Effect of a multicomponent quality improvement strategy on sustained achievement of diabetes care goals and macrovascular and microvascular complications in South Asia at 6.5 years follow-up: Post hoc analyses of the CARRS randomized clinical trial.

BACKGROUND: Diabetes control is poor globally and leads to burdensome microvascular and macrovascular complications. We aimed to assess post hoc between-group differences in sustained risk factor control and macrovascular and microvascular endpoints at 6.5 years in the Center for cArdiovascular Risk Reduction in South Asia (CARRS) randomized trial. METHODS AND FINDINGS: This parallel group individual randomized clinical trial was performed at 10 outpatient diabetes clinics in India and Pakistan from January 2011 through September 2019. A total of 1,146 patients with poorly controlled type 2 diabetes (HbA1c ≥8% and systolic BP ≥140 mm Hg and/or LDL-cholesterol ≥130 mg/dL) were randomized to a multicomponent quality improvement (QI) strategy (trained nonphysician care coordinator to facilitate care for patients and clinical decision support system for physicians) or usual care. At 2.5 years, compared to usual care, those receiving the QI strategy were significantly more likely to achieve multiple risk factor control. Six clinics continued, while 4 clinics discontinued implementing the QI strategy for an additional 4-year follow-up (overall median 6.5 years follow-up). In this post hoc analysis, using intention-to-treat, we examined between-group differences in multiple risk factor control (HbA1c <7% plus BP <130/80 mm Hg and/or LDL-cholesterol <100 mg/dL) and first macrovascular endpoints (nonfatal myocardial infarction, nonfatal stroke, death, revascularization [angioplasty or coronary artery bypass graft]), which were co-primary outcomes. We also examined secondary outcomes, namely, single risk factor control, first microvascular endpoints (retinopathy, nephropathy, neuropathy), and composite first macrovascular plus microvascular events (which also included amputation and all-cause mortality) by treatment group and whether QI strategy implementation was continued over 6.5 years. At 6.5 years, assessment data were available for 854 participants (74.5%; n = 417 [intervention]; n = 437 [usual care]). In terms of sociodemographic and clinical characteristics, participants in the intervention and usual care groups were similar and participants at sites that continued were no different to participants at sites that discontinued intervention implementation. Patients in the intervention arm were more likely to exhibit sustained multiple risk factor control than usual care (relative risk: 1.77; 95% confidence interval [CI], 1.45, 2.16), p < 0.001. Cumulatively, there were 233 (40.5%) first microvascular and macrovascular events in intervention and 274 (48.0%) in usual care patients (absolute risk reduction: 7.5% [95% CI: -13.2, -1.7], p = 0.01; hazard ratio [HR] = 0.72 [95% CI: 0.61, 0.86]), p < 0.001. Patients in the intervention arm experienced lower incidence of first microvascular endpoints (HR = 0.68 [95% CI: 0.56, 0.83), p < 0.001, but there was no evidence of between-group differences in first macrovascular events. Beneficial effects on microvascular and composite vascular outcomes were observed in sites that continued, but not sites that discontinued the intervention. CONCLUSIONS: In urban South Asian clinics, a multicomponent QI strategy led to sustained multiple risk factor control and between-group differences in microvascular, but not macrovascular, endpoints. Between-group reductions in vascular outcomes at 6.5 years were observed only at sites that continued the QI intervention, suggesting that practice change needs to be maintained for better population health of people with diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01212328.

Cost-effectiveness of a multicomponent quality improvement care model for diabetes in South Asia: The CARRS randomized clinical trial.

OBJECTIVES: To assess the cost-effectiveness of a multicomponent strategy versus usual care in people with type 2 diabetes in South Asia. DESIGN: Economic evaluation from healthcare system and societal perspectives. SETTING: Ten diverse urban clinics in India and Pakistan. PARTICIPANTS: 1146 people with type 2 diabetes (575 in the intervention group and 571 in the usual care group) with mean age of 54.2 years, median diabetes duration: 7 years and mean HbA1c: 9.9% (85 mmol/mol) at baseline. INTERVENTION: Multicomponent strategy comprising decision-supported electronic health records and non-physician care coordinator. Control group received usual care. OUTCOME MEASURES: Incremental cost-effectiveness ratios (ICERs) per unit achievement in multiple risk factor control (HbA1c <7% (53 mmol/mol) and SBP <130/80 mmHg or LDLc <2.58 mmol/L (100 mg/dL)), ICERs per unit reduction in HbA1c, 5-mmHg unit reductions in systolic BP, 10-unit reductions in LDLc (mg/dl) (considered as clinically relevant) and ICER per quality-adjusted life years (QALYs) gained. ICERs were reported in 2020 purchasing power parity-adjusted international dollars (INT$). The probability of ICERs being cost-effective was considered depending on the willingness to pay (WTP) values as a share of GDP per capita for India (Int$ 7041.4) and Pakistan (Int$ 4847.6). RESULTS: Compared to usual care, the annual incremental costs per person for intervention group were Int$ 1061.9 from a health system perspective and Int$ 1093.6 from a societal perspective. The ICER was Int$ 10,874.6 per increase in multiple risk factor control, $2588.1 per one percentage point reduction in the HbA1c, and $1744.6 per 5 unit reduction in SBP (mmHg), and $1271 per 10 unit reduction in LDLc (mg/dl). The ICER per QALY gained was $33,399.6 from a societal perspective. CONCLUSIONS: In a trial setting in South Asia, a multicomponent strategy for diabetes care resulted in better multiple risk factor control at higher costs and may be cost-effective depending on the willingness to pay threshold with substantial uncertainty around cost-effectiveness for QALYs gained in the short term (2.5 years). Future research needs to confirm the long-term cost-effectiveness of intensive multifactorial intervention for diabetes care in diverse healthcare settings in LMICs.

X-ray Diffraction of Water in Polyvinylpyrrolidone.

PVP is a hydrophilic polymer commonly used as an excipient in pharmaceutical formulations. Here we have performed time-resolved high-energy X-ray scattering experiments on pellets of PVP at different humidity conditions for 1-2 days. A two-phase exponential decay in water sorption is found with a peak in the differential pair distribution function at 2.85 Å, which is attributed to the average (hydrogen bonded) carbonyl oxygen-water oxygen distance. Additional scattering measurements on powders with fixed compositions ranging from 2 to 12.3 wt % H2O were modeled with Empirical Potential Structure Refinement (EPSR). The models reveal approximately linear relations between the carbonyl oxygen-water oxygen coordination number (nOC-OW) and the water oxygen-water oxygen coordination number (nOW-OW) versus water content in PVP. A stronger preference for water-water hydrogen bonding over carbonyl-water bonding is found. At all the concentrations studied the majority of water molecules were found to be randomly isolated, but a wide distribution of coordination environments of water molecules is found within the PVP polymer strands at the highest concentrations. Overall, the EPSR models indicate a continuous evolution in structure versus water content with nOW-OW=1 occurring at ∼12 wt % H2O, i.e., the composition where, on average, each water molecule is surrounded by one other water molecule.

The prevalence of Schmorl's nodes in osteoporotic vs normal patients: a Middle Eastern population study.

The study was conducted to establish the association of Schmorl's nodes and osteoporosis in a Middle Eastern cohort. The prevalence of SN in this sample was 41.1%. It was most frequent in the lumbar spine typically solitary central lesions. Over 88% Schmorl's node cases were osteoporotic/osteopenic and only 11.6% normal. INTRODUCTION: This study aims to identify the prevalence of Schmorl's nodes (SNs) in a cohort of Omani nationals, and also to determine any relation between osteoporosis and Schmorl's nodes. METHODS: This retrospective observational study was conducted on Omani nationals. One thousand three hundred and forty-eight DEXA scan patients were included. Of these, 545 patients had complete X-rays and MRI scans that would help determine the SN status. The X-rays and sagittal, coronal, and axial T2-weighted MR images were used to identify the presence and exact location of the Schmorl nodes by one orthopedic trainee and confirmed by the senior author. The correlation of each parameter with the presence of SN was analyzed by the independent-samples T test and one-way ANOVA. RESULTS: The overall prevalence of SN in this population sample appeared to be 41.1%. Over 88% of the SN-positive cases were either osteopenic or frankly osteoporotic by the WHO definition. Vast majority of SNs (87.1%) occurred in the lumbar spine and were central in location and mostly solitary. Statistical analysis of the data revealed significant correlation between osteopenia or osteoporosis and the presence of SNs. CONCLUSIONS: The prevalence of SN in the sample of Omanis studied was 41.1% and was most frequently seen in older men in the lumbar spine. It is strongly associated with osteoporosis/osteopenia (88.4%) and frequently presents as solitary central lesions.

Effect of a multicomponent intervention on achievement and improvements in quality-of-care indices among people with Type 2 diabetes in South Asia: the CARRS trial.

AIMS: To evaluate whether and what combinations of diabetes quality metrics were achieved in a multicentre trial in South Asia evaluating a multicomponent quality improvement intervention that included non-physician care coordinators to promote adherence and clinical decision-support software to enhance physician practices, in comparision with usual care. METHODS: Using data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) trial, we evaluated the proportions of trial participants achieving specific and combinations of five diabetes care targets (HbA1c <53 mmol/mol [7%], blood pressure <130/80 mmHg, LDL cholesterol <2.6 mmol/L, non-smoking status, and aspirin use). Additionally, we examined the proportions of participants achieving the following risk factor improvements from baseline: ≥11-mmol/mol (1%) reduction in HbA1c , ≥10-mmHg reduction in systolic blood pressure, and/or ≥0.26-mmol/l reduction in LDL cholesterol. RESULTS: Baseline characteristics were similar in the intervention and usual care arms. Overall, 12.3%, 29.4%, 36.5%, 19.5% and 2.2% of participants in the intervention group and 16.2%, 38.3%, 31.6%, 11.3% and 0.8% of participants in the usual care group achieved any one, two, three, four or five targets, respectively. We noted sizeable improvements in HbA1c , blood pressure and cholesterol, and found that participants in the intervention group were twice as likely to achieve improvements in all three indices at 12 months that were sustained over 28 months of the study [relative risk 2.1 (95% CI 1.5,2.8) and 1.8 (95% CI 1.5,2.3), respectively]. CONCLUSIONS: The intervention was associated with significantly higher achievement of and greater improvements in composite diabetes quality care goals. However, among these higher-risk participants, very small proportions achieved the complete group of targets, which suggests that achievement of multiple quality-of-care goals is challenging and that other methods may be needed in closing care gaps.

Efficacy of vitamin D supplementation in major depression: A meta-analysis of randomized controlled trials.

Background: There is a need to develop and periodically evaluate new treatment strategies in major depression due to the high burden of nonresponse and inadequate response to antidepressants. Aim: We aimed to assess the effect of vitamin D supplementation on depression symptom scores among individuals with clinically diagnosed major depression. Materials and Methods: Electronic search of databases was carried out for published randomized controlled trials in English language, peer-reviewed journals from inception till August 2017. Outcome measure used for effect size calculation was depression symptom scores. Effect sizes for the trials were computed using standardized mean difference (Cohen's d), and I2 test was used to assess sample heterogeneity. Pooled mean effect sizes were derived using both fixed and random-effects model. Critical appraisal of studies was done using the Cochrane risk of bias assessment tool. Results: A total of four trials involving 948 participants were included in the study. In three trials, the intervention group received oral vitamin D supplementation whereas in one parenteral vitamin D was given. Pooled mean effect size for vitamin D supplementation on depressive symptom ratings in major depression was 0.58 (95% confidence interval, 0.45-0.72). The I2 value for heterogeneity was 0 suggesting low heterogeneity among studies. Egger plot intercept indicated minimal publication bias. Conclusion: Vitamin D supplementation favorably impacted depression ratings in major depression with a moderate effect size. These findings must be considered tentative owing to the limited number of trials available and inherent methodological bias noted in few of them.

Directional emission of rhodamine 6G on top of a silver grating.

We have observed directional spontaneous emission of rhodamine 6G dye deposited on top of a silver grating and found that its angular distribution patterns were very different in TE and TM polarizations. The latter was related to the dispersion curves determined based on the polarized reflection spectra measured at multiple incidence angles. The most intriguing finding of this Letter was a resonance, which was coupled with TE-polarized light and determined the characteristic double-crescent patterns in the TE-polarized spontaneous emission. This observation, as well as nearly similar resonance observed in TM polarization, was tentatively explained in terms of leaky waveguide modes supported by a film of dye-doped polymer.

Patient Self-reported quality of life assessment in Type 2 diabetes mellitus: A pilot study.

BACKGROUND: Quality of life (QoL) is an important outcome measure to assess the diabetic care and is increasingly replacing the traditional indicators of health. AIM: The aim is to evaluate the QoL in patients with type 2 diabetes mellitus (DM) using a third generation individualized QoL instrument like an audit of diabetes-dependent QoL (ADDQoL) questionnaire and to determine the predictors. MATERIALS AND METHODS: Patients who met the inclusion and exclusion criteria were recruited from a tertiary care hospital by convenience sampling. Sociodemographic and other relevant details were collected from the study patients, and ADDQoL questionnaire were administered to them. RESULTS: A total of 200 patients were included in the study among which 66% of patients had uncontrolled type 2 DM as suggested by their glycated hemoglobin (HbA1c) values. The mean QoL score was 0.07 (0.91) and diabetes-dependent QoL was -1.33 (0.58). Approximately 38% were associated with poor health-related QoL with a mean average weighted impact score of -0.51 (0.51). Most frequently affected life domain was the freedom to eat. A positive correlation was observed between QoL and gender, age, domicile, education status, occupation, family structure, duration of type 2 DM, HbA1c, insulin treatment, and the presence of comorbidities. CONCLUSION: The study highlights the impact of type 2 DM on QoL. Improving QoL of type 2 diabetic patients is important and knowledge of these preventable risk factors help to implement strategies to better management of type 2 DM and ultimately improve therapeutic outcome.

Effectiveness of a Multicomponent Quality Improvement Strategy to Improve Achievement of Diabetes Care Goals: A Randomized, Controlled Trial.

BACKGROUND: Achievement of diabetes care goals is suboptimal globally. Diabetes-focused quality improvement (QI) is effective but remains untested in South Asia. OBJECTIVE: To compare the effect of a multicomponent QI strategy versus usual care on cardiometabolic profiles in patients with poorly controlled diabetes. DESIGN: Parallel, open-label, pragmatic randomized, controlled trial. (ClinicalTrials.gov: NCT01212328). SETTING: Diabetes clinics in India and Pakistan. PATIENTS: 1146 patients (575 in the intervention group and 571 in the usual care group) with type 2 diabetes and poor cardiometabolic profiles (glycated hemoglobin [HbA1c] level ≥8% plus systolic blood pressure [BP] ≥140 mm Hg and/or low-density lipoprotein cholesterol [LDLc] level ≥130 mg/dL). INTERVENTION: Multicomponent QI strategy comprising nonphysician care coordinators and decision-support electronic health records. MEASUREMENTS: Proportions achieving HbA1c level less than 7% plus BP less than 130/80 mm Hg and/or LDLc level less than 100 mg/dL (primary outcome); mean risk factor reductions, health-related quality of life (HRQL), and treatment satisfaction (secondary outcomes). RESULTS: Baseline characteristics were similar between groups. Median diabetes duration was 7.0 years; 6.8% and 39.4% of participants had preexisting cardiovascular and microvascular disease, respectively; mean HbA1c level was 9.9%; mean BP was 143.3/81.7 mm Hg; and mean LDLc level was 122.4 mg/dL. Over a median of 28 months, a greater percentage of intervention participants achieved the primary outcome (18.2% vs. 8.1%; relative risk, 2.24 [95% CI, 1.71 to 2.92]). Compared with usual care, intervention participants achieved larger reductions in HbA1c level (-0.50% [CI, -0.69% to -0.32%]), systolic BP (-4.04 mm Hg [CI, -5.85 to -2.22 mm Hg]), diastolic BP (-2.03 mm Hg [CI, -3.00 to -1.05 mm Hg]), and LDLc level (-7.86 mg/dL [CI, -10.90 to -4.81 mg/dL]) and reported higher HRQL and treatment satisfaction. LIMITATION: Findings were confined to urban specialist diabetes clinics. CONCLUSION: Multicomponent QI improves achievement of diabetes care goals, even in resource-challenged clinics. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute and UnitedHealth Group.

Psychiatric disorders and obesity: A review of association studies.

BACKGROUND: Inconsistent evidence exists regarding the strength, direction, and moderators in the relationship between obesity and psychiatric disorders. AIM: This study aims to summarize the evidence on the association between psychiatric illness and obesity with particular attention to the strength and direction of association and also the possible moderators in each postulated link. MATERIALS AND METHODS: Systematic electronic searches of MEDLINE through PubMed, ScienceDirect, PsycINFO, and Google Scholar were carried out from inception till October 2016. Generated abstracts were screened for eligibility to be included in the review. Study designs that evaluated the strength of relationship between obesity and psychiatric disorders were included in the study. Quality assessment of included studies was done using the Newcastle-Ottawa checklist tool. RESULTS: From a total of 2424 search results, 21 eligible articles were identified and reviewed. These included studies on obesity and depression (n = 15), obesity and anxiety (four) and one each on obesity and personality disorders, eating disorder (ED), attention deficit hyperactivity disorder, and alcohol use. Maximal evidence existed for the association between depression and obesity with longitudinal studies demonstrating a bidirectional link between the two conditions. The odds ratios (ORs) were similar for developing depression in obesity (OR: 1.21-5.8) and vice versa (OR: 1.18-3.76) with a stronger association observed in women. For anxiety disorders, evidence was mostly cross-sectional, and associations were of modest magnitude (OR: 1.27-1.40). Among other disorders, obesity, and EDs appear to have a close link (OR: 4.5). Alcohol use appears to be a risk factor for obesity and not vice versa but only among women (OR: 3.84). CONCLUSION: Obesity and depression have a significant and bidirectional association. Evidence is modest for anxiety disorders and inadequate for other psychiatric conditions. Gender appears to be an important mediator in these relationships.

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus.

AIM: As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin. METHODS: We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke. RESULTS: The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies. CONCLUSION: These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus.

Decoding subject-driven cognitive states with whole-brain connectivity patterns.

Decoding specific cognitive states from brain activity constitutes a major goal of neuroscience. Previous studies of brain-state classification have focused largely on decoding brief, discrete events and have required the timing of these events to be known. To date, methods for decoding more continuous and purely subject-driven cognitive states have not been available. Here, we demonstrate that free-streaming subject-driven cognitive states can be decoded using a novel whole-brain functional connectivity analysis. Ninety functional regions of interest (ROIs) were defined across 14 large-scale resting-state brain networks to generate a 3960 cell matrix reflecting whole-brain connectivity. We trained a classifier to identify specific patterns of whole-brain connectivity as subjects rested quietly, remembered the events of their day, subtracted numbers, or (silently) sang lyrics. In a leave-one-out cross-validation, the classifier identified these 4 cognitive states with 84% accuracy. More critically, the classifier achieved 85% accuracy when identifying these states in a second, independent cohort of subjects. Classification accuracy remained high with imaging runs as short as 30-60 s. At all temporal intervals assessed, the 90 functionally defined ROIs outperformed a set of 112 commonly used structural ROIs in classifying cognitive states. This approach should enable decoding a myriad of subject-driven cognitive states from brief imaging data samples.

Population-based intervention for cardiovascular diseases related knowledge and behaviours in Asian Indian women.

BACKGROUND & OBJECTIVES: There is poor knowledge and behaviors regarding chronic diseases related nutritional and lifestyle factors among women in low income countries. To evaluate efficacy of a multilevel population-based intervention in improving knowledge and practices for related factors we performed a study in India. METHODS: Population based study among women 35-70 years was performed in four urban and five rural locations. Stratified sampling was performed and we enrolled 4624 (rural 2616, urban 2008) of eligible 8000 women (58%). Demographic details, medical history, diet, physical activity and anthropometry were recorded and blood hemoglobin, glucose and total cholesterol determined. Knowledge and behaviors regarding diet in chronic diseases were inquired in a randomly selected 100 women at each site (n = 900). A systematic multilevel population based intervention (using posters, handouts, street plays, public lectures, group lectures and focused group discussions) was administered over 6 months at each site. The questionnaire was re-administered at the end in random 100 women (n = 900) and differences determined. Descriptive statistics are reported. Comparison of parameters before and after intervention was assessed using Mann Whitney test. RESULTS: Prevalence (%) of chronic disease related lifestyles and risk factors in rural/urban women, respectively, was illiteracy in 63.6/29.4, smoking/tobacco use 39.3/18.9, high fat intake 93.6/93.4, high salt intake 18.2/12.6, low physical activity 59.5/70.2, overweight/obesity 22.5/45.6, truncal obesity 13.0/44.3, hypertension 31.6/48.2, hypercholesterolemia 13.5/27.7, and diabetes in 4.3/15.1 percent. Composite chronic diseases knowledge at baseline vs after intervention increased significantly in overall (32.0 vs 62.0), rural (29.0 vs 63.5) and urban (39.5 vs 60.5) groups (p < 0.001). Significant increase in knowledge regarding diet in hypertension, diabetes, heart disease and anemia as well as importance of dietary proteins, fats, fibres and fruits was observed (p < 0.001). There was insignificant change in most of the practices regarding intake of low fat, high protein, high fibre diet except sieving the flour which declined significantly (80.1 vs 53.6, p < 0.001). CONCLUSIONS: A short-term multilevel population-wide intervention among women in rural and urban locations in India increased chronic disease knowledge but failed to influence practices.

RNA- and ATAC-sequencing Reveals a Unique CD83+ Microglial Population Focally Depleted in Parkinson's Disease.

All brain areas affected in Parkinson's disease (PD) show an abundance of microglia with an activated morphology together with increased expression of pro-inflammatory cytokines, suggesting that neuroinflammation may contribute to the neurodegenerative process in this common and incurable disorder. We applied a single nucleus RNA- and ATAC-sequencing approach using the 10x Genomics Chromium platform to postmortem PD samples to investigate microglial heterogeneity in PD. We created a multiomic dataset using substantia nigra (SN) tissues from 19 PD donors and 14 non-PD controls (NPCs), as well as three other brain regions from the PD donors which are differentially affected in this disease: the ventral tegmental area (VTA), substantia inominata (SI), and hypothalamus (HypoTs). We identified thirteen microglial subpopulations within these tissues as well as a perivascular macrophage and a monocyte population, of which we characterized the transcriptional and chromatin repertoires. Using this data, we investigated whether these microglial subpopulations have any association with PD and whether they have regional specificity. We uncovered several changes in microglial subpopulations in PD, which appear to parallel the magnitude of neurodegeneration across these four selected brain regions. Specifically, we identified that inflammatory microglia in PD are more prevalent in the SN and differentially express PD-associated markers. Our analysis revealed the depletion of a CD83 and HIF1A- expressing microglial subpopulation, specifically in the SN in PD, that has a unique chromatin signature compared to other microglial subpopulations. Interestingly, this microglial subpopulation has regional specificity to the brainstem in non-disease tissues. Furthermore, it is highly enriched for transcripts of proteins involved in antigen presentation and heat-shock proteins, and its depletion in the PD SN may have implications for neuronal vulnerability in disease.

Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk.

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase ~50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Persistent Rhodococcus equi infection in a renal transplant patient: case report and review of the literature.

Rhodococcus equi is a pathogen that mainly causes infection in immunocompromised hosts. We report a case of relapsing R. equi pulmonary infection in a 57-year-old male renal transplant recipient who was treated with 12 months of antibiotics, adjunctive surgery, and a reduction in his immunosuppression. He suffered from relapsing disease, treatment-related complications, and ultimately died of Pneumocystis pneumonia. Case reports in the literature portray a good cure rate for transplant-related R. equi infections, with shorter durations of antibiotics. The case illustrates the difficulties in the management of R. equi infections. Forty cases from the literature were reviewed and compared in terms of epidemiology, location of infection, transplant type, immunosuppression used, treatment used, outcomes, and possible exposures.

