Perceived impacts of COVID-19 responses on routine health service delivery in Liberia and UK: cross-country lessons for resilient health systems for equitable service delivery during pandemics

Background COVID-19 has caused significant public health problems globally, with catastrophic impacts on health systems. This study explored the adaptations to health services in Liberia and Merseyside UK at the beginning of the COVID-19 pandemic (January–May 2020) and their perceived impact on routine service delivery. During this period, transmission routes and treatment pathways were as yet unknown, public fear and health care worker fear was high and death rates among vulnerable hospitalised patients were high. We aimed to identify cross-context lessons for building more resilient health systems during a pandemic response. Methods he study employed a cross-sectional qualitative design with a collective case study approach involving simultaneous comparison of COVID-19 response experiences in Liberia and Merseyside. Between June and September 2020, we conducted semi-structured interviews with 66 health system actors purposively selected across different levels of the health system. Participants included national and county decision-makers in Liberia, frontline health workers and regional and hospital decision-makers in Merseyside UK. Data were analysed thematically in NVivo 12 software. Results There were mixed impacts on routine services in both settings. Major adverse impacts included diminished availability and utilisation of critical health services for socially vulnerable populations, linked with reallocation of health service resources for COVID-19 care, and use of virtual medical consultation in Merseyside. Routine service delivery during the pandemic was hampered by a lack of clear communication, centralised planning, and limited local autonomy. Across both settings, cross-sectoral collaboration, community-based service delivery, virtual consultations, community engagement, culturally sensitive messaging, and local autonomy in response planning facilitated delivery of essential services. Conclusion Our findings can inform response planning to assure optimal delivery of essential routine health services during the early phases of public health emergencies. Pandemic responses should prioritise early preparedness, with investment in the health systems building blocks including staff training and PPE stocks, address both pre-existing and pandemic-related structural barriers to care, inclusive and participatory decision-making, strong community engagement, and effective and sensitive communication. Multisectoral collaboration and inclusive leadership are essential

Analysis of Male Pheromones That Accelerate Female Reproductive Organ Development

Male odors can influence a female's reproductive physiology. In the mouse, the odor of male urine results in an early onset of female puberty. Several volatile and protein pheromones have previously been reported to each account for this bioactivity. Here we bioassay inbred BALB/cJ females to study pheromone-accelerated uterine growth, a developmental hallmark of puberty. We evaluate the response of wild-type and mutant mice lacking a specialized sensory transduction channel, TrpC2, and find TrpC2 function to be necessary for pheromone-mediated uterine growth. We analyze the relative effectiveness of pheromones previously identified to accelerate puberty through direct bioassay and find none to significantly accelerate uterine growth in BALB/cJ females. Complementary to this analysis, we have devised a strategy of partial purification of the uterine growth bioactivity from male urine and applied it to purify bioactivity from three different laboratory strains. The biochemical characteristics of the active fraction of all three strains are inconsistent with that of previously known pheromones. When directly analyzed, we are unable to detect previously known pheromones in urine fractions that generate uterine growth. Our analysis indicates that pheromones emitted by males to advance female puberty remain to be identified

Mapping the distribution of the Sunda pangolin (Manis javanica) within natural forest in Sabah, Malaysian Borneo

Pangolins are the most trafficked mammals in the world and are severely threatened by poaching the loss, degradation, and fragmentation of habitat. In Malaysian Borneo, conservation initiatives for the Sunda pangolin (Manis javanica) are hindered by a paucity of data on their distribution and population size. Using MaxEnt niche modelling and consolidated species location data, we projected the distribution of Sunda pangolins in Sabah. Additionally, we assessed the accessibility of their forest habitats to humans to understand potential threats. Our model indicated that, as of 2015, approximately half of Sabah’s land area (39,530 km²) is suitable for pangolins, with 43% in protected forests, 38% in production forests, and 19% outside of these areas. Alarmingly, our data suggest that nearly all (91%) of these suitable habitats are relatively easily accessible to poachers. Our findings provide a state-level baseline understanding of Sunda pangolin distribution and assess potential threats in Sabah. These can inform short- and long-term conservation management plans for pangolin to safeguard this critically endangered species

Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, abeta, and alzheimer's disease.

Background: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). Methodology/Principal findings: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association. Conclusions: Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Ass40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Qualitative study exploring lessons from Liberia and the UK for building a people-centred resilient health systems response to COVID-19

Introduction: COVID-19 has tested the resilience of health systems globally and exposed existing strengths and weaknesses. We sought to understand health systems COVID-19 adaptations and decision making in Liberia and Merseyside, UK. Methods: We used a people-centred approach to carry out qualitative interviews with 24 health decision-makers at national and county level in Liberia and 42 actors at county and hospital level in the UK (Merseyside). We explored health systems’ decision-making processes and capacity to adapt and continue essential service delivery in response to COVID-19 in both contexts. Results: Study respondents in Liberia and Merseyside had similar experiences in responding to COVID-19, despite significant differences in health systems context, and there is an opportunity for multidirectional learning between the global south and north. The need for early preparedness; strong community engagement; clear communication within the health system and health service delivery adaptations for essential health services emerged strongly in both settings. We found the Foreign, Commonwealth and Development Office (FCDO) principles to have value as a framework for reviewing health systems changes, across settings, in response to a shock such as a pandemic. In addition to the eight original principles, we expanded to include two additional principles: (1) the need for functional structures and mechanisms for preparation and (2) adaptable governance and leadership structures to facilitate timely decision making and response coordination. We find the use of a people-centred approach also has value to prompt policy-makers to consider the acceptance of service adaptations by patients and health workers, and to continue the provision of ‘routine services’ for individuals during health systems shocks. Conclusion: Our study highlights the importance of a people-centred approach, placing the person at the centre of the health system, and value in applying and adapting the FCDO principles across diverse settings

Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers

Contains fulltext : 118733.pdf (publisher's version ) (Open Access)Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27 x 10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve = 0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer

Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers . PLoS Genet . 9:e1003225. ht tp : / /dx .doi .org/10 .1371/ journal.pgen.1003225

Abstract Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P,2.27610 29 ) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn&apos;s disease, diabetes type 1, multiple sclerosis, Graves&apos; disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG Nglycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve = 0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer