TDP-43 Nuclear Bodies: A NEAT Response to Stress?

In this issue of Molecular Cell, Wang et al. (2020) investigate stress-induced nuclear condensates of the RNA-binding protein TDP-43, uncovering a protective function for these granules as well as an RNA-dependent mechanism for scaffolding them.

Neuronal activity regulates Matrin 3 abundance and function in a calcium-dependent manner through calpain-mediated cleavage and calmodulin binding.

RNA-binding protein (RBP) dysfunction is a fundamental hallmark of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Abnormal neuronal excitability is also a conserved feature in ALS patients and disease models, yet little is known about how activity-dependent processes regulate RBP levels and functions. Mutations in the gene encoding the RBP Matrin 3 (MATR3) cause familial disease, and MATR3 pathology has also been observed in sporadic ALS, suggesting a key role for MATR3 in disease pathogenesis. Here, we show that glutamatergic activity drives MATR3 degradation through an NMDA receptor-, Ca2+-, and calpain-dependent mechanism. The most common pathogenic MATR3 mutation renders it resistant to calpain degradation, suggesting a link between activity-dependent MATR3 regulation and disease. We also demonstrate that Ca2+ regulates MATR3 through a nondegradative process involving the binding of Ca2+/calmodulin to MATR3 and inhibition of its RNA-binding ability. These findings indicate that neuronal activity impacts both the abundance and function of MATR3, underscoring the effect of activity on RBPs and providing a foundation for further study of Ca2+-coupled regulation of RBPs implicated in ALS and related neurological diseases.

Development of a specific live-cell assay for native autophagic flux.

Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating drugs is hampered by fundamental deficiencies in available methods for measuring autophagic activity or flux. To overcome these limitations, we introduced the photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of autophagy in living cells by optical pulse labeling. We used this assay to perform high-throughput drug screens of four chemical libraries comprising over 30,000 diverse compounds, identifying several clinically relevant drugs and novel autophagy modulators. A select series of candidate compounds also modulated autophagy flux in human motor neurons modified by CRISPR/Cas9 to express GFP-labeled LC3. Using automated microscopy, we tested the therapeutic potential of autophagy induction in several distinct neuronal models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In doing so, we found that autophagy induction exhibited discordant effects, improving survival in disease models involving the RNA binding protein TDP-43, while exacerbating toxicity in neurons expressing mutant forms of UBQLN2 and C9ORF72 associated with familial ALS/FTD. These studies confirm the utility of the Dendra2-LC3 assay, while illustrating the contradictory effects of autophagy induction in different ALS/FTD subtypes.

Effect of intravenous scopolamine before stapling, on postoperative nausea and vomiting in sleeve gastrectomy patients: a randomized controlled trial.

INTRODUCTION: Postoperative nausea and vomiting (PONV) is a common complication of general anesthesia that is further potentiated in an obese patient undergoing a bariatric procedure. Literature shows trials of myriad of drugs used alone or in combination, as a prophylaxis for this cohort of patients with varied benefits. OBJECTIVE: The objective of the study was to determine the effect of intravenous scopolamine prior to stapling in obese patients undergoing sleeve gastrectomy. METHODOLOGY: A prospective randomized controlled trial of consecutive patients with BMI > 35 kg/m2, undergoing laparoscopic sleeve gastrectomy (LSG) was performed after approval of the hospital's ethical committee, explanation of trial to the patients and obtaining a consent. Patients were randomized into two groups; patients receiving intravenous scopolamine just before firing first stapler (Group 1) and patients receiving placebo (Group 2). Primary outcome parameter was PONV. The secondary outcome parameters were use of rescue antiemetic and time to oral intake. RESULTS: In our study, out of 100 cases of patients undergoing LSG, 50 received scopolamine before stapling and 50 were assigned to the control group. There was no significant difference between the two groups in terms of PONV. The group receiving scopolamine had lesser use of rescue antiemetic but no difference in time to oral intake. CONCLUSION: We concluded that incidence of PONV in obese patients undergoing LSG is not affected by scopolamine. Further trials are needed to validate the results.

DDX3X and specific initiation factors modulate FMR1 repeat-associated non-AUG-initiated translation.

A CGG trinucleotide repeat expansion in the 5' UTR of FMR1 causes the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). This repeat supports a non-canonical mode of protein synthesis known as repeat-associated, non-AUG (RAN) translation. The mechanism underlying RAN translation at CGG repeats remains unclear. To identify modifiers of RAN translation and potential therapeutic targets, we performed a candidate-based screen of eukaryotic initiation factors and RNA helicases in cell-based assays and a Drosophila melanogaster model of FXTAS. We identified multiple modifiers of toxicity and RAN translation from an expanded CGG repeat in the context of the FMR1 5'UTR. These include the DEAD-box RNA helicase belle/DDX3X, the helicase accessory factors EIF4B/4H, and the start codon selectivity factors EIF1 and EIF5. Disrupting belle/DDX3X selectively inhibited FMR1 RAN translation in Drosophila in vivo and cultured human cells, and mitigated repeat-induced toxicity in Drosophila and primary rodent neurons. These findings implicate RNA secondary structure and start codon fidelity as critical elements mediating FMR1 RAN translation and identify potential targets for treating repeat-associated neurodegeneration.

Treatment of high-energy intra-articular fractures of tibia with Ilizarov external fixator in adults: A tertiary centre experience.

OBJECTIVE: To evaluate the clinical and radiological outcomes of the Ilizarov fixator in the proximal and distal fractures of the tibia. MATERIALS AND METHODOLOGY: This retrospective study reviewed 59 patients having high-energy intra-articular proximal and distal tibia fractures associated with severe soft-tissue injury, who were managed surgically with an Ilizarov fixator. The functional outcome was evaluated by using the American Orthopaedic Foot and Ankle Society scoring system (AOFAS) and the Association for the Study and Application of the Method of Ilizarov (ASAMI) Italy scoring system for tibial plateau and plafond fractures respectively. RESULTS: The most common mode of injury was road traffic accidents. According to the Gustilo open fracture classification, there were 16 patients with grade-I and nine with grade II open fractures. The remaining had closed fractures. According to the Schatzker classification of plateau fractures, 20 were graded as type V and 15 as type VI. According to the AO classification of plafond fractures, 12 fractures were graded as Type-43C1, 5 as Type-43C2, and 7 as Type-43C3. There was delayed union in 11 proximal and four distal fractures, all of which achieved union without additional bone grafting. In proximal fractures, according to AOFAS, out of 35, 26 had an acceptable while nine had a fair result. In distal fractures, according to ASAMI, out of 24, 16 had an acceptable while five had fair results. There were 192/448 wires in 58 patients with pin site infection; all were superficial and settled. Posttraumatic joint arthrosis was noted in nineteen. CONCLUSIONS: The postoperative clinical and radiological outcome indicated that primary Ilizarov external fixator is a reliable minimal invasive surgery and definitive fixation method for high-energy intra-articular proximal and distal tibial fractures with compromised soft-tissue. It also offers early stabilisation and painless joint motion without a high rate of complications.

Pregnancy in advanced age and the risk of stroke in postmenopausal women: analysis of Women's Health Initiative Study.

BACKGROUND: The incidence of pregnancy in advanced age among women is increasing because of the availability of assisted reproduction, although the long-term health consequences are not known. OBJECTIVE: The purpose of this study was to determine the effect of pregnancy in advanced age on the occurrence of cardiovascular events in a large cohort of postmenopausal women. STUDY DESIGN: We analyzed the data for 72,221 women aged 50-79 years who were enrolled in the observational arm of the Women's Health Initiative study. We determined the effect of pregnancy in advanced age (last pregnancy at age ≥40 year) on the risk of ischemic stroke, hemorrhagic stroke, myocardial infarction, and cardiovascular death over a mean period (±standard deviation) of 12±1 years using Cox Proportional Hazards analysis after adjusting for potential confounders. RESULTS: A total of 3306 of the 72,221 participants (4.6%) reported pregnancy in advanced age. Compared with pregnancy in normal age, the rates of ischemic stroke (3.8% vs 2.4%), hemorrhagic stroke (1.0% vs 0.5%), and cardiovascular death (3.9% vs 2.3%) were significantly higher among women with pregnancy in advanced age. In multivariate analysis, women with pregnancy in advanced age were 50% more likely to experience a hemorrhagic stroke (hazard ratio, 1.5; 95% confidence interval, 1.0-2.1) after adjustment for age, race/ethnicity, congestive heart failure, systolic blood pressure, atrial fibrillation, alcohol use, and cigarette smoking. There was no significant difference in the risk of ischemic stroke, myocardial infarction, and cardiovascular death among women with pregnancy in advanced age after adjustment for potential confounders. CONCLUSION: Women with pregnancy at an advanced age have a higher risk for hemorrhagic stroke in the postmenopausal period.

The kinetic characterization and X-ray structure of a putative benzoylformate decarboxylase from M. smegmatis highlights the difficulties in the functional annotation of ThDP-dependent enzymes.

Benzoylformate decarboxylase (BFDC) is a thiamin diphosphate (ThDP)-dependent enzyme that catalyzes the nonoxidative decarboxylation of benzoylformate. It is the penultimate enzyme in both the mandelate pathway and the d-phenylglycine degradation pathway. The ThDP-dependent Enzyme Engineering Database (TEED) now lists more than 800 sequences annotated as BFDCs, including one from Mycobacterium smegmatis (MsBFDC). However, there is no evidence that either pathway for benzoylformate formation exists in the M. smegmatis genome. Further, sequence alignments of MsBFDC with the well characterized enzyme isolated from Pseudomonas putida (PpBFDC) indicate that there will be active site substitutions in MsBFDC likely to reduce activity with benzoylformate. Taken together these data would suggest that the annotation is unlikely to be correct. To test this hypothesis the putative MsBFDC was cloned, expressed, purified, and the X-ray structure was solved to a resolution of 2.2Å. While showing no evidence for ThDP in the active site, the structure was very similar to that of PpBFDC. A number of 2-oxo acids were tested as substrates. For MsBFDC the K(m) value for benzoylformate was ~23 mM, nearly 100-fold greater than that of PpBFDC while the k(cat) value was reduced 60-fold. These values would suggest that benzoylformate is not the physiological substrate for this enzyme, and that annotation as a 2-oxo acid decarboxylase may be more appropriate.

Risk of Ischemic Stroke in High Risk Atrial Fibrillation Patients during Periods of Warfarin Discontinuation for Surgical Procedures.

IMPORTANCE: The risk of ischemic stroke during periods of warfarin discontinuation for surgical procedures is recognized but not well characterized. OBJECTIVE: The study aimed to quantitate the risk of ischemic stroke associated with high risk atrial fibrillation during periods of warfarin discontinuation. DESIGN, SETTING AND PARTICIPANTS: A cohort of 4,060 patients (mean follow-up period of 3.5 ± 1.3 years) were randomized into the Atrial Fibrillation Follow-Up Investigation of Rhythm Management study. Patients enrolled in the study had atrial fibrillation plus at least one other risk factor for stroke or death: age ≥65 years', systemic hypertension, diabetes mellitus, congestive heart failure, transient ischemic attack, prior stroke, left atrium >50 mm, left ventricular fractional shortening <25% or left ventricular ejection fraction <40%. EXPOSURE: Warfarin discontinuation for procedure. MAIN OUTCOME AND MEASURES: The association of warfarin discontinuation with the incidence of ischemic stroke using pooled repeated measures and Cox proportional hazards analyses during follow-up after adjusting for age, gender, obesity, diabetes mellitus, hypercholesterolemia, cigarette smoking and study period. RESULTS: Warfarin discontinuation for procedure occurred in 265 (0.4%) of the 71,355 person observations. Compared with those without warfarin discontinuation, the rate of ischemic stroke was higher among participants with surgery-related warfarin discontinuation (1.1% of 265 person observations vs. 0.2% of 71,090 person observations, p = 0.001). Warfarin discontinuation was associated with an increased risk for ischemic stroke (relative risk 5.8; 95% CI 1.8-18.4) after adjusting for potential confounders. The population-attributable risk associated with surgery-related warfarin discontinuation was estimated to be 23.1% (95% CI 15.2-30.9%) for ischemic stroke. CONCLUSIONS AND RELEVANCE: The 6-fold higher risk of ischemic stroke associated with discontinuation of warfarin for surgical procedures must be recognized in high risk atrial fibrillation patients and considered in the risk-benefit analysis of any procedure.

Outcomes of In-Hospital Cardiopulmonary Resuscitation in Maintenance Dialysis Patients.

Outcomes of cardiopulmonary resuscitation (CPR) in hospitalized patients with ESRD requiring maintenance dialysis are unknown. Outcomes of in-hospital CPR in these patients were compared with outcomes in the general population using data from the Nationwide Inpatient Sample (NIS; 2005-2011). The study population included all adults (≥ 18 years old) from the general population and those with a history of ESRD. Baseline characteristics, in-hospital complications, and discharge outcomes were compared between the two groups. The effects of in-hospital CPR on mortality, length of stay, hospitalization charges, and discharge destination were analyzed. Yearly national trends in survival, discharge to home, and length of stay were also examined using the Cochran-Armitage trend test. During the study period, 56,069 patients with ESRD underwent in-hospital CPR compared with 323,620 patients from the general population. Unadjusted in-hospital mortality rates were higher in patients with ESRD (73.9% versus 71.8%, P<0.001) on univariate analysis. After adjusting for age, gender, and potential confounders, patients with ESRD had higher odds of mortality (odds ratio, 1.24; 95% confidence interval, 1.11 to 1.3; P<0.001). Survival after CPR improved in the year 2011 compared with 2005 (31% versus 21%, P<0.001). Multivariate analysis also revealed that a greater proportion of patients with ESRD who survived were discharged to skilled nursing facilities. In conclusion, outcomes after in-hospital CPR are improving in patients with ESRD but remain worse than outcomes in the general population. Patients with ESRD who survive are more likely to be discharged to nursing homes.

Comparative Outcomes of Carotid Artery Stent Placement and Carotid Endarterectomy in Patients with Chronic Kidney Disease and End-Stage Renal Disease.

BACKGROUND: Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have a high prevalence of carotid artery stenosis but are excluded from clinical trials. We sought to determine the clinical characteristics and outcomes related to carotid endarterectomy (CEA) and carotid artery stenting (CAS) in ESRD and CKD patients. METHODS: We determined the frequency of CAS and CEA performed in patients with ESRD and CKD and associated in-hospital outcomes using data from the nationwide inpatient sample data files from 2005 to 2011. All the in-hospital outcomes were analyzed after adjusting for potential confounders using multivariate analysis. RESULTS: Of the 43,875 CKD patients who underwent CEA, 3888 (8.8%) were ESRD patients. After adjusting for age, gender, race, presence of hypertension, congestive heart failure (CHF), dyslipidemia, nicotine dependence and alcohol abuse, CEA performed in ESRD patients was associated with higher rates of in-hospital mortality (odds ratio [OR] 4.3, 95% confidence interval [CI] 2.1-9.0; P ≤ .0001) and moderate to severe disability (OR 1.4, 95% CI 1.1-1.8; P = .009). Of the 8148 CKD patients who underwent CAS, 693 (8.5%) were ESRD patients. After adjusting for age, gender, race/ethnicity, presence of dyslipidemia, CHF, and hypertension, CAS performed in ESRD patients was associated with higher rates of in-hospital mortality (OR 3.7, 95% CI 1.0-13.9; P = .04) and moderate to severe disability (OR 1.7, 95% CI 1.0-3.3; P = .05). CONCLUSIONS: Both CAS and CEA were associated with 4-folds higher odds of in-hospital mortality in ESRD patients and such observations raise concerns regarding the risk : benefit ratio of carotid revascularization in these patients.

Assessment Of Preanalytical Blood Sampling Errors In Clinical Settings.

BACKGROUND: Blood sampling is one of the common procedures done in every ward for disease diagnosis and prognosis. Daily hundreds of samples are collected from different wards but lack of appropriate knowledge of blood sampling by paramedical staff and accidental errors make the samples inappropriate for testing. Thus the need to avoid these errors for better results still remains. We carried out this research with an aim to determine the common errors during blood sampling; find factors responsible and propose ways to reduce these errors. METHODS: A cross sectional descriptive study was carried out at the Military and Combined Military Hospital Rawalpindi during February and March 2014. A Venous Blood Sampling questionnaire (VBSQ) was filled by the staff on voluntary basis in front of the researchers. The staff was briefed on the purpose of the survey before filling the questionnaire. Sample size was 228. Results were analysed using SPSS-21. RESULTS: When asked in the questionnaire, around 61.6% of the paramedical staff stated that they cleaned the vein by moving the alcohol swab from inward to outwards while 20.8% of the staff reported that they felt the vein after disinfection. On contrary to WHO guidelines, 89.6% identified that they had a habit of placing blood in the test tube by holding it in the other hand, which should actually be done after inserting it into the stand. Although 86% thought that they had ample knowledge regarding the blood sampling process but they didn't practice it properly. CONCLUSIONS: Pre analytical blood sampling errors are common in our setup. Eighty six percent participants though thought that they had adequate knowledge regarding blood sampling, but most of them were not adhering to standard protocols. There is a need of continued education and refresher courses.

Incident cancer in a cohort of 3,247 cancer diagnosis free ischemic stroke patients.

BACKGROUND: Subclinical cancer can manifest as a thromboembolic event and may be detected at a later interval in ischemic stroke survivors. We determined the rate of incident cancer and effect on cardiovascular endpoints in a large cohort of ischemic stroke survivors. METHODS: An analysis of 3,680 adults with nondisabling cerebral infarction who were followed for two years within the randomized, double-blinded VISP trial was performed. The primary intervention was best medical/surgical management plus a daily supplementation of vitamin B6, vitamin B12, and folic acid. We calculated age-adjusted rates of incidence of cancer among ischemic stroke survivors and standardized incidence ratios (SIR) with 95% confidence intervals (CI) based on comparison with age-adjusted rates in the general population. The significant variables from univariate analysis were entered in a Cox Proportional Hazards analysis to identify the association between various baseline factors and incident cancer after adjusting age, gender, and race/ethnicity. A logistic regression analysis evaluated the association between incident cancer and various endpoints including stroke, coronary heart disease, myocardial infarction, and death after adjusting age, gender, and race/ethnicity. RESULTS: A total of 3,247 patients (mean age ± SD of 66 ± 11; 2,013 were men) were cancer free at the time of enrollment. The incidence of new cancer was 0.15, 0.80, 1.2, and 2.0 per 100 patients at 1 month, 6 months, 1 year, and 2 years, respectively. The age-adjusted annual rate of cancer in patients with ischemic stroke was higher than in persons in the general population at 1 year (581.8/100,000 persons vs. 486.5/100,000 persons, SIR 1.2, 95% CI 1.16-1.24) and 2 years (1,301.7/100,000 vs. 911.5/100,000, SIR 1.4, 95% CI 1.2-1.6) after recruitment. There was a higher risk for death (odds ratio (OR) 3.1, 95% CI 1.8-5.4), and composite endpoint of stroke, coronary heart disease, and/or death (OR 1.4, 95% CI 1.0-2.2) among participants who developed incident cancer compared with those who were cancer free after adjusting for potential confounders. CONCLUSIONS: The annual rate of age-adjusted cancer incidence was higher among ischemic stroke patients compared with those in the general population. The odds of mortality were three folds higher among stroke survivors who developed incident cancer.

Readministration of intravenous alteplase in acute ischemic stroke patients: case series and systematic review.

BACKGROUND: Because of a high risk of recurrence of ischemic events, some patients may be candidates for readministration of intravenous (IV) alteplase. METHODS: We performed a single-center review and performed a search on PubMed from January 1966 to April 2014 for cases of readministration of alteplase. Favorable outcome was defined by a modified Rankin scale of 0 to 2 at discharge or at 1 to 3 months, improvement of greater than or equal to 4 points within 24 hours in the National Institutes of Health Stroke Scale score, or as a major improvement in the 72-hour National Institutes of Health Stroke Scale score. RESULTS: Four ischemic stroke patients underwent readministration of IV alteplase in our single-center review. None of the patients had symptomatic or asymptomatic intracerebral hemorrhage.In 2 patients, IV alteplase had been administered for a previous acute ischemic stroke, 6 and 49 days before the index ischemic stroke.At discharge, both patients had a favorable outcome. A total of 22 cases of readministration of alteplase for ischemic stroke have been reported in literature. The mean interval between the 2 administrations of alteplase was 428 days (range, 3 hours to 2280 days).Asymptomatic post thrombolytic intracerebral hemorrhages were seen in 2 patients. Favorable outcome was seen in 16 patients. A total of 9 underwent readministration of IV alteplase within 3 months for recurrent ischemic stroke. Favorable outcome was seen in 5 of these 9 patients. CONCLUSIONS: We observed a relatively high rate of favorable outcomes and a small rate of adverse events after readministration of IV alteplase in ischemic stroke patients.

A population-based study of the incidence and case fatality of non-aneurysmal subarachnoid hemorrhage.

BACKGROUND: There is a paucity of reliable and recent data regarding epidemiology of non-aneurysmal subarachnoid hemorrhage (SAH) in population-based studies. OBJECTIVES: To determine the incidence and case fatality of non-aneurysmal SAH using a population-based design. METHODS: Medical records and angiographic data of all patients from Stearns and Benton Counties, Minnesota, admitted with SAH were reviewed to identify incident case of non-aneurysmal SAH. Patients with a first-time diagnosis of non-aneurysmal SAH (based on two negative cerebral angiograms performed ≥7 days apart) between June 1st, 2012 and June 30th, 2014 were considered incident cases. We calculated the incidences of non-aneurysmal and aneurysmal SAH adjusted for age and sex based on the 2010 US census. RESULTS: Of the 18 identified SAH among 189,093 resident populations, five were true incident cases of non-aneurysmal SAH in this population-based study. The age- and sex-adjusted incidence of non-aneurysmal SAH were 2.8 [95 % confidence interval (CI) 2.7-2·9] per 100,000 person-years which was lower than aneurysmal SAH incidence of 7.2 [95 % CI 7.1-7.4] per 100,000 person-years. The age-adjusted incidence of non-aneurysmal SAH was similar (compared with aneurysmal SAH) among men; 3.2 [95 % CI 3.1-3.3] per 100,000 person-years versus 2.2 [95 % CI 2.1-2.3] per 100,000 person-years, respectively. The age-adjusted case fatality rate at 3 months was 4.46 and 0.0 per 100,000 persons for aneurysmal and non-aneurysmal SAH, respectively. CONCLUSIONS: The incidence of non-aneurysmal SAH was higher than previously reported particularly among men.

Incidental asymptomatic intracerebral hemorrhages and risk of subsequent cardiovascular events and cognitive decline in elderly persons.

BACKGROUND: The long-term prognostic significance of incidental asymptomatic intracerebral hemorrhages (aICHs) detected on brain magnetic resonance imaging (MRI) is unknown. METHODS: We analyzed clinical and baseline MRI data from the cohort of 5888 study participants aged 65 years and older recruited in the Cardiovascular Health Study from 4 US communities. We identified participants who had aICHs on MRI and selected 3 age- and gender-matched controls without aICHs. We compared the rates of cardiovascular events using logistic regression analysis including incident myocardial infarction, stroke, and death between those with and without aICHs. RESULTS: A total of 23 participants had aICHs classified as acute (n = 3), subacute (n = 4), and chronic (n = 16). During 14 years of follow-up, the risk of incident stroke (relative risk [RR], .6; 95% confidence interval [CI], .2-2.0), myocardial infarction (RR, .3; 95% CI, .06-1.4), and death (RR, .6; 95% CI, .2-1.7) was not different between participants with aICHs compared with controls (n = 69). There was no difference between the 2 groups with regard to time to ischemic stroke or time to death by Kaplan-Meier analysis. CONCLUSIONS: The risks of stroke, myocardial infarction, and death were similar between persons with aICHs detected on MRI compared with age- and gender-matched controls.

Worse in-hospital outcomes in patients with transient ischemic attack in association with acute kidney injury: analysis of nationwide in-patient sample.

OBJECTIVES: The effect of acute kidney injury (AKI) on outcomes of transient ischemic attack (TIA) is largely unknown. We wanted to determine the impact of AKI on the outcomes of patients admitted with TIA. METHODS: Data from all adult patients admitted to the U.S. hospitals between 2005 and 2011 with a primary discharge diagnosis of TIA and secondary diagnosis of AKI were included, using the nationwide in-patient dataset. The association of AKI with TIA-related mortality and discharge outcomes was analyzed after adjusting for potential confounders using logistic regression analysis. RESULTS: Of the 1,173,340 patients admitted with TIA, 45,974 (3.8%) had AKI. Dialysis was required in 29 (0.06%) patients. TIA patients with AKI had higher rates of moderate-to-severe disability (21.2 vs. 13.7%, p ≤ 0.0001), and in-hospital mortality (0.6 vs. 0.1%, p ≤ 0.0001) compared with those without AKI. After adjusting for age, sex, and potential confounders; TIA patients with AKI had higher odds of moderate-to-severe disability [OR 1.3, 95% CI 1.2-1.4, p < 0.0001] and death (OR 4.2, 95% CI 3.0-6.1, p < 0.0001). CONCLUSIONS: AKI in patients with TIA is associated with significantly higher rates of moderate-to-severe disability at discharge and in-hospital mortality compared with those without AKI.

Efficacy of Platelet-Rich Plasma in the Treatment of Diabetic Foot Ulcer.

Introduction Diabetic foot complications leading to limb amputations pose a global health concern. Platelet-rich plasma (PRP) gel has emerged as a promising method for ulcer healing, leveraging the growth factors provided by autologous PRP to enhance tissue healing. Therefore, we aimed to assess the frequency of the success of PRP therapy in the treatment of non-healing diabetic foot ulcers. Methods This quasi-experimental study, conducted in Lahore, Pakistan, from April 2021 to October 2022, enrolled 80 eligible individuals with non-responsive diabetic foot ulcers using a consecutive sampling technique. Inclusion criteria involved patients of both genders, aged 45-75 years, with unhealed diabetic foot ulcers, and exclusion criteria considered factors such as recurrent ulcers at the same site, smoking, and immunosuppressive or anticoagulant drug therapy. Baseline demographic details, ulcer measurements using a scale, and AutoCAD (Autodesk, Inc., San Francisco, California, United States)-assisted quantification of ulcer base were recorded. Autologous PRP injections were administered following strict aseptic protocols, with dressing changes and assessments performed at specified intervals over four weeks. Treatment success, defined as >90% healing after four weeks, was the primary outcome. Data analysis utilized IBM SPSS Statistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, United States), employing post-stratification chi-square and t-tests where appropriate for significant differences. Results The mean age of the patients was 60.40 ± 9.72 years, the mean duration of diabetes was 9.48 ± 2.21 years, and the mean ulcer duration was 11.41 ± 1.63 months. The treatment success rate was 63.7%. Age, gender, and disease duration showed no significant impact on treatment success. However, patients with a normal BMI and shorter ulcer duration exhibited a significantly higher success rate (p <0.001 and p = 0.002, respectively). Conclusions This study reaffirms the efficacy of PRP in treating non-healing diabetic foot ulcers, aligning with previous research. Despite a slightly lower success rate compared to literature reports, PRP remains a promising agent for managing diabetic foot ulcers.

Pathophysiology of Work-Related Neuropathies.

Work-related injuries are common. The cost of these injuries is around USD 176 billion to USD 350 billion a year. A significant number of work-related injuries involve nerve damage or dysfunction. Injuries may heal with full recovery of function, but those involving nerve damage may result in significant loss of function or very prolonged recovery. While many factors can predispose a person to suffer nerve damage, in most cases, it is a multifactorial issue that involves both intrinsic and extrinsic factors. This makes preventing work-related injuries hard. To date, no evidence-based guidelines are available to clinicians to evaluate work-related nerve dysfunction. While the symptoms range from poor endurance to cramping to clear loss of motor and sensory functions, not all nerves are equally vulnerable. The common risk factors for nerve damage are a superficial location, a long course, an acute change in trajectory along the course, and coursing through tight spaces. The pathophysiology of acute nerve injury is well known, but that of chronic nerve injury is much less well understood. The two most common mechanisms of nerve injury are stretching and compression. Chronic mild to moderate compression is the most common mechanism of nerve injury and it elicits a characteristic response from Schwann cells, which is different from the one when nerve is acutely injured. It is important to gain a better understanding of work-related nerve dysfunction, both from health and from regulatory standpoints. Currently, management depends upon etiology of nerve damage, recovery is often poor if nerves are badly damaged or treatment is not instituted early. This article reviews the current pathophysiology of chronic nerve injury. Chronic nerve injury animal models have contributed a lot to our understanding but it is still not complete. Better understanding of chronic nerve injury pathology will result in identification of novel and more effective targets for pharmacological interventions.

The Emotional Impact of Novel Coronavirus on Healthcare Workers: A Cross-Sectional Study.

Introduction Healthcare workers (HCWs) are the foundation of the response to a pandemic. Also termed as frontline workers, not only are they at a health risk but also suffer from emotional and psychological stress. Objective The objective of the study was to determine the emotional impact of novel coronavirus on healthcare workers. Methodology An online survey was completed by 239 HCWs from five different countries during the peak of the coronavirus disease 2019 (COVID-19) outbreak amidst the lockdown. Their feelings and concerns as well as the safety measures they adopted were identified. Results The response rate was 100%. Most of the respondents were 20-40 years old (85.36%) and working as doctors (73.22%); 44.77% were working at middle grade. The majority felt confused (19.67%), whereas others felt stressed/overworked (17.15%), unhappy (16.74%), scared (13.81%), nervous (13.39%), motivated (8.79%), and privileged (5.86%). A few felt pressurized to perform their duty (4.6%), and 69.87% felt that it was their moral obligation to continue their duty, whereas 13.39% felt administrative pressure for the same. Of the respondents, 53.97% feared transferring the disease to their family and friends, while others feared the lack of personal protective equipment (PPE) (13.39%). According to the majority of the respondents (25.94%), support from family and friends had them going through the crisis. The most common safety measure adopted by the HCWs was strict hand hygiene (43.51%). The HCWs (28.87%) felt that adequate and easy access to PPE would have helped them better during the pandemic. Conclusion Healthcare institutions are responsible for protecting HCWs or frontline workers during pandemics so they can continue with their duty. From our study, we have concluded that simple protective measures as uninterrupted and easy access to PPE would have helped HCWs deal with their stress and concerns.