Ferulic acid influences hepatic expression pattern of matrix metalloproteinases during alcohol and PUFA induced toxicity.

BACKGROUND AND OBJECTIVES: Alcoholic fibrosis and its end stage cirrhosis represent a major health problem worldwide. Liver fibrosis occurs when the rate of matrix synthesis exceeds matrix degradation. The degree of matrix remodeling depends on the ratio of active matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The objective of the present work was to study the influence of ferulic acid, a polyphenolic compound, on the expression of MMPs and TIMPs during alcohol and heated polyunsaturated fatty acid (delta PUFA) induced liver toxicity in male albino Wistar rats. MATERIALS AND METHODS: The levels of collagen, the activity of MMPs, the activity of TIMPs, the expression pattern of MMP were analyzed in liver. RESULTS: The matrix metalloproteinase expression was found to be significantly increased in alcohol as well as delta PUFA treated rats and significantly decreased in alcohol + delta PUFA treated rats. The levels of TIMPs and the collagen were significantly increased in alcohol, delta PUFA and alcohol + delta PUFA groups. Administration of ferulic acid significantly decreased the levels of collagen, TIMPs and positively modulated the expression of MMPs. CONCLUSIONS: Ferulic acid influences MMPs, TIMPs expression and effectively protects liver against alcohol and DPUFA induced liver fibrosis.

Transfusion-associated anxiety: Recognised and overcome in an adolescent child.

A 12-year-old boy presented to our palliative care cancer clinic with Ewing Sarcoma and anaemia in failure. Transfusion reactions were noted during several blood transfusions, which manifested as acute onset of breathlessness, mild chest pain, sweating, general discomfort, increased heart rate, respiratory rate, and blood pressure. All the possible causes of transfusion reaction were ruled out, other than transfusion-associated anxiety resembling transfusion reaction. In this case, adequate reassurance, counselling about the blood transfusion, distraction techniques, and the visual technique of masking the blood bag with black polythene foil helped overcome the patient's anxiety during the blood transfusion, and was uneventful henceforth. Since transfusion-associated anxiety is not an established and well-studied aspect of transfusion medicine yet, there is a need to have high clinical suspicion to recognise, assess, and forthwith prevent any such transfusion reactions without any delay.

Oral Levothyroxine is an Effective Option for Myxedema Coma: A Single-Centre Experience.

INTRODUCTION: Myxedema coma is an endocrine emergency with a very high mortality rate. As per the American Thyroid Association, initial thyroid hormone replacement for myxedema coma should be intravenous levothyroxine (LT4). However, in India, the availability of intravenous LT4 is limited. Often, crushed LT4 tablets are given through the enteral route when parenteral therapy is unavailable. No data or protocol is available for the administration of oral LT4 in myxedema coma. The aim of this study was to assess the effectiveness of oral LT4 in patients diagnosed with myxedema coma and to formulate a protocol for oral LT4 that can be used to guide the treatment of patients when intravenous LT4 is unavailable. METHODS: This retrospective observational study included patients diagnosed with myxedema coma between January 2010 and December 2019. The diagnosis of myxedema coma was based on the diagnostic scoring system for myxedema coma proposed by Popoveniuc et al. [Endocr Pract. 2014 Aug;20(8):808-17]. Dosing of oral LT4 was decided as per our institutional protocol. RESULTS: Fourteen patients (11 males and 3 females) with a median age of 67.5 years (range 11-82) with myxedema coma were included. All patients had central nervous system manifestations, and sepsis was the most common precipitating factor. The median myxedema score was 72.5 (normal ≤25), and the median length of hospital stay was 12 days (range 3-18). The oral LT4 regimen consisted of a loading dose of 300-500 µg, followed by taper over the next 3-5 days. With this regimen, 13 patients survived, and only 1 patient died. CONCLUSION: Oral LT4 is an effective treatment option for myxedema coma when intravenous LT4 is unavailable.