METTL17 is an Fe-S cluster checkpoint for mitochondrial translation.

Friedreich's ataxia (FA) is a debilitating, multisystemic disease caused by the depletion of frataxin (FXN), a mitochondrial iron-sulfur (Fe-S) cluster biogenesis factor. To understand the cellular pathogenesis of FA, we performed quantitative proteomics in FXN-deficient human cells. Nearly every annotated Fe-S cluster-containing protein was depleted, indicating that as a rule, cluster binding confers stability to Fe-S proteins. We also observed depletion of a small mitoribosomal assembly factor METTL17 and evidence of impaired mitochondrial translation. Using comparative sequence analysis, mutagenesis, biochemistry, and cryoelectron microscopy, we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+ cluster required for its stability. METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN-depleted cells. These findings suggest that METTL17 acts as an Fe-S cluster checkpoint, promoting translation of Fe-S cluster-rich oxidative phosphorylation (OXPHOS) proteins only when Fe-S cofactors are replete.

Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells.

Iron-sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC-containing proteins are the ferredoxin (FDX) family of electron carriers. Humans have two FDXs- FDX1 and FDX2, both of which are localized to mitochondria, and the latter of which is itself important for ISC synthesis. We have previously shown that hypoxia can eliminate the requirement for some components of the ISC biosynthetic pathway, but FDXs were not included in that study. Here, we report that FDX1, but not FDX2, is dispensable under 1% O2 in cultured human cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC-containing enzyme lipoyl synthase. While hypoxia can rescue the growth phenotype of either FDX1 or lipoyl synthase KO cells, lipoylation in these same cells is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work reveals the divergent roles of FDX1 and FDX2 in mitochondria, identifies a role for FDX1 in lipoate synthesis, and suggests that loss of lipoic acid can be tolerated under low oxygen tensions in cell culture.

Excess Mortality Risk Due to Heat Stress in Different Climatic Zones of India.

India is at a high risk of heat stress-induced health impacts and economic losses owing to its tropical climate, high population density, and inadequate adaptive planning. The health impacts of heat stress across climate zones in India have not been adequately explored. Here, we examine and report the vulnerability to heat stress in India using 42 years (1979-2020) of meteorological data from ERA-5 and developed climate-zone-specific percentile-based human comfort class thresholds. We found that the heat stress is usually 1-4 °C higher on heatwave (HW) days than on nonheatwave (NHW) days. However, the stress on NHW days remains considerable and cannot be neglected. We then showed the association of a newly formulated India heat index (IHI) with daily all-cause mortality in three cities - Delhi (semiarid), Varanasi (humid subtropical), and Chennai (tropical wet and dry), using a semiparametric quasi-Poisson regression model, adjusted for nonlinear confounding effects of time and PM2.5. The all-cause mortality risk was enhanced by 8.1% (95% confidence interval, CI: 6.0-10.3), 5.9% (4.6-7.2), and 8.0% (1.7-14.2) during "sweltering" days in Varanasi, Delhi, and Chennai, respectively, relative to "comfortable" days. Across four age groups, the impact was more severe in Varanasi (ranging from a 3.2 to 7.5% increase in mortality risk for a unit rise in IHI) than in Delhi (2.6-4.2% higher risk) and Chennai (0.9-5.7% higher risk). We observed a 3-6 days lag effect of heat stress on mortality in these cities. Our results reveal heterogeneity in heat stress impact across diverse climate zones in India and call for developing an early warning system keeping in mind these regional variations.

Social connections as determinants of cognitive health and as targets for social interventions in persons with or at risk of Alzheimer's disease and related disorders: a scoping review.

BACKGROUND: Social connections have a significant impact on health across age groups, including older adults. Loneliness and social isolation are known risk factors for Alzheimer's disease and related dementias (ADRD). Yet, we did not find a review focused on meta-analyses and systematic reviews of studies that had examined associations of social connections with cognitive decline and trials of technology-based and other social interventions to enhance social connections in people with ADRD. STUDY DESIGN: We conducted a scoping review of 11 meta-analyses and systematic reviews of social connections as possible determinants of cognitive decline in older adults with or at risk of developing ADRD. We also examined eight systematic reviews of technology-based and other social interventions in persons with ADRD. STUDY RESULTS: The strongest evidence for an association of social connections with lower risk of cognitive decline was related to social engagement and social activities. There was also evidence linking social network size to cognitive function or cognitive decline, but it was not consistently significant. A number of, though not all, studies reported a significant association of marital status with risk of ADRD. Surprisingly, evidence showing that social support reduces the risk of ADRD was weak. To varying degrees, technology-based and other social interventions designed to reduce loneliness in people with ADRD improved social connections and activities as well as quality of life but had no significant impact on cognition. We discuss strengths and limitations of the studies included. CONCLUSIONS: Social engagement and social activities seem to be the most consistent components of social connections for improving cognitive health among individuals with or at risk for ADRD. Socially focused technology-based and other social interventions aid in improving social activities and connections and deserve more research.

MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.

The mammalian mitochondrial proteome is under dual genomic control, with 99% of proteins encoded by the nuclear genome and 13 originating from the mitochondrial DNA (mtDNA). We previously developed MitoCarta, a catalogue of over 1000 genes encoding the mammalian mitochondrial proteome. This catalogue was compiled using a Bayesian integration of multiple sequence features and experimental datasets, notably protein mass spectrometry of mitochondria isolated from fourteen murine tissues. Here, we introduce MitoCarta3.0. Beginning with the MitoCarta2.0 inventory, we performed manual review to remove 100 genes and introduce 78 additional genes, arriving at an updated inventory of 1136 human genes. We now include manually curated annotations of sub-mitochondrial localization (matrix, inner membrane, intermembrane space, outer membrane) as well as assignment to 149 hierarchical 'MitoPathways' spanning seven broad functional categories relevant to mitochondria. MitoCarta3.0, including sub-mitochondrial localization and MitoPathway annotations, is freely available at http://www.broadinstitute.org/mitocarta and should serve as a continued community resource for mitochondrial biology and medicine.

Association between Acute Exposure to PM2.5 Chemical Species and Mortality in Megacity Delhi, India.

The association between daily all-cause mortality and short-term fine particulate matter (PM2.5) exposure is well established in the literature. However, association between acute exposure to PM2.5 chemical species and mortality is not well known, especially in developing countries like India. Here we examined associations between mortality and acute exposure to PM2.5 mass concentration and their 15 chemical components using data from 2013 to 2016 in megacity Delhi using a semiparametric quasi-Poisson regression model, adjusting for mean temperature, relative humidity, and long-term time trend as the major potential confounders. Mortality estimates were further checked for effect modification by sex, age group, and season. The subspecies of NO3-, NH4NO3, Cr, NH4+, EC, and OC showed a higher mortality impact than the total PM2.5 mass. Males were at higher risk from NO3-, SO42-, and their NH4+ compounds along with carcinogen Cr, whereas female group was at higher risk from EC and OC. Among all age groups, the elderly above 65 years were the most vulnerable group prone to mortality effects from maximum species. The major mortality risk from all hazardous species arose from their winter exposures. Our study provides the first evidence of association between acute exposure to PM2.5 chemical species and mortality anywhere in India and recommends similar studies in other regions so that sectoral mitigation emitting the most toxic species can be prioritized to maximize the health benefits.

Is there evidence for using anticonvulsants in the prevention and/or treatment of delirium among older adults?

OBJECTIVE: This systematic review aims to identify published randomized controlled trials (RCTs) that evaluated the use of anticonvulsants for the prevention and/or treatment of delirium among older adults. METHODS: A comprehensive search of databases: MEDLINE ALL (Ovid), Embase (Ovid), PsycINFO (Ovid), Web of Science Core Collection and Cochrane Central Register of Controlled was conducted. RESULTS: The search identified four RCTs that evaluated the use of anticonvulsants among older adults with delirium. One RCT evaluated the perioperative use of gabapentin among individuals undergoing spinal surgery and the development of postoperative delirium. One RCT evaluated the relationship between the use of perioperative gabapentin and the development of postoperative delirium among individuals undergoing spinal surgery and hip and knee arthroplasty. Two post-hoc analyses of RCTs evaluated the use of gabapentin and pregabalin among individuals undergoing total knee arthroplasty (TKA) and total hip arthroplasty (THA). The perioperative use of gabapentin reduced the incidence of postoperative delirium among older adults undergoing spinal surgery. The perioperative use of gabapentin did not reduce the rates, severity or duration of postoperative delirium among older adults who were undergoing spine and hip and knee arthroplasty. The perioperative use of gabapentin did not reduce the incidence or duration of postoperative delirium among older adults undergoing elective TKA. The perioperative use of pregabalin did not reduce the incidence of postoperative delirium among older adults undergoing elective THA. Gabapentin and pregabalin were well tolerated among the individuals enrolled in these trials. There were no RCTs identified that evaluated the use of other anticonvulsants for the prevention and/or treatment of delirium among older adults. CONCLUSIONS: Based on current evidence, the routine use of anticonvulsants for the prevention and/or treatment of delirium among older adults cannot be recommended.

Trust-Aware Routing Mechanism through an Edge Node for IoT-Enabled Sensor Networks.

Although IoT technology is advanced, wireless systems are prone to faults and attacks. The replaying information about routing in the case of multi-hop routing has led to the problem of identity deception among nodes. The devastating attacks against the routing protocols as well as harsh network conditions make the situation even worse. Although most of the research in the literature aim at making the IoT system more trustworthy and ensuring faultlessness, it is still a challenging task. Motivated by this, the present proposal introduces a trust-aware routing mechanism (TARM), which uses an edge node with mobility feature that can collect data from faultless nodes. The edge node works based on a trust evaluation method, which segregates the faulty and anomalous nodes from normal nodes. In TARM, a modified gray wolf optimization (GWO) is used for forming the clusters out of the deployed sensor nodes. Once the clusters are formed, each cluster's trust values are calculated, and the edge node starts collecting data only from trustworthy nodes via the respective cluster heads. The artificial bee colony optimization algorithm executes the optimal routing path from the trustworthy nodes to the mobile edge node. The simulations show that the proposed method exhibits around a 58% hike in trustworthiness, ensuring the high security offered by the proposed trust evaluation scheme when validated with other similar approaches. It also shows a detection rate of 96.7% in detecting untrustworthy nodes. Additionally, the accuracy of the proposed method reaches 91.96%, which is recorded to be the highest among the similar latest schemes. The performance of the proposed approach has proved that it has overcome many weaknesses of previous similar techniques with low cost and mitigated complexity.

Antidepressants for anxiety disorders in late-life: A systematic review.

BACKGROUND: Anxiety in late-life is a frequently encountered condition. The aim of this review is to systematically examine the efficacy and tolerability of antidepressants for treating anxiety disorders among older adults. METHODS: Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases PubMed, MEDLINE, EMBASE, and PsycINFO were performed in August 2018 and updated in October 2018 for randomized controlled trials (RCTs) evaluating antidepressants for late-life anxiety. The quality of each study was appraised using criteria developed by the Centre for Evidence-Based Medicine. RESULTS: Data from 12 papers describing 10 RCTs of antidepressants for late-life anxiety are included in this review. There were 2 studies each of sertraline, escitalopram, and duloxetine, and 1 study each of citalopram, paroxetine, venlafaxine, and imipramine. Across all trials, antidepressants were associated with a significant reduction in anxiety symptoms at the end of the study period. Limitations of the trials include a preponderance of generalized anxiety disorder and relatively less data on other anxiety disorders, and limited data on long-term use of antidepressants for anxiety. CONCLUSIONS: Antidepressants are beneficial for treating anxiety disorders in late life and are generally well tolerated.

Leaf concentrate fortification of antenatal protein-calorie snacks improves pregnancy outcomes.

Ready-to-eat (RTE) snacks are routinely distributed to pregnant women in India. These provide protein and calories but are low in micronutrients. We investigated whether RTE snacks fortified with leaf concentrate (LC) could improve pregnancy outcomes, including maternal haemoglobin (Hb) concentrations and infants' birthweight. This randomized controlled two-arm trial was conducted over 18 months: control (sRTE) group received standard 120 g RTE snack (102 g wheat flour, 18 g soya flour); intervention (lcRTE) group received the same snack fortified with 7 g LC. The study was conducted in Jaipur, Rajasthan, India. One hundred and five pregnant women aged 18-35 years were studied. Among the 105 women randomized to the two arms of the trial, 2 (1.9%) were severely anaemic (Hb ≤ 6.0 g/dL); 55 (53.4%) were moderately anaemic (Hb 6.0-8.0 g/dL); 34 (33.0%) were mildly anaemic (Hb 8.6-10.9 g/dL); and 12 (11.7%) were not anaemic (Hb ≥ 11.0 g/dL). In the final month of pregnancy, 83.0% (39/47) of women in the sRTE group had Hb ≤ 8.5 g/dL compared to 37.8% (17/45) in the lcRTE group (p<0.001). After adjustment for age and baseline Hb concentration, the difference in Hb concentrations due to LC fortification was 0.94 g/dL (95% CI 6.8-12.0; p<0.001). Mean live birthweight in the lcRTE group was 2,695 g (SD 325 g) compared to 2,545 g (297 g) in the sRTE group (p=0.02). The lcRTE snacks increased infants' birthweight by 133.7 g (95% CI 7.3-260.2; p=0.04) compared to sRTE snacks. Leaf concentrate fortification of antenatal protein-calorie snacks in a low-income setting in India protected against declining maternal haemoglobin concentrations and increased infants' birthweight when compared with unfortified snacks. These findings require replication in a larger trial.

Non-pharmacological interventions for traumatic brain injury.

Heterogeneity and variability of symptoms due to the type, site, age, sex, and severity of injury make each case of traumatic brain injury (TBI) unique. Considering this, a universal treatment strategy may not be fruitful in managing outcomes after TBI. Most of the pharmacological therapies for TBI aim at modifying a particular pathway or molecular process in the sequelae of secondary injury rather than a holistic approach. On the other hand, non-pharmacological interventions such as hypothermia, hyperbaric oxygen, preconditioning with dietary adaptations, exercise, environmental enrichment, deep brain stimulation, decompressive craniectomy, probiotic use, gene therapy, music therapy, and stem cell therapy can promote healing by modulating multiple neuroprotective mechanisms. In this review, we discussed the major non-pharmacological interventions that are being tested in animal models of TBI as well as in clinical trials. We evaluated the functional outcomes of various interventions with an emphasis on the links between molecular mechanisms and outcomes after TBI.

Measurement of change in angle kappa and its correlation with ocular biometric parameters pre- and post-phacoemulsification.

Purpose: Angle kappa has been considered to play a role in causing glare and haloes despite accurate centration during implantation of multifocal intraocular lenses following phacoemulsification. There is a lack of substantial data regarding whether angle kappa is a constant entity or changes following ocular surgical procedures. To answer this question, in this prospective observational study, we measured change in angle kappa following phacoemulsification, and studied the ocular biometric parameters correlating with this change. Methods: Angle kappa was measured objectively using synoptophore. Ocular Biometric parameters (Anterior Chamber Depth, Corneal White-to-White measurement, Lens Thickness, and Axial Length) using LenStar LS 900 Haag Streit Anterior Segment imaging system. outcome measures were a quantitative change in angle kappa from the preoperative value by one degree or more and observation of correlation between change in angle kappa and ocular biometric parameters. The Wilcoxin Signed Rank Test was used to determine the difference between pre-operative and post-operative measurements for angle kappa. A p-value of less than 0.05 was considered statistically significant. Pearson's correlation coefficient was employed to find the relationship between preoperative ocular biometric parameters and a change in angle kappa. A linear regression model was used to derive an equation considering corneal white-to-white measurement as the predictor and change in angle kappa as the outcome measure. Results: A significant change in angle kappa was recorded, and a significant correlation was found with corneal white to white measurements. This change could be predicted preoperatively, for a known corneal white to white measurement using the standard equation y=mx+c. Conclusion: This study explains the possible cause of dissatisfaction among seemingly ideal patients who undergo multifocal IOL implantation and the potential for better decision-making during patient selection for multifocal IOL implantation.

Genotype Study of Filaggrin Gene Loss-of-Function Mutations in Central India Population with Atopic Dermatitis and Ichthyosis Vulgaris.

Background: A genotype study of filaggrin gene loss-of-function mutations in central India can provide valuable insights into the prevalence and association of these mutations with atopic dermatitis (AD) and ichthyosis vulgaris (IV) in the region. The FLG R501X and 2282del4 are both genetic variants in the human gene called filaggrin gene (FLG), which encodes a protein that plays an important role in the formation and maintenance of the skin barrier. In this study, we determined the FLG R501X and 2282del4 variants association with both AD and IV in Central Indian populations. Materials and Methods: This case-control study was conducted in the Departments of Dermatology and Molecular and Virology Research and Diagnostic Laboratory at Sri Aurobindo Medical College and Post Graduate Institute, Indore (Madhya Pradesh). The study was approved by the Clinical Research and Ethics Committee. A total of 180 patients aged between 3 months - 60 years who attended the skin outpatient department between March-2021 to June-2022 were recruited in this study. Among them, 60 patients were in AD-group, 60 patients in IV-group, and 60 patients were in the healthy control group. Polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) was used in genotyping for FLG mutations (R501X and 2282del4). Results: The most common FLG mutations were R501X (31.6% and 23.3%) and 2282del4 (18.3% and 13.3%) in AD and IV patients with heterozygous (AT) genotype, respectively. The combined mutation (FLG R501X and 2282del4) association was 10% and 5% in the AD and IV groups with heterozygous (AT) genotype, respectively, and in all the patients of control group with wild genotype (AA). There were no significant (P = 0.09) associations found with 2282del14 genotype. Conclusion: The R501X mutation in the gene encoding filaggrin is one of the robust genetic associations of AD and IV. The 2282del4 polymorphism was marginally less as compared to R501X.

Cognitive Impairment in Older Adults: Epidemiology, Diagnosis, and Treatment.

Cognitive impairment and dementia affect dozens of millions of people worldwide and cause significant distress to patients and caregivers and a financial burden to families and health care systems. Careful history-taking, cognitive and physical examination, and supplemental neuroimaging and fluid-based biomarkers can accurately diagnose neurocognitive disorders. Management includes non-pharmacological and pharmacological treatments tailored to the etiology and to the individual.

Propranolol for the management of behavioural and psychological symptoms of dementia.

Propranolol is a ß-adrenergic antagonist used in the management of hypertension, cardiac arrhythmia, and angina pectoris. There is some evidence that propranolol may benefit individuals with behavioural and psychological symptoms of dementia (BPSD). A total of three case series, one randomized controlled trial and one case report were identified (from a literature search of three major databases: PubMed, Ovid, and Cochrane collaboration) that assessed the use of propranolol for the management of BPSD. From these studies, it appears that propranolol improves BPSD, including agitation and aggression. Propranolol is also well tolerated with no significant bradycardia or hypotension noted in these studies. Current data on the use of propranolol for the management of BPSD are limited in comparison to other pharmacological agents (atypical antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, and cannabinoids) and treatment modalities (repetitive transcranial magnetic stimulation and electroconvulsive therapy). The efficacy and safety of these treatments among individuals with BPSD has been evaluated in multiple controlled studies. In clinical practice, the routine use of propranolol among people with BPSD cannot be recommended at this time given the limited data. However, propranolol can be trialled among individuals with BPSD when symptoms have not responded adequately to other medications. Propranolol may also be used prior to embarking on trials of repetitive transcranial magnetic stimulation and electroconvulsive therapy among people with BPSD given the greater acceptance of this medication in the general population.

Keratoconus Classifier for Smartphone-based Corneal Topographer.

Keratoconus is a severe eye disease that leads to deformation of the cornea. It impacts people aged 10-25 years and is the leading cause of blindness in that demography. Corneal topography is the gold standard for keratoconus diag-nosis. It is a non-invasive process performed using expensive and bulky medical devices called corneal topographers. This makes it inaccessible to large populations, especially in the Global South. Low-cost smartphone-based corneal topographers, such as SmartKC, have been proposed to make keratoconus diagnosis accessible. Similar to medical-grade topographers, SmartKC outputs curvature heatmaps and quantitative metrics that need to be evaluated by doctors for keratoconus diagnosis. An auto-matic scheme for evaluation of these heatmaps and quantitative values can play a crucial role in screening keratoconus in areas where doctors are not available. In this work, we propose a dual-head convolutional neural network (CNN) for classifying keratoconus on the heatmaps generated by SmartKC. Since SmartKC is a new device and only had a small dataset (114 sam-ples), we developed a 2-stage transfer learning strategy-using historical data collected from a medical-grade topographer and a subset of SmartKC data-to satisfactorily train our network. This, combined with our domain-specific data augmentations, achieved a sensitivity of 91.3% and a specificity of 94.2%.