result in a reasonable salvage rate.

Helpful advice and hidden expertize: pharmacy users' experiences of community pharmacy accessibility.

Background: In recent years community pharmacies have emerged as strategically important settings to deliver services aimed at promoting public health. In order to develop evidence-based approaches to public health interventions that exploit the unique accessibility of community pharmacies, it is important to determine how people experience care in this context. This study, therefore, aimed to describe how care is perceived and experienced in community pharmacies with particular focus on community pharmacy access. Methods: In-depth semi-structured interviews were used to explore the perceptions and experiences' of people using community pharmacies. Results: A total of 30 participants were interviewed. Themes specifically emerged in relation to community pharmacy access; these fell into four main categories: relationships; time; lack of awareness; and empowerment. Conclusions: The experience of developing a trusting relationship with the pharmacist is an important consideration in the context of community pharmacy accessibility. This could be an important consideration when a person uses a community pharmacy to access a public health service. There is also a perceived lack of awareness among the general public about the extended role of community pharmacy; this is a potential barrier toward people using them.

Nasal Unit Transplantation: A Cadaveric Anatomical Feasibility Study.

Background The science and technical acumen in the field of vascularized composite allotransplantation has progressed rapidly over the past 15 years, and transplantation of specialized units of the face, such as the nose, appears possible. No study to date has evaluated the technical feasibility of isolated nasal unit transplantation (NUT). In this study, we explore the anatomy and technical specifics of NUT. Methods In this study, four fresh cadaver heads were studied. Bilateral vascular pedicle dissections were performed in each cadaver. The facial artery was cannulated and injected with food dye under physiologic pressure in two cadavers, and with lead oxide mixture in two cadavers to evaluate perfusion territories supplied by each vascular pedicle. Results The facial artery and vein were found to be adequate pedicles for NUT. Divergent courses of the vein and artery were consistently identified, which made for a bulky pedicle with necessary inclusion of large amounts of subcutaneous tissue. In all cases, the artery remained superficial, while the vein coursed in a deeper plane, and demonstrated consistent anastomoses with the superior transverse orbital arcade. While zinc oxide injection of the facial artery demonstrated filling of the nasal vasculature across the midline, dye perfusion studies suggested that unilateral arterial inflow may be insufficient to perfuse contralateral NUT components. Discrepancies in these two studies underscore the limitations of nondynamic assessment of nutritive perfusion. Conclusion NUT based on the facial artery and facial vein is technically feasible. Angiosome evaluation suggests that bilateral pedicle anastomoses may be required to ensure optimal perfusion.

What works for whom in pharmacist-led smoking cessation support: realist review.

BACKGROUND: New models of primary care are needed to address funding and staffing pressures. We addressed the research question "what works for whom in what circumstances in relation to the role of community pharmacies in providing lifestyle interventions to support smoking cessation?" METHODS: This is a realist review conducted according to RAMESES standards. We began with a sample of 103 papers included in a quantitative review of community pharmacy intervention trials identified through systematic searching of seven databases. We supplemented this with additional papers: studies that had been excluded from the quantitative review but which provided rigorous and relevant additional data for realist theorising; citation chaining (pursuing reference lists and Google Scholar forward tracking of key papers); the 'search similar citations' function on PubMed. After mapping what research questions had been addressed by these studies and how, we undertook a realist analysis to identify and refine candidate theories about context-mechanism-outcome configurations. RESULTS: Our final sample consisted of 66 papers describing 74 studies (12 systematic reviews, 6 narrative reviews, 18 RCTs, 1 process detail of a RCT, 1 cost-effectiveness study, 12 evaluations of training, 10 surveys, 8 qualitative studies, 2 case studies, 2 business models, 1 development of complex intervention). Most studies had been undertaken in the field of pharmacy practice (pharmacists studying what pharmacists do) and demonstrated the success of pharmacist training in improving confidence, knowledge and (in many but not all studies) patient outcomes. Whilst a few empirical studies had applied psychological theories to account for behaviour change in pharmacists or people attempting to quit, we found no studies that had either developed or tested specific theoretical models to explore how pharmacists' behaviour may be affected by organisational context. Because of the nature of the empirical data, only a provisional realist analysis was possible, consisting of five mechanisms (pharmacist identity, pharmacist capability, pharmacist motivation and clinician confidence and public trust). We offer hypotheses about how these mechanisms might play out differently in different contexts to account for the success, failure or partial success of pharmacy-based smoking cessation efforts. CONCLUSION: Smoking cessation support from community pharmacists and their staff has been extensively studied, but few policy-relevant conclusions are possible. We recommend that further research should avoid duplicating existing literature on individual behaviour change; seek to study the organisational and system context and how this may shape, enable and constrain pharmacists' extended role; and develop and test theory.

INFECTIOUS DISEASE AND TOXICOLOGICAL MONITORING OF STRANDED PACIFIC HARBOR SEALS (PHOCA VITULINA RICHARDSI) IN COOK INLET AS SURROGATES FOR MONITORING ENDANGERED BELUGAS (DELPHINAPTERUS LEUCAS).

Pacific harbor seals ( Phoca vitulina richardsi) and belugas ( Delphinapterus leucas ) eat many of the same prey species, occupy the same geographic area, and demonstrate site fidelity in Cook Inlet, Alaska. Although most direct research involving the critically endangered belugas is currently prohibited, studying harbor seals may provide important information about this beluga population. In recent years, harbor seal populations in Alaska have declined for unknown reasons. As part of its stranding program, the Alaska SeaLife Center (ASLC) managed 59 cases of live and dead stranded harbor seals from Cook Inlet between 1997 and 2011. Animals were screened for a variety of diseases and contaminants of concern. Animals were negative by serology to the following diseases: avian influenza, canine distemper virus, dolphin morbillivirus, porpoise morbillivirus, Leptospira canicola, L. grippotyphosa, L. pomona, Neospora caninum , Sarcocystis neurona , and Toxoplasma gondii . Positive titers were found against Brucella spp., phocine distemper virus, seal herpesvirus-1, L. bratislava, L. hardjo, and L. icterohemorrhagiae. All titers were stable or declining except in one animal with an increasing titer for seal herpesvirus-1. Fecal pathogen screenings identified normal flora as well as stable or declining low levels of potentially pathogenic and opportunistic bacteria, though most were of little concern for seal health. In most animals, toxicology screening showed that the majority of tested contaminants were below detectable limits. The level of evidence of exposure to pathogens of concern was low in harbor seals. Although the infectious disease burden and contaminant levels in belugas in Cook Inlet cannot be definitively determined without direct testing, pathogen and contaminant exposure is expected to be similar to that found in harbor seals in this region, as the harbor seals and belugas share the habitat and food resources.

Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs).

RATIONALE: Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma. Trials of vitamin D in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking. OBJECTIVE: To conduct a randomised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI (coprimary outcomes). MEASUREMENTS AND METHODS: 250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year. Secondary outcomes included asthma control test and St George's Respiratory Questionnaire scores, fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum. Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes. MAIN RESULTS: 206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype. CONCLUSIONS: Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency. TRIAL REGISTRATION NUMBER: NCT00978315 (ClinicalTrials.gov).

Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution.

BACKGROUND: Cytochrome P450 CYP2C19 metabolizes a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated.We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese + Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models. RESULTS: Bifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19*2 and *3). REHH was high around CYP2C19*2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at -29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity < = 0.037, p <0.001. CONCLUSIONS: We found some evidence that the slow metabolizing allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices.

Associations between inflammatory and immune response genes and adverse respiratory outcomes following exposure to outdoor air pollution: a HuGE systematic review.

Variants of inflammatory and immune response genes have been associated with adverse respiratory outcomes following exposure to air pollution. However, the genes involved and their associations are not well characterized, and there has been no systematic review. Thus, we conducted a review following the guidelines of the Human Genome Epidemiology Network. Six observational studies and 2 intervention studies with 14,903 participants were included (2001-2010). Six studies showed at least 1 significant gene-pollutant interaction. Meta-analysis was not possible due to variations in genes, pollutants, exposure estimates, and reported outcomes. The most commonly studied genes were tumor necrosis factor α (TNFA) (n = 6) and toll-like receptor 4 (TLR4) (n = 3). TNFA -308G>A modified the action of ozone and nitrogen dioxide on lung function, asthma risk, and symptoms; however, the direction of association varied between studies. The TLR4 single-nucleotide polymorphisms rs1927911, rs10759931, and rs6478317 modified the association of particulate matter and nitrogen dioxide with asthma. The transforming growth factor ß1 (TGFB1) polymorphism -509C>T also modified the association of pollutants with asthma. This review indicates that genes controlling innate immune recognition of foreign material (TLR4) and the subsequent inflammatory response (TGFB1, TLR4) modify the associations of exposure to air pollution with respiratory function. The associations observed have biological plausibility; however, larger studies with improved reporting are needed to confirm these findings.

Maternal genotype and severe preeclampsia: a HuGE review.

Severe preeclampsia is a common cause of maternal and perinatal morbidity worldwide. The disease clusters in families; however, individual genetic studies have produced inconsistent results. We conducted a review to examine relationships between maternal genotype and severe preeclampsia. We searched the MEDLINE and Embase databases for prospective and retrospective cohort and case-control studies reporting associations between genes and severe preeclampsia. Four reviewers independently undertook study selection, quality assessment, and data extraction. We performed random-effects meta-analyses by genotype and predefined functional gene group (thrombophilic, vasoactive, metabolic, immune, and cell signalling). Fifty-seven studies evaluated 50 genotypes in 5,049 cases and 16,989 controls. Meta-analysis showed a higher risk of severe preeclampsia with coagulation factor V gene (proaccelerin, labile factor) (F5) polymorphism rs6025 (odds ratio = 1.90, 95% confidence interval: 1.42, 2.54; 23 studies, I(2) = 29%), coagulation factor II (thrombin) gene (F2) mutation G20210A (rs1799963) (odds ratio = 2.01, 95% confidence interval: 1.14, 3.55, 9 studies, I(2) = 0%), leptin receptor gene (LEPR) polymorphism rs1137100 (odds ratio = 1.75, 95% confidence interval: 1.15, 2.65; 2 studies, I(2) = 0%), and the thrombophilic gene group (odds ratio = 1.87, 95% confidence interval: 1.43, 2.45, I(2) = 27%). There were no associations with other gene groups. There was moderate heterogeneity between studies and potential for bias from poor-quality genotyping and inconsistent definition of phenotype. Further studies with robust methods should investigate genetic factors that might potentially be used to stratify pregnancies according to risk of complications.

HMOX1 gene promoter alleles and high HO-1 levels are associated with severe malaria in Gambian children.

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)(n) repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)(n) repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.

Interferon-γ ELISPOT as a biomarker of treatment efficacy in latent tuberculosis infection: a clinical trial.

RATIONALE: Biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (LTBI) and predict reactivation TB disease are urgently required. OBJECTIVES: To evaluate ESAT-6 and CFP-10 (EC) IFN-γ ELISPOT as a biomarker for treatment efficacy in LTBI. METHODS: This was a randomized, blinded, and placebo-controlled trial of INH in EC ELISPOT and Mantoux test positive participants. MEASUREMENTS AND MAIN RESULTS: Participants received a 6-month course of 900 mg INH twice weekly or a matching placebo. INH acetylator genotypes were determined and urine tested for INH metabolites to confirm adherence. The proportion of positive responders for CFP-10 and ESAT-6 between treatment arms was compared using mixed effects logistic regression models. A Tweedie (compound Poisson) model was fitted to allow for zero inflation and overdispersion of quantitative response. The proportions of EC ELISPOT-positive subjects reduced over time (P < 0.001) but did not differ by study arm (P = 0.36). Median spot-forming units for ESAT-6 and CFP-10 also declined significantly with time (P < 0.001) but did not differ by study arm (P = 0.74 and 0.71, respectively). There was no evidence of an interaction between acetylator status and INH treatment with respect to ELISPOT results over time. CONCLUSIONS: In contacts with LTBI, INH therapy plays no role in observed decreases in Mycobacterium tuberculosis antigen-specific T-cell responses over time. IFN-γ ELISPOT is probably not a useful biomarker of treatment efficacy in LTBI. Clinical trial registered with www.clinicaltrials.gov (NCT 00130325).