WHAT FACTORS CONTRIBUTE TO HOSPITAL VARIATION IN OBSTETRIC TRANSFUSION RATES?

Background & Objectives: To explore variation in red blood cell transfusion rates between hospitals, and the extent to which this can be explained. A secondary objective was to assess whether hospital transfusion rates are associated with maternal morbidity. Materials & Methods: Linked hospital discharge and birth data were used to identify births (N=279,145) in hospitals with at least 10 deliveries per annum between 2008-2010 in New South Wales, Australia. To investigate transfusion rates, a series of random effects multilevel logistic regression models were fitted, progressively adjusting for maternal, obstetric and hospital factors. Correlations between hospital transfusion and maternal, neonatal morbidity and readmission rates were assessed. Results: Overall, the transfusion rate was 1.4% (hospital range 0.6 to 2.9) across 89 hospitals. Adjusting for maternal casemix, reduced the variation between hospitals by 26%. Adjustment for obstetric interventions further reduced variation by 8% and a further 39% after adjustment for hospital type. At a hospital level, high transfusion rates were moderately correlated with maternal morbidity (0.56, p=0.01) and low Apgar scores (0.54, p=0.002), but not with readmission rates (0.18, p=0.28). Conclusion: Both casemix and practice differences contributed to the variation in transfusion rates between hospitals. The relationship between outcomes and transfusion rates was variable, however low transfusion rates were not associated with worse outcomes.Partnership Grant from the Australian National Health and Medical Research Council NHMRC (#1027262), the Australian Red Cross and the NSW Clinical Excellence Commission, NHMRC Senior Research Fellowship (#1021025). ARC Future Fellowship (#120100069)

WHAT FACTORS CONTRIBUTE TO HOSPITAL VARIATION IN OBSTETRIC TRANSFUSION RATES?

Background & Objectives: To explore variation in red blood cell transfusion rates between hospitals, and the extent to which this can be explained. A secondary objective was to assess whether hospital transfusion rates are associated with maternal morbidity. Materials & Methods: Linked hospital discharge and birth data were used to identify births (N=279,145) in hospitals with at least 10 deliveries per annum between 2008-2010 in New South Wales, Australia. To investigate transfusion rates, a series of random effects multilevel logistic regression models were fitted, progressively adjusting for maternal, obstetric and hospital factors. Correlations between hospital transfusion and maternal, neonatal morbidity and readmission rates were assessed. Results: Overall, the transfusion rate was 1.4% (hospital range 0.6 to 2.9) across 89 hospitals. Adjusting for maternal casemix, reduced the variation between hospitals by 26%. Adjustment for obstetric interventions further reduced variation by 8% and a further 39% after adjustment for hospital type. At a hospital level, high transfusion rates were moderately correlated with maternal morbidity (0.56, p=0.01) and low Apgar scores (0.54, p=0.002), but not with readmission rates (0.18, p=0.28). Conclusion: Both casemix and practice differences contributed to the variation in transfusion rates between hospitals. The relationship between outcomes and transfusion rates was variable, however low transfusion rates were not associated with worse outcomes.Partnership Grant from the Australian National Health and Medical Research Council NHMRC (#1027262), the Australian Red Cross and the NSW Clinical Excellence Commission, NHMRC Senior Research Fellowship (#1021025). ARC Future Fellowship (#120100069)

Heaviness, health and happiness: a cross-sectional study of 163 066 UK Biobank participants

<b>Background</b><p></p> Obesity is known to increase the risk of many diseases and reduce overall quality of life. This study examines the relationship with self-reported health (SRH) and happiness.<p></p> <b>Methods</b> <p></p>We conducted a cross-sectional study of the 163 066 UK Biobank participants who completed the happiness rating. The association between adiposity and SRH and happiness was examined using logistic regression. SRH was defined as good (excellent, good), or poor (fair, poor). Self-reported happiness was defined as happy (extremely, very, moderately) or unhappy (moderately, very, extremely). <p></p> <b>Results</b> <p></p>Poor health was reported by 44 457 (27.3%) participants. The adjusted ORs for poor health were 3.86, 2.92, 2.60 and 6.41 for the highest, compared with lowest, deciles of Body Mass Index, waist circumference, waist to hip ratio and body fat percent, respectively. The associations were stronger in men (p<0.001). Overall, 7511 (4.6%) participants felt unhappy, and only class III obese participants were more likely to feel unhappy (adjusted OR 1.33, 95% CI 1.15 to 1.53, p<0.001) but the associations differed by sex (p<0.001). Among women, there was a significant association between unhappiness and all levels of obesity. By contrast, only class III obese men had significantly increased risk and overweight and class I obese men were less likely to be unhappy. <p></p> <b>Conclusions</b><p></p>Obesity impacts adversely on happiness as well as health, but the association with unhappiness disappeared after adjustment for self-reported health, indicating this may be mediated by health. Compared with obese men, obese women are less likely to report poor health, but more likely to feel unhappy. <p></p&gt

Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma

© 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND licensePurpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective, multicenter case series. Participants A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency < 4×10−5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest–derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment

Gender differences in the association between adiposity and probable major depression: a cross-sectional study of 140,564 UK Biobank participants

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Previous studies on the association between adiposity and mood disorder have produced contradictory results, and few have used measurements other than body mass index (BMI). We examined the association between probable major depression and several measurements of adiposity: BMI, waist circumference (WC), waist-hip-ratio (WHR), and body fat percentage (BF%).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt;&lt;p&gt;&lt;/p&gt; We conducted a cross-sectional study using baseline data on the sub-group of UK Biobank participants who were assessed for mood disorder. Multivariate logistic regression models were used, adjusting for potential confounders including: demographic and life-style factors, comorbidity and psychotropic medication.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Of the 140,564 eligible participants, evidence of probable major depression was reported by 30,145 (21.5%). The fully adjusted odds ratios (OR) for obese participants were 1.16 (95% confidence interval (CI) 1.12, 1.20) using BMI, 1.15 (95% CI 1.11, 1.19) using WC, 1.09 (95% CI 1.05, 1.13) using WHR and 1.18 (95% CI 1.12, 1.25) using BF% (all p &#60;0.001). There was a significant interaction between adiposity and gender (p = 0.001). Overweight women were at increased risk of depression with a dose response relationship across the overweight (25.0-29.9 kg/m2), obese I (30.0-34.9 kg/m2), II (35.0-39.9 kg/m2) and III (≥40.0 kg/m2) categories; fully adjusted ORs 1.14, 1.20, 1.29 and 1.48, respectively (all p &#60; 0.001). In contrast, only obese III men had significantly increased risk of depression (OR 1.29, 95% CI 1.08, 1.54, p = 0.006).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusion&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Adiposity was associated with probable major depression, irrespective of the measurement used. The association was stronger in women than men. Physicians managing overweight and obese women should be alert to this increased risk

Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials

Background Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. Methods Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. Results We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. Conclusions There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers

Chronic multisite pain in major depression and bipolar disorder:cross-sectional study of 149,611 participants in UK Biobank

&lt;b&gt;Background&lt;/b&gt; Chronic pain has a strong association with major depressive disorder (MDD), but there is a relative paucity of studies on the association between chronic multisite pain and bipolar disorder (BD). Such studies are required to help elucidate the complex biological and psychological overlap between pain and mood disorders. The aim of this study is to investigate the relationship between chronic multisite pain and mood disorder across the unipolar-bipolar spectrum.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; We conducted a cross-sectional study of 149,611 UK Biobank participants. Self-reported depressive and bipolar features were used to categorise participants into MDD and BD groups and a non-mood disordered comparison group. Multinomial logistic regression was used to establish whether there was an association between extent of chronic pain (independent variable) and mood disorder category (dependent variable), using no pain as the referent category, and adjusting for a wide range of potential sociodemographic, lifestyle and comorbidity confounders.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; Multisite pain was significantly more prevalent in participants with BD and MDD, for example, 4-7 pain sites: BD 5.8%, MDD 4.5%, and comparison group 1.8% (p&#8805;0.001). A relationship was observed between extent of chronic pain and risk of BD and persisted after adjusting for confounders (relative to individuals with no chronic pain): 2-3 sites RRR of BD 1.84 (95% CI 1.61, 2.11); 4-7 sites RRR of BD 2.39 (95%CI 1.88, 3.03) and widespread pain RRR of BD 2.37 (95%CI 1.73, 3.23). A similar relationship was observed between chronic pain and MDD: 2-3 sites RRR of MDD 1.59 (95%CI 1.54, 1.65); 4?7 sites RRR of MDD 2.13 (95%CI 1.98, 2.30); widespread pain RRR of MDD 1.86 (95%CI 1.66, 2.08).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions &lt;/b&gt;Individuals who report chronic pain and multiple sites of pain are more likely to have MDD and are at higher risk of BD. These findings highlight an important aspect of comorbidity in MDD and BD and may have implications for understanding the shared neurobiology of chronic pain and mood disorders

The histone demethylase LSD1 regulates inner ear progenitor differentiation through interactions with Pax2 and the NuRD repressor complex

The histone demethylase LSD1 plays a pivotal role in cellular differentiation, particularly in silencing lineage-specific genes. However, little is known about how LSD1 regulates neurosensory differentiation in the inner ear. Here we show that LSD1 interacts directly with the transcription factor Pax2 to form the NuRD co-repressor complex at the Pax2 target gene loci in a mouse otic neuronal progenitor cell line (VOT-N33). VOT-N33 cells expressing a Pax2-response element reporter were GFP-negative when untreated, but became GFP positive after forced differentiation or treatment with a potent LSD inhibitor. Pharmacological inhibition of LSD1 activity resulted in the enrichment of mono- and di-methylation of H3K4, upregulation of sensory neuronal genes and an increase in the number of sensory neurons in mouse inner ear organoids. Together, these results identify the LSD1/NuRD complex as a previously unrecognized modulator for Pax2-mediated neuronal differentiation in the inner ear

Cataract-Causing Defect of a Mutant γ-Crystallin Proceeds through an Aggregation Pathway Which Bypasses Recognition by the α-Crystallin Chaperone

Background: The transparency of the eye lens depends upon maintenance of the native state of the γ- and β-crystallins, which is aided by the abundant chaperones αA- and αB-crystallin. Mature onset cataract, the leading cause of blindness worldwide, involves the polymerization of covalently damaged or partially unfolded crystallins into light-scattering aggregates. A number of single amino acid substitutions and truncations of γ-crystallins result in congenital cataract in both humans and mice, though in many cases the coupling between the protein alterations and the accumulation of aggregates is poorly defined. Methodology/Principal Findings: We have studied the aggregation properties and chaperone interactions of human γD-crystallin carrying substitutions of two buried core mutants, I90F and V75D, which cause congenital cataract in mice. The in vitro aggregation pathway competing with productive refolding was not altered by either substitution. Furthermore, this aggregation pathway for both mutant proteins–originating from a partially folded intermediate–was efficiently suppressed by αB-crystallin. Thus the cataract pathology was unlikely to be associated with a direct folding defect. The native state of wild-type human γD-crystallin exhibited no tendency to aggregate under physiological conditions. However both I90F and V75D native-like proteins exhibited slow (days) aggregation to high molecular weight aggregates under physiological conditions. The perturbed conformation of I90F was recognized and bound by both αA and αB chaperones. In contrast, the aggregation derived from the perturbed state of V75D was not suppressed by either chaperone, and the aggregating species were not bound by the chaperone. Conclusions/Significance: The cataract phenotype of I90F in mice may be due to premature saturation of the finite α- crystallin pool. The V75D aggregation pathway and its escape from chaperone surveillance and aggregation suppression can account for the congenital cataract pathology of this mutant. Failure of chaperone recognition may be an important source of pathology for many other protein folding defects.National Eye Institute (Grant no. EY015834 )National Institutes of Health (U.S.) (Grant no. GM17980

Ethnic differences in the association between depression and chronic pain:cross sectional results from UK Biobank

&lt;b&gt;Background&lt;/b&gt; Comorbid chronic pain and depression is a challenging dyad of conditions to manage in primary care and reporting has shown to vary by ethnic group. Whether the relationship between depression and chronic pain varies by ethnicity is unclear. This study aims to explore chronic pain and depression reporting across ethnic groups and examine whether this association differs, independently of potential confounding factors. &lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; Cross-sectional study of UK Biobank participants with complete data on chronic pain and probable lifetime history of depression, who reported their ethnic group as White, Asian/Asian British or Black/Black British. Chronic pain classification: present if participants had ≥ 1 site of body pain (up to seven sites or “pain all over the body” could be selected) that lasted ≥ 3 months; extent of chronic pain categories: 0, 1, 2–3, 4–7 sites or pain all over the body. Probable depression classification: an algorithm of low mood, anhedonia and help-seeking behaviour. Relationship between depression and presence/extent of chronic pain assessed using logistic/multinomial regression models (odds ratio (OR); relative risk ratio (RRR), 95 % confidence intervals), adjusted for sociodemographic, lifestyle, and morbidity factors; and a final adjustment for current depressive symptoms. &lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; The number of participants eligible for inclusion was 144,139: 35,703 (94 %) White, 4539 (3 %) Asian, and 3897 (3 %) Black. Chronic pain was less (40.5 %, 45.8 %, 45.0 %, respectively) and depression more (22.1 %, 12.9 %, 13.8 %, respectively) commonly reported in White participants than Asian and Black participants. Statistically significant associations between depression and presence/extent of chronic pain persisted following adjustment for potential confounding variables; this relationship was strongest for Black participants (presence of chronic pain: OR 1.86 (1.52, 2.27); RRR 1 site 1.49 (1.16, 1.91), 2–3 sites 1.98 (1.53, 2.56), 4–7 sites 3.23 (2.09, 4.99), pain all over the body 3.31 (2.05, 5.33). When current depressive symptoms were considered these relationships were attenuated. &lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; Chronic pain and depression reporting varies across ethnic groups. Differences in health seeking behaviour between ethnic groups may impact on the results reported. Clinicians, particularly in primary care, need to be aware of the cultural barriers within certain ethic groups to expressing concern over mood and to consider their approach accordingly