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Summary Background We report the clinical efficacy against COVID-19 infection of BBV152, a whole virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) in Indian adults. Methods We did a randomised, double-blind, placebo-controlled, multicentre, phase 3 clinical trial in 25 Indian hospitals or medical clinics to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Adults (age γ18 years) who were healthy or had stable chronic medical conditions (not an immunocompromising condition or requiring treatment with immunosuppressive therapy) were randomised 1:1 with a computer-generated randomisation scheme (stratified for the presence or absence of chronic conditions) to receive two intramuscular doses of vaccine or placebo administered 4 weeks apart. Participants, investigators, study coordinators, study-related personnel, the sponsor, and nurses who administered the vaccines were masked to treatment group allocation; an unmasked contract research organisation and a masked expert adjudication panel assessed outcomes. The primary outcome was the efficacy of the BBV152 vaccine in preventing a first occurrence of laboratory-confirmed (RT-PCR-positive) symptomatic COVID-19 (any severity), occurring at least 14 days after the second dose in the per-protocol population. We also assessed safety and reactogenicity throughout the duration of the study in all participants who had received at least one dose of vaccine or placebo. This report contains interim results (data cutoff May 17, 2021) regarding immunogenicity and safety outcomes (captured on days 0 to 56) and efficacy results with a median of 99 days for the study population. The trial was registered on the Indian Clinical Trials Registry India, CTRI/2020/11/028976, and ClinicalTrials.gov, NCT04641481 (active, not recruiting). Findings Between Nov 16, 2020, and Jan 7, 2021, we recruited 25 798 participants who were randomly assigned to receive BBV152 or placebo; 24 419 received two doses of BBV152 (n=12 221) or placebo (n=12 198). Efficacy analysis was dependent on having 130 cases of symptomatic COVID-19, which occurred when 16 973 initially seronegative participants had at least 14 days follow-up after the second dose. 24 (0·3%) cases occurred among 8471 vaccine recipients and 106 (1·2%) among 8502 placebo recipients, giving an overall estimated vaccine efficacy of 77·8% (95% CI 65·2–86·4). In the safety population (n=25 753), 5959 adverse events occurred in 3194 participants. BBV152 was well tolerated; the same proportion of participants reported adverse events in the vaccine group (1597 [12·4%] of 12 879) and placebo group (1597 [12·4%] of 12 874), with no clinically significant differences in the distributions of solicited, unsolicited, or serious adverse events between the groups, and no cases of anaphylaxis or vaccine-related deaths. Interpretation BBV152 was highly efficacious against laboratory-confirmed symptomatic COVID-19 disease in adults. Vaccination was well tolerated with no safety concerns raised in this interim analysis. Funding Bharat Biotech International and Indian Council of Medical Research.

This Letter reports results from the first long-baseline search for sterile antineutrinos mixing in an accelerator-based antineutrino-dominated beam. The rate of neutral-current interactions in the two NOvA detectors, at distances of 1 km and 810 km from the beam source, is analyzed using an exposure of $12.51\times10^{20}$ protons-on-target from the NuMI beam at Fermilab running in antineutrino mode. A total of $121$ of neutral-current candidates are observed at the Far Detector, compared to a prediction of $122\pm11$(stat.)$\pm15$(syst.) assuming mixing between three active flavors. No evidence for $\bar{\nu}_{\mu}\rightarrow\bar{\nu}_{s}$ oscillation is observed. Interpreting this result within a 3+1 model, constraints are placed on the mixing angles ${\theta}_{24} < 25^{\circ}$ and ${\theta}_{34} < 32^{\circ}$ at the 90% C.L. for $0.05$eV$^{2} \leq \Delta m^{2}_{41} \leq 0.5$eV$^{2}$, the range of mass splittings that produces no significant oscillations at the Near Detector. These are the first 3+1 confidence limits set using long-baseline accelerator antineutrinos., Comment: 8 pages, 4 figures

Acquired mutations in the ligand-binding domain (LBD) of the gene encoding estrogen receptor α (ESR1) are common mechanisms of endocrine therapy resistance in patients with metastatic ER+ breast cancer. The ESR1 Y537S mutation, in particular, is associated with development of resistance to most endocrine therapies used to treat breast cancer. Employing a high-throughput screen of nearly 1,200 Federal Drug Administration-approved (FDA-approved) drugs, we show that OTX015, a bromodomain and extraterminal domain (BET) inhibitor, is one of the top suppressors of ESR1 mutant cell growth. OTX015 was more efficacious than fulvestrant, a selective ER degrader, in inhibiting ESR1 mutant xenograft growth. When combined with abemaciclib, a CDK4/6 inhibitor, OTX015 induced more potent tumor regression than current standard-of-care treatment of abemaciclib + fulvestrant. OTX015 has preferential activity against Y537S mutant breast cancer cells and blocks their clonal selection in competition studies with WT cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant-induced endocrine therapy resistance in breast cancer.

Current ultrasound methods for recognition and motion-tracking of arterial walls are suited for image-based B-mode or M-mode scans but not adequately robust for single-line image-free scans. We introduce a time-warping-based technique to address this need. Its performance was validated through simulations and in-vivo trials on 21 subjects. The method recognized wall locations with 100 % precision for simulated frames (SNR 10 dB). Clustering detections for multiple frames achieved sensitivity 98 %, while it was ∼90 % without clustering. The absence of arterial walls was predicted with 100 % specificity. In-vivo results corroborated the performance outcomes yielding a sensitivity ≥94 %, precision ≥98 %, and specificity ≥98 % using the clustering scheme. Further, excellent frame-to-frame tracking accuracy (absolute error 3 %, RMSE 2 μm) was demonstrated. Image-free measurements of peak arterial distension agreed with the image-based ones, within an error of 1.08 ± 3.65 % and RMSE of 38 μm. The method discerned the presence of arterial walls in A-mode frames, robustly localized, and tracked them even when they were proximal to hyperechoic regions or slow-moving tissue structures. Unification of delineation techniques with the proposed methods facilitates a complete image-free framework for measuring arterial dynamics and the development of reliable A-mode devices.

Constructed wetlands are a nature-based engineering solution enabling polishing of septic tank effluents at low-cost. However to date, the influence of planting on treatment efficiency remains little understood. Here we report a case study evaluating the performance of two near-identical Horizontal Sub-Surface Flow Constructed Wetlands (HSSF-CW) deployed at a school in southern India. The HSSF-CWs were of similar size and construction with the exception that one system was planted (Canna indica) whilst the other was operated without plants. Both systems were operated at similar hydraulic loading rate (HLR) and hydraulic retention time (HRT) of 84 mm day−1 and 3.7 days, respectively to treat the effluent from septic tanks. The systems were monitored fortnightly for one year and the performance kinetics, nutrient and organics removal efficiencies were evaluated. Significant reduction in biochemical oxygen demand (BOD5) and chemical oxygen demand (COD) (p < 0.05) were observed in both systems with BOD5 removal efficiency of 67% and 61% in the planted and unplanted systems, respectively. Whilst the effluent from both systems met the environmental discharge standards set by Central Pollution Control Board (CPCB), India, the total phosphorus (TP) and total suspended solids (TSS) removal in the unplanted system were significantly greater than in the planted system. The first-order decay rate constants (K) obtained for TN (KTN) and BOD5 (KBOD5) in the planted system (0.16 day−1 and 0.30 day−1) were higher than in the unplanted system (0.09 day−1 and 0.27 day−1). Greater R2 values obtained for the planted system (~ 0.90) suggests applicability of a first-order decay model to assess contaminant degradation. Plants contributed to 7% (0.3 g/m2/day) BOD5, 18% (1.9 g/m2/day) COD and 5% (0.09 g/m2/day) TN load removal. Our data demonstrates that planting is effective in improving treatment efficiency in constructed wetlands, and whilst the improvement is marginal here, it is noted that a rust infection could have limited effectiveness of the plants in this case.

