Outcomes and treatment strategy of transcatheter aortic valve replacement with balloon-expandable valve in borderline-size annulus.

BACKGROUND: Candidates for transcatheter aortic valve replacement (TAVR) occasionally have a "borderline-size" aortic annulus between 2 transcatheter heart valve sizes, based on the manufacturer's sizing chart. Data on TAVR outcomes in such patients are limited. METHODS: We retrospectively reviewed 1816 patients who underwent transfemoral-TAVR with balloon-expandable valve (BEV) at our institution between 2016 and 2020. We divided patients into borderline and non-borderline groups based on computed tomography-derived annular measurements and compared outcomes. Furthermore, we analyzed procedural characteristics and compared outcomes between the smaller- and larger-valve strategies in patients with borderline-size annulus. RESULTS: During a median follow-up of 23.3 months, there was no significant difference between the borderline (n = 310, 17.0 %) and non-borderline (n = 1506) groups in mortality (17.3 % vs. 19.5 %; hazard ratio [HR] = 0.86 [95% CI = 0.62-1.20], p = 0.39), major adverse cardiac/cerebrovascular events (MACCE: death/myocardial infarction/stroke, 21.2 % vs. 21.5 %; HR = 0.97 [0.71-1.32], p = 0.85), paravalvular leak (PVL: mild 21.8 % vs. 20.6 %, p = 0.81; moderate 0 % vs. 1.2 %; p = 0.37), or mean gradient (12.9 ± 5.8 vs. 12.6 ± 5.2 mmHg, p = 0.69) at 1 year. There was no significant difference between the larger-(n = 113) and smaller-valve(n = 197) subgroups in mortality (23.7 % vs. 15.2 %; HR = 1.57 [0.89-2.77], p = 0.12), MACCE (28.1 % vs. 18.4 %; HR = 1.52 [0.91-2.54], p = 0.11), mild PVL (13.3 % vs. 25.9 %; p = 0.12), or mean gradient (12.3 ± 4.5 vs. 13.6 ± 5.3 mmHg, p = 0.16); however, the rate of permanent pacemaker implantation (PPI) was higher in the larger-valve subgroup (15.9 % vs. 2.6 %, p < 0.001). CONCLUSION: Borderline-size annulus is not associated with higher risk of adverse outcomes after BEV-TAVR. However, the larger-valve strategy for borderline-size annulus is associated with higher PPI risk, suggesting a greater risk of injury to the conduction system.

Multicomponent depolymerization of actin filament pointed ends by cofilin and cyclase-associated protein depends upon filament age.

Intracellular actin networks assemble through the addition of ATP-actin subunits at the growing barbed ends of actin filaments. This is followed by "aging" of the filament via ATP hydrolysis and subsequent phosphate release. Aged ADP-actin subunits thus "treadmill" through the filament before being released back into the cytoplasmic monomer pool as a result of depolymerization at filament pointed ends. The necessity for aging before filament disassembly is reinforced by preferential binding of cofilin to aged ADP-actin subunits over newly-assembled ADP-P i actin subunits in the filament. Consequently, investigations into how cofilin influences pointed-end depolymerization have, thus far, focused exclusively on aged ADP-actin filaments. Using microfluidics-assisted Total Internal Reflection Fluorescence (mf-TIRF) microscopy, we reveal that, similar to their effects on ADP filaments, cofilin and cyclase-associated protein (CAP) also promote pointed-end depolymerization of ADP-P i filaments. Interestingly, the maximal rates of ADP-P i filament depolymerization by CAP and cofilin together remain approximately 20-40 times lower than for ADP filaments. Further, we find that the promotion of ADP-P i pointed-end depolymerization is conserved for all three mammalian cofilin isoforms. Taken together, the mechanisms presented here open the possibility of newly-assembled actin filaments being directly disassembled from their pointed-ends, thus bypassing the slow step of P i release in the aging process.

Functional redundancy and formin-independent localization of tropomyosin isoforms in Saccharomyces cerevisiae.

Tropomyosin is an actin binding protein which protects actin filaments from cofilin-mediated disassembly. Distinct tropomyosin isoforms have long been hypothesized to differentially sort to subcellular actin networks and impart distinct functionalities. Nevertheless, a mechanistic understanding of the interplay between Tpm isoforms and their functional contributions to actin dynamics has been lacking. In this study, we present acetylation-mimic engineered mNeonGreen-Tpm fusion proteins that exhibit complete functionality as a sole copy, surpassing limitations of existing probes and enabling real-time dynamic tracking of Tpm-actin filaments in vivo. Using these functional Tpm fusion proteins, we find that both Tpm1 and Tpm2 indiscriminately bind to actin filaments nucleated by either formin isoform- Bnr1 and Bni1 in vivo, in contrast to the long-held paradigm of Tpm-formin pairing. We also show that Tpm2 can protect and organize functional actin cables in absence of Tpm1. Overall, our work supports a concentration-dependent and formin-independent model of Tpm-actin binding and demonstrates for the first time, the functional redundancy of the paralog Tpm2 in actin cable maintenance in S. cerevisiae.

Maternal prenatal depressive symptoms and child brain responses to affective touch at two years of age.

BACKGROUND: Touch is an essential form of mother-child interaction, instigating better social bonding and emotional stability. METHODS: We used diffuse optical tomography to explore the relationship between total haemoglobin (HbT) responses to affective touch in the child's brain at two years of age and maternal self-reported prenatal depressive symptoms (EPDS). Affective touch was implemented via slow brushing of the child's right forearm at 3 cm/s and non-affective touch via fast brushing at 30 cm/s and HbT responses were recorded on the left hemisphere. RESULTS: We discovered a cluster in the postcentral gyrus exhibiting a negative correlation (Pearson's r = -0.84, p = 0.015 corrected for multiple comparisons) between child HbT response to affective touch and EPDS at gestational week 34. Based on region of interest (ROI) analysis, we found negative correlations between child responses to affective touch and maternal prenatal EPDS at gestational week 14 in the precentral gyrus, Rolandic operculum and secondary somatosensory cortex. The responses to non-affective touch did not correlate with EPDS in these regions. LIMITATIONS: The number of mother-child dyads was 16. However, by utilising high-density optode arrangements, individualised anatomical models, and video and accelerometry to monitor movement, we were able to minimize methodological sources of variability in the data. CONCLUSIONS: The results show that maternal depressive symptoms during pregnancy may be associated with reduced child responses to affective touch in the temporoparietal cortex. Responses to affective touch may be considered as potential biomarkers for psychosocial development in children. Early identification of and intervention in maternal depression may be important already during early pregnancy.

National and regional prevalence of gestational diabetes mellitus in India: a systematic review and Meta-analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is frequently misdiagnosed during pregnancy. There is an abundance of evidence, but little is known regarding the regional prevalence estimates of GDM in India. This systematic review and meta-analysis aims to provide valuable insights into the national and regional prevalence of GDM among pregnant women in India. METHODS: We conducted an initial article search on PubMed, Scopus, Google Scholar, and ShodhGanga searches to identify quantitative research papers (database inception till 15th June,2022). This review included prevalence studies that estimated the occurrence of GDM across different states in India. RESULTS: Two independent reviewers completed the screening of 2393 articles, resulting in the identification of 110 articles that met the inclusion criteria, which collectively provided 117 prevalence estimates. Using a pooled estimate calculation (with an Inverse square heterogeneity model), the pooled prevalence of GDM in pregnant women was estimated to be 13%, with a 95% confidence interval (CI) ranging from 9 to 16%.. In India, Diabetes in Pregnancy Study of India (DIPSI) was the most common diagnostic criteria used, followed by International Association of Diabetes and Pregnancy Study Groups (IADPSG) and World Health Organization (WHO) 1999. It was observed that the rural population has slightly less prevalence of GDM at 10.0% [6.0-13.0%, I2=96%] when compared to the urban population where the prevalence of GDM was 12.0% [9.0-16.0%, I2 = 99%]. CONCLUSIONS: This review emphasizes the lack of consensus in screening and diagnosing gestational diabetes mellitus (GDM), leading to varied prevalence rates across Indian states. It thoroughly examines the controversies regarding GDM screening by analyzing population characteristics, geographic variations, diagnostic criteria agreement, screening timing, fasting vs. non-fasting approaches, cost-effectiveness, and feasibility, offering valuable recommendations for policy makers. By fostering the implementation of state-wise screening programs, it can contribute to improving maternal and neonatal outcomes and promoting healthier pregnancies across the country.

Intracardiac Thrombus in COVID-19 Inpatients: A Nationwide Study of Incidence, Predictors, and Outcomes.

COronaVIrus Disease-2019 (COVID-19) is associated with a hypercoagulable state. Intracardiac thrombosis is a potentially serious complication but has seldom been evaluated in COVID-19 patients. We assessed the incidence, associated factors, and outcomes of COVID-19 patients with intracardiac thrombosis. In 2020, COVID-19 inpatients were identified from the National Inpatient Sample (NIS) database. Data on clinical characteristics, intracardiac thrombosis, and adverse outcomes were collected. Multivariable logistic regression was used to identify factors associated with intracardiac thrombosis, in-hospital mortality, and morbidities. In 2020, 1,683,785 COVID-19 inpatients (mean age 63.8 years, 32.2% females) were studied. Intracardiac thrombosis occurred in 0.10% (1830) of cases. In-hospital outcomes included 13.2% all-cause mortality, 3.5% cardiovascular mortality, 2.6% cardiac arrest, 4.4% acute coronary syndrome (ACS), 16.1% heart failure, 1.3% stroke, and 28.3% acute kidney injury (AKI). Key factors for intracardiac thrombosis were congestive heart failure history and coagulopathy. Intracardiac thrombosis independently linked to higher risks of all-cause mortality (odds ratio [OR]: 3.32 (2.42-4.54)), cardiovascular mortality (OR: 2.95 (1.96-4.44)), cardiac arrest (OR: 2.04 (1.22-3.43)), ACS (OR: 1.62 (1.17-2.22)), stroke (OR: 3.10 (2.11-4.56)), and AKI (OR: 2.13 (1.68-2.69)), but not heart failure. While rare, intracardiac thrombosis in COVID-19 patients independently raised in-hospital mortality and morbidity risks.

Gallbladder carcinoma presenting with disseminated bony metastasis.

Gallbladder cancer (GBC) is the 23rd most common cancer worldwide and one of the three leading cancers in North and Northeast India. GBC has inferior outcomes due to its advanced presentation and poor response to chemotherapy. The approximate 5-year survival rate for metastatic GBC is less than 5%, with a median survival of around 6 months. Distant metastases from GBC to the bones happen in the later part of the natural history of the disease. Presentation with bony metastasis is infrequent, and less than 25 cases have been reported. Our case was an elderly man in his 70s who presented with back pain and, on workup, was detected to have adenocarcinoma of the gall bladder with disseminated lytic bony metastasis without any visceral metastasis. This case describes the natural history of such cases and discusses the role of bone scan or fluorodeoxyglucose positron emission tomography in the workup for GBC.

Extragonadal Nongestational Choriocarcinoma With a Widespread Metastasis in a Young Female: A Case Report and Literature Analysis With a Focus on Unmet Needs.

Choriocarcinoma is a highly aggressive malignant tumor that occurs due to the formation of an abnormal trophoblast. Choriocarcinoma is classified into gestational (GC) and nongestational (NGC) subtypes. The majority of nongestational diseases are limited to ovaries. Extragonadal NGC is a sporadic occurrence and a diagnostic and therapeutic dilemma. Here, we present a young 24-year-old female who presented with a widespread metastatic disease to the brain, bilateral kidneys, lungs, liver, pancreas, and small bowel. She was diagnosed with extragonadal NGC, probably originating from her kidneys. She responded poorly to standard first-, second-, and third-line chemotherapies. Detailed literature analysis with various aspects of pathogenesis, diagnostic criteria, clinical presentation, and treatment options are discussed. There is an unmet need for further research and consensus on many aspects of this rare disease.

Cyclase-associated protein is a pro-formin anti-capping processive depolymerase of actin barbed and pointed ends.

Cellular actin networks display distinct assembly and disassembly dynamics resulting from multicomponent reactions occurring primarily at the two ends and the sides of actin filaments [1-3]. While barbed ends are considered the hotspot of actin assembly [4], disassembly is thought to primarily occur via reactions on filament sides and pointed ends [3, 5-11]. Cyclase-associated protein (CAP) has emerged as the main protagonist of actin disassembly and remodeling - it collaborates with cofilin to increase pointed-end depolymerization by 300-fold [6, 7], promotes filament "coalescence" in presence of Abp1 [12], and accelerates nucleotide exchange to regenerate monomers for new rounds of assembly [13-15]. CAP has also been reported to enhance cofilin-mediated severing [16, 17], but these claims have since been challenged [7]. Using microfluidics-assisted three-color single-molecule imaging, we now reveal that CAP also has important functions at filament barbed ends. We reveal that CAP is a processive barbed-end depolymerase capable of tracking both ends of the filament. Each CAP binding event leads to removal of about 5,175 and 620 subunits from the barbed and pointed ends respectively. We find that the WH2 domain is essential, and the CARP domain is dispensable for barbed-end depolymerization. We show that CAP co-localizes with barbed-end bound formin and capping protein, in the process increasing residence time of formin by 10-fold and promoting dissociation of CP by 4-fold. Our barbed-end observations combined with previously reported activities of CAP at pointed ends and sides, firmly establish CAP as a key player in actin dynamics.

Upfront debulking surgery or delayed surgery after neoadjuvant chemotherapy for advanced-stage epithelial ovarian cancer: Comparison of survival from a noncancer center in India.

BACKGROUND: In advanced-stage epithelial ovarian cancer (EOC) standard of care is upfront debulking surgery (UDS) followed by adjuvant chemotherapy. Interval debulking surgery after neoadjuvant chemotherapy(NACT-IDS) is a reasonable alternative. METHODS: This study was a retrospective review of patients of Stage III/IV EOC treated either by UDS or NACT-IDS between January 2016 and December 2018 to report the comparison of progression-free survival(PFS) and overall survival(OS) of patients with advanced-stage EOC treated with either UDS or NACT-IDS. RESULTS: Out of 50 patients, 19 (38%) underwent UDS, and 31 (62%) received NACT. The mean follow-up duration was 27.7 months. No gross residual disease was achieved in 52.6% of the UDS group and in 70.4% of the NACT-IDS group. The median PFS of 20 and 30 months was observed in the UDS and NACT-IDS groups, respectively (log-rank P = 0.054). The median OS was 36 months in the NACT-IDS group and could not be reached in the UDS group (log-rank P = 0.329). Only residual disease was significantly associated with survival (hazards ratio 3.03, 95% confidence interval: 1.19-7.74) on multivariate Cox regression analysis. CONCLUSIONS: In advanced-stage EOC, the survival outcomes of NACT-IDS are comparable with those of UDS. Apart from the patient-specific parameters, the decision for UDS or NACT-IDS should take in account the expertise of the surgeon and the institutional capacity as a whole.

Large Urethral Diverticular Calculus Clinically Mimicking a Metastatic Deposit in a Case of Ovarian Mass.

Calculus in the urethra of the female is very unusual. The patient remains asymptomatic or uncommonly presents with symptoms of dysuria, post-void urinary dribbling, and dyspareunia. If asymptomatic, it can be diagnosed incidentally on gynecological examination. Being hard in consistency, it may mimic metastatic lesion. We present a case of a female who presented to us for management of ovarian mass. On routine examination there was a hard mass in her vagina which was suspected to be a metastatic lesion. This mass on evaluation came out to be a urethral diverticulum with a large calculus. Very large urethral calculus are a very rare presentation in a female.

Mechanisms of actin disassembly and turnover.

Cellular actin networks exhibit a wide range of sizes, shapes, and architectures tailored to their biological roles. Once assembled, these filamentous networks are either maintained in a state of polarized turnover or induced to undergo net disassembly. Further, the rates at which the networks are turned over and/or dismantled can vary greatly, from seconds to minutes to hours or even days. Here, we review the molecular machinery and mechanisms employed in cells to drive the disassembly and turnover of actin networks. In particular, we highlight recent discoveries showing that specific combinations of conserved actin disassembly-promoting proteins (cofilin, GMF, twinfilin, Srv2/CAP, coronin, AIP1, capping protein, and profilin) work in concert to debranch, sever, cap, and depolymerize actin filaments, and to recharge actin monomers for new rounds of assembly.

Visual impairment cell non-autonomously dysregulates brain-wide proteostasis.

Loss of hearing or vision has been identified as a significant risk factor for dementia but underlying molecular mechanisms are unknown. In different Drosophila models of blindness, we observe non-autonomous induction of stress granules in the brain and their reversal upon restoration of vision. Stress granules include cytosolic condensates of p62, ATF4 and XRP1. This cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets during cellular stress. Cytosolic condensates of p62 and ATF4 were also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate conservation of the link between loss of sensory input and dysregulation of stress responses critical for protein quality control in the brain.

Neuromodulation for Post-Stroke Motor Recovery: a Narrative Review of Invasive and Non­Invasive Tools.

PURPOSE OF REVIEW: Stroke remains a leading disabling condition, and many survivors have permanent disability despite acute stroke treatment and subsequent standard-of-care rehabilitation therapies. Adjunctive neuromodulation is an emerging frontier in the field of stroke recovery. In this narrative review, we aim to highlight and summarize various neuromodulation techniques currently being investigated to enhance recovery and reduce impairment in patients with stroke. RECENT FINDINGS: For motor recovery, repetitive transcranial magnetic simulation (rTMS) and direct current stimulation (tDCS) have shown promising results in many smaller-scale trials. Still, their efficacy has yet to be proven in large-scale pivotal trials. A promising large-scale study investigating higher dose tDCS combined with constraint movement therapy to enhance motor recovery is currently underway. MRI-guided tDCS studies in subacute and chronic post-stroke aphasia showed promising benefits for picture-naming recovery. rTMS, particularly inhibitory stimulation over the contralesional homolog, could represent a pathway forward in post-stroke motor recovery in the setting of a well-designed and adequately powered clinical trial. Recently evidenced-based guideline actually supported Level A (definite efficacy) for the use of low-frequency rTMS of the primary motor cortex for hand motor recovery in the post-acute stage of stroke based on the meta-analysis result. Adjunctive vagal nerve stimulation has recently received FDA approval to enhance upper limb motor recovery in chronic ischemic stroke with moderate impairment, and progress has been made to implement it in real-world practice. Despite a few small and large-scale studies in epidural stimulation (EDS), further research on the utilization of EDS in post-stroke recovery is needed. Deep brain stimulation or stent-based neuromodulation has yet to be further tested regarding safety and efficacy. Adjunctive neuromodulation to rehabilitation therapy is a promising avenue for promoting post-stroke recovery and decreasing the overall burden of disability. The pipeline for neuromodulation technology remains strong as they span from the preclinical stage to the post-market stage. We are optimistic to see that more neuromodulation tools will be available to stroke survivors in the not-to-distant future.

A Case of Hairy Cell Leukemia Variant: Literature Analysis With Focus on Unmet Needs.

Hairy cell leukemia variant (HCLv) is a sporadic, B-cell non-Hodgkin lymphoma classified under chronic lymphoproliferative disorders. HCLv usually presents with easy fatigue, dragging pain abdomen, anemia, splenomegaly, hepatomegaly, initially leukocytosis followed by leucopenia, hairy cells in the smear and bone marrow, and an increased risk of infections. There is hypercellular bone marrow, and cytopenias are secondary to hypersplenism. It is essential to differentiate HCL from disorders like classic hairy cell leukemia (HCLc), splenic marginal zone lymphoma, and splenic diffuse red pulp lymphoma, as these are biologically different, with divergent approaches and outcomes. HCLv is poorly responsive or primary refractory to standard purine analogs cladribine or pentostatin. It has lower response rates to even cladribine and rituximab combination, a standard of care for classic HCL with very good response rates. Here, we present a case of an elderly male who presented with splenomegaly and leukocytosis, diagnosed as HCLv, and was treated with a cladribine and rituximab-based regime but showed residual cells in bone marrow on flow cytometry at six months post-treatment. There were no residual cells in peripheral blood in flow cytometry. Various aspects of the disease are discussed here with a detailed literature analysis. There is a definite unmet need for research on better treatment options in HCLv to improve its overall outcome.

Metal-free sp2 -C7-H Borylation of Tryptophan Containing Peptides and Late-stage Modification.

The discovery of milder and robust strategies to enable the introduction of organoboronates in peptides remains conspicuously underdeveloped. Herein, we demonstrate an efficient method for the site-selective sp2 -C7-H borylation of tryptophan under metal-free condition using BBr3 directed by pivaloyl group. The versatility of this approach is that gram scale synthesis and C7-borylated N-Phth-Trp(N-Piv)(C7-BPin)-OMe was modified into various C7-substituted derivatives. Moreover, the strategy enables for the peptide elongation and late-stage borylation of peptides, natural product Brevianamide F and drug Oglufanide.

Implications of Renal Disease in Patients Undergoing Structural Interventions.

Percutaneous structural interventions have a major impact on the morbidity, mortality, and quality of life of patients by providing a lower-risk alternative to cardiac surgery. However, renal disease has a significant impact on outcomes of these interventions. This review explores the incidence, outcomes, pathophysiology, and preventative measures of acute kidney injury and chronic kidney disease on transcatheter aortic valve replacement, transcatheter mitral valve repair, and percutaneous balloon mitral valvuloplasty. Given the expanding indications for percutaneous structural interventions, further research is needed to identify ideal patients with chronic kidney disease or end-stage renal disease who would benefit from intervention.