Introduction COVID-19 led to global disruption of healthcare and many students volunteered to provide clinical support. Volunteering to work was a unique medical education opportunity; however, it is unknown whether this was a positive learning experience. Methods The COVID Ready 2 study is a national cross-sectional study of all medical students at UK medical schools. We will compare opinions of those who did and did not volunteer to determine the educational benefit and issues they faced. We will use thematic analysis to identify themes in qualitative responses, in addition to quantitative analysis. Results The primary objective is to explore the effect of volunteering during the pandemic on medical education in comparison to those who did not volunteer. Our secondary objectives are to identify: whether students would be willing to assume similar roles in a non-pandemic setting; if students found the experience more or less beneficial than traditional hospital placements and reasons for this; what the perceived benefits and disadvantages of volunteering were; the difference in perceived preparedness between students who did and did not volunteer for foundation training year one and the next academic year; training received by volunteers; and to explore issues associated with volunteering, including safety issues and issues with role and competence. Conclusions We anticipate this study will help identify volunteer structures that have been beneficial for students, so that similar infrastructures can be used in the future; and help determine whether formal voluntary roles should be introduced into the non-pandemic medical curriculum.

The heterogeneity of cancer necessitates developing a multitude of targeted therapies. We propose the view that cancer drug discovery is a low rank tensor completion problem. We implement this vision by using heterogeneous public data to construct a tensor of drug-target-disease associations. We show the validity of this approach computationally by simulations, and experimentally by testing drug candidates. Specifically, we show that a novel drug candidate, SU11652, controls melanoma tumor growth, including BRAFWT melanoma. Independently, we show that another molecule, TC-E 5008, controls tumor proliferation on ex vivo ER+ human breast cancer. Most importantly, we identify these chemicals with only a few computationally selected experiments as opposed to brute-force screens. The efficiency of our approach enables use of ex vivo human tumor assays as a primary screening tool. We provide a web server, the Cancer Vulnerability Explorer (accessible at https://cavu.biohpc.swmed.edu), to facilitate the use of our methodology.

Prostate cancer (PCa) and breast cancer (BCa) are both hormone-dependent cancers that require the androgen receptor (AR) and estrogen receptor (ER, ESR1) for growth and proliferation, respectively. Endocrine therapies that target these nuclear receptors (NRs) provide significant clinical benefit for metastatic patients. However, these therapeutic strategies are seldom curative and therapy resistance is prevalent. Because the vast majority of therapy-resistant PCa and BCa remain dependent on the augmented activity of their primary NR driver, common mechanisms of resistance involve enhanced NR signaling through overexpression, mutation, or alternative splicing of the receptor, coregulator alterations, and increased intracrine hormonal synthesis. In addition, a significant subset of endocrine therapy-resistant tumors become independent of their primary NR and switch to alternative NR or transcriptional drivers. While these hormone-dependent cancers generally employ similar mechanisms of endocrine therapy resistance, distinct differences between the two tumor types have been observed. In this review, we compare and contrast the most frequent mechanisms of antiandrogen and antiestrogen resistance, and provide potential therapeutic strategies for targeting both advanced PCa and BCa.

Rice is the most significant cultivated harvests everywhere throughout the world, specifically in Asian nations. Nowadays the evaluation of rice quality has a great impact on the market due to adulteration by plastic rice and stones. The assessment of rice is prepared physically by experienced a rancher which is a tedious and monotonous errand and in particular it is a dangerous strategy where the rice might be pulverized by growth pollution. In this paper, a quick, programmed and non-destructive assessment practice is endeavored to measure the nature of rice based on deep learning neural system model. The pre-processing is started by the Median channel to expel noises from the input pictures. By utilizing Fuzzy c-means clustering, the edges of the rice pictures are appropriately depicted. The features like contour, edge, and region are chosen with the assistance of a genetic algorithm. A probabilistic neural system is created to characterize the portioned rice picture. The presentation of PNN model is introduced to show its viability with regards to exactness, accuracy, f-score, and review, and the outcomes are compared with the existing SVM method.

In this paper, experimental investigations on tool wear have been made to facilitate increasing the tool life by sub-zero treatment of carbide insert tool. The effect of computer numerical control (CNC) inserts during orthogonal machining of AISI4340/EN 24 steel, cutting parameters are originated, and the tool life is predictable and compared with untreated and sub-zero treated insert. Generally, the inserts are treated under sub-zero temperature treatment as there is an increase in tool life. Turning parameters such as depth of cut, feed and speed are considered to analyze tool wear. Micro-hardness measurements have been carried out to identify the hardness of treated and untreated insert. Equations are developed using Buckingham’s π theorem, and the results have been validated against experiments. For further implementation, manufacturing with respect to the tool life optimization is discussed.

The study of DNA damage repair response (DDR) in prostate cancer is restricted by the limited number of prostate cancer cell lines and lack of surrogates for heterogeneity in clinical samples. Here, we sought to leverage our experience with patient derived explants (PDEs) cultured ex vivo to study dynamics of DDR in primary tumors following application of clinically relevant doses of ionizing radiation (IR) to tumor cells in their native 3-dimensional microenvironment. We compared DDR dynamics between prostate cancer cell lines, PDEs and xenograft derived explants (XDEs) following treatment with IR (2Gy) either alone or in combination with pharmacological modulators of DDR. We have shown that following treatment with 2Gy, DDR can be consistently detected in PDEs from multiple solid tumors, including prostate, kidney, testes, lung and breast, as evidenced by γ-H2AX, 53BP1, phospho-ATM and phospho-DNA-PKcs foci. By examining kinetics of resolution of IR-induced foci, we have shown that DDR in prostate PDEs (complete resolution in 8 h) is much faster than in prostate cancer cell lines (, Highlights • IR induces distinct DNA damage repair kinetics in prostate cancer PDEs and cell lines. • IR induces a distinct transcriptional program in prostate cancer PDE and cell lines. • DNA-PKcs inhibition blocks IR-induced DDR in prostate cancer PDE. • Inhibition of AR impairs NHEJ in prostate cancer PDEs.

As the frequency and intensity of tropical cyclones, and the degree of urbanization increase, a systematic strengthening of power transmission networks in the coastal regions becomes imperative. An effective strategy for the same can be to strengthen select transmission towers, which requires consideration of network at holistic scale and its orientation relative to the coastline, the fragility of towers, and properties of cyclones. Since necessary information is often missing, actionable frameworks for prioritization remain elusive. Based on publicly available data, we assess efficacies of strategic interventions in the network that serves 40 million people. After evaluating 72 strategies for prioritization, we find that strategies that consider rather simplistic properties of the network and its orientation with respect to the coastline work much better than those based purely on the network's properties, in spite of minor variations in fragilities of towers. This integrated approach opens avenues for actionable engineering and policy interventions in resource-constrained and data-deprived settings.

Commercially used inorganic phosphors heavily depend on lanthanide doped host materials which are becoming more expensive and also their availability is limited due to scarcity. In this regard, a new lanthanide-free self-activated full-color emission phosphor in Y

The two-detector design of the NOvA neutrino oscillation experiment, in which two functionally identical detectors are exposed to an intense neutrino beam, aids in canceling leading order effects of cross-section uncertainties. However, limited knowledge of neutrino interaction cross sections still gives rise to some of the largest systematic uncertainties in current oscillation measurements. We show contemporary models of neutrino interactions to be discrepant with data from NOvA, consistent with discrepancies seen in other experiments. Adjustments to neutrino interaction models in GENIE that improve agreement with our data are presented. We also describe systematic uncertainties on these models, including uncertainties on multi-nucleon interactions from a newly developed procedure using NOvA near detector data., Comment: Code implementing adjustments to GENIE 2.12.2 described in this paper is available at https://github.com/novaexperiment/NOvARwgt-public

Background: Ultrasonographic imaging to record changes in peripheral arterial diameter associated with Flow mediated dilatation or Low flow mediated constriction is routinely used to assess various facets of vascular endothelial function. Imaging poses many challenges including requirement of costly ultrasound machines, trained manpower to perform imaging and effort-intensive steps to analyse the images subsequently using manual or automated methods. We tested the feasibility and validity of using an imaging-free technology to record resting arterial diameters of brachial and radial arteries. Methods: Eight healthy volunteers initially underwent ultrasonographic imaging (M7, Mindray; Shenzhen, P.R. China) of brachial artery and proximal radial artery. The brachial and radial artery ‘zones’ thereby identified through imaging were surface marked on subject’s arm. Imaging-free ARTSENS® Pen device [1] (Healthcare Technology Innovation Centre, IIT Madras, India) consisting of highly integrated hardware for operating a single element broadband ultrasound transducer (centre-frequency = 5 MHz, spatial half angle

Background: Arterial stiffness index (β) is a clinically accepted vascular metric, calculated from arterial pressure and diameter obtained simultaneously from a single arterial site [1]. Hence, accurate measurement of β can only be performed on arteries where pressure can be recorded along with the diameter. We present a method to evaluate β from superficial arteries using arterial force (F) and diameter (D) waveforms, employing mathematical models (shown below) exploiting the non-linear pressure-diameter relationship [2], without requiring absolute pressure. Methods: Pilot functionality assessment was performed on eight participants (24 ± 5 years). A custom-developed frequency-matched system, combining single-element ultrasound and force-sensing transducers, was used to measure D and F waveforms from the common carotid artery. A hemodynamic-loop was formed from these measures and optimised to eliminate viscous components, and evaluate the elastic stiffness index β. Traditional β-formula [2] yielded reference values for comparison. fe(t)=fmx×(eβ(D(t)Dd−1)−1eβ(DsDd−1)−1) fe(t): Viscosity eliminated arterial force fmx: Maxima of viscosity eliminated arterial force β : Stiffness index D(t): Arterial diameter Ds: Systolic diameter Dd: Diastolic diameter Results: The system captured high fidelity D and F waveforms, adequate for reliable β evaluation. Measured group-average β (4.7 ± 0.8) was concurrent with literature. The measured β values statistically agreed (LoA = ±0.83 and bias = –0.32; non-significant p > 0.05) and strongly correlated (r = 0.93, p < 0.001) with the reference values. Further, they exhibited acceptable beat-to-beat repeatability (variation

Mastocytosis represents an uncommon spectrum of disorders where mast cells proliferate and accumulate in different organs and tissues throughout the body, most frequently affecting the skin. Here we present a case of systemic mastocytosis and review the manifestations of cutaneous and systemic mastocytosis to raise awareness and try to reduce the typical delay in diagnosis.

OBJECTIVE To evaluate the legacy of endocrinologist Jean Wilson, whose discovery in 1969 of 5 alpha-reductase (5AR) and description of dihydrotestosterone (DHT) as the primary hormone associated with prostatic growth ushered in a golden age of collaboration between endocrinologists, oncologists, and urologists that led to some of the critical discoveries in the understanding and treatment of prostatic pathology. MATERIALS AND METHODS A review of the medical literature between 1969 and 2020 was conducted and multiple authors interviewed. RESULTS In 1969, Gloyna and Wilson demonstrated the reduction of testosterone to DHT in the prostate. With Bruchovsky, Wilson established that DHT was the primary hormone associated with prostatic growth. Wilson went on to show that androgens are involved in every aspect of prostate development, growth, and function. Wenderoth and Wilson then showed that a 5AR inhibitor blocked the prostatic growth. Subsequently, clinical trials with therapies targeting 5AR were led by Roehrborn and McConnell. Tilley and Wilson with Marcelli and McPhaul cloned the human androgen receptor at UT Southwestern in 1989 and provided the first evidence that androgen receptor was a transcriptional factor that could regulate its own expression in prostate cancer. Androgen receptor mutations explaining the molecular basis of androgen resistance syndromes were first described by Wilson, McPhaul, et al in the early 1990s. CONCLUSION Basic, translational, and clinical research has played a pivotal role in our current understanding of prostatic disease. Much of this legacy is credited to Jean Wilson and the cross-pollination of world-class scientists across fields, whom he inspired.

Safe surgical dislocation with a trochanteric flip osteotomy has been shown to be a reliable technique that provides excellent exposure for treating femoral-head fractures with minimal complications. This technique also allows associated labral injuries and acetabular fractures to be treated through the same approach. DESCRIPTION: The procedure is performed with use of a conventional Kocher-Langenbeck exposure with the patient in the lateral position. The trochanteric flip is performed, allowing exposure of the anterior capsule, which is incised to dislocate the head anteriorly. Fracture fixation is performed with use of mini-fragment screws followed by relocation of the head, closure of the capsulotomy, and fixation of the osteotomy. ALTERNATIVES: Fixation of femoral-head fractures can also be performed with use of alternate surgical approaches. Anterior-based surgical approaches like the Hueter approach or the Smith-Petersen approach are preferred with the goal of preserving the posterior extraosseous blood supply to the femoral head. The posterior Kocher-Langenbeck approach can also be utilized because there is no clear evidence suggesting that a properly performed posterior approach affects the blood supply of the femoral head. RATIONALE: Surgical hip dislocation is 1 of the preferred techniques for operative treatment of femoral-head fractures and is a versatile approach that provides circumferential exposure of the femoral head and acetabulum through an anterior dislocation. A compromised blood supply to the femoral head is much less likely with use of this approach compared with posterior-based surgical approaches. Compared with anterior-based surgical approaches, which are often restrictive, surgical dislocation is extensile and provides adequate exposure to treat associated injuries to the acetabulum and the labrum of the hip. EXPECTED OUTCOMES: Outcomes following surgical dislocation for femoral-head fractures are reportedly good to excellent in >80% patients. Urgent reduction of the hip joint followed by anatomical reduction of the fracture and stable fixation of the fracture and osteotomy leads to predictably good results. Notable complications include heterotopic ossification, which has been reported in up to 60% patients, as well as osteonecrosis of the femoral head (often related to the initial injury rather than the approach) and degenerative arthritis of the hip joint. IMPORTANT TIPS: The Gibson interval may be utilized to preserve the gluteus maximus. Identify all of the posterior structures starting proximally from the posterior border of the gluteus medius, and continuing to the piriformis, triceps coxae, quadratus femoris, and the vastus lateralis. Aim for a thickness of 1 to 1.5 cm when performing the osteotomy; an osteotomy that is either too thick or too thin can negatively affect outcomes. The osteotomy should begin just anterior to the posterior fibers of the gluteus medius to ensure that the osteotomy is anterior to the piriformis tendon. It should exit distally to the vastus lateralis origin. Carefully elevate the posterior margin of the gluteus minimis from the capsule to avoid the tethering effect during anterior translation of the osteotomized fragment. Capsular tears during the initial dislocation are common and should be incorporated into the anterior capsulotomy. Repair of large posterosuperior labral tears may improve outcomes. Fixation of the fracture can be performed with mini-fragment screws or headless screws. Non-fixable small fragments can be excised. The osteotomy should be reduced and fixed in a stable manner to prevent trochanteric nonunion and preserve abductor function.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

BackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole.MethodsWe tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent,ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell linesin vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole, in combination with either Fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growthin vitro. Single-agent Riluzole significantly inhibited HCI-013EI patient-derived xenograft growthin vivo, and the combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures.ConclusionsRiluzole, alone or combined with endocrine therapy, may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.

Accurate component positioning is the key for successful outcome after total hip arthroplasty (THA). Positioning acetabular and femoral components in a safe zone of 25°-50° on the basis of combined anteversion (CA) has shown to reduce instability and impingement. This safe zone was described for THAs performed through the posterior approach and has not been validated for other surgical approaches.Seventy patients who underwent unilateral uncemented THA were included in the study; 35 patients-using posterior approach and the remaining 35-using trans-gluteal approach. All patients included had a stable and impingement-free THA at a mean follow-up of 39.2 ± 9.5 months. CT scan was performed to assess component positioning by calculating CA. The values were compared between the two groups to study possible differences.CA in the trans-gluteal group was significantly lower (32° ± 3.7° vs 38.4° ± 4.6°, P .001) compared to posterior group. The difference in CA was due to the differences in acetabular anteversion, which was significantly low in the trans-gluteal group than the posterior group (22.1° ± 3.6° vs 27.8° ± 4.2°, P .001). The mean femoral anteversion was similar in both groups. All trans-gluteal hips fell within the safe zone of 20°-40°, and all posterior hips fell within the safe zone of 25°-50°.A safe zone of 25°-50° is valid for THAs performed from the posterior approach but not universally applicable. For trans-gluteal approach, a safe zone of 20°-40° is better to provide a stable and impingement-free THA. CA varies with the surgical approach. THAs performed through the trans-gluteal approach can be stable and impingement-free with lesser CA compared to THAs performed through the posterior approach.

IFNγ, a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in patients with prostate cancer after radiation. In this study, we demonstrate that IFNγ can induce epithelial-to-mesenchymal transition (EMT) in prostate cancer cells via the JAK–STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as IFN-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor miRNAs (pre-miRNA) that includes pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5′-end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in prostate cancer cells. Depletion of IFIT5 decreased IFNγ-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a prometastatic role of the IFNγ pathway via a new mechanism of action, which raises concerns about its clinical application. Significance: A unique IFIT5–XRN1 complex involved in the turnover of specific tumor suppressive microRNAs is the underlying mechanism of IFNγ-induced epithelial-to-mesenchymal transition in prostate cancer. See related commentary by Liu and Gao, p. 1032

Transcriptional dysregulation is a hallmark of prostate cancer (PCa). We mapped the RNA polymerase II-associated (RNA Pol II-associated) chromatin interactions in normal prostate cells and PCa cells. We discovered thousands of enhancer-promoter, enhancer-enhancer, as well as promoter-promoter chromatin interactions. These transcriptional hubs operate within the framework set by structural proteins - CTCF and cohesins - and are regulated by the cooperative action of master transcription factors, such as the androgen receptor (AR) and FOXA1. By combining analyses from metastatic castration-resistant PCa (mCRPC) specimens, we show that AR locus amplification contributes to the transcriptional upregulation of the AR gene by increasing the total number of chromatin interaction modules comprising the AR gene and its distal enhancer. We deconvoluted the transcription control modules of several PCa genes, notably the biomarker KLK3, lineage-restricted genes (KRT8, KRT18, HOXB13, FOXA1, ZBTB16), the drug target EZH2, and the oncogene MYC. By integrating clinical PCa data, we defined a germline-somatic interplay between the PCa risk allele rs684232 and the somatically acquired TMPRSS2-ERG gene fusion in the transcriptional regulation of multiple target genes - VPS53, FAM57A, and GEMIN4. Our studies implicate changes in genome organization as a critical determinant of aberrant transcriptional regulation in PCa.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and represents a disproportional share of the breast cancer mortality, primarily due to a lack of targeted therapies. There is a major unmet need for rationally designed novel therapies that can extend survival of patients with TNBC. TNBCs are characterized by a high basal level of endoplasmic reticulum stress, due to high protein turnover and need for proliferation. Recent studies revealed the role of several members of the Nuclear Receptor (NR) superfamily as molecular drivers in TNBC, including the androgen receptor (AR), glucocorticoid receptor (GR) and the orphan NR tailless (TLX). Methods: Recently, using peptidomimetics, we have developed small molecules that specifically target and block interactions of multiple coregulators with oncogenic NRs. We performed a screen of our 500+ compound peptidomimetic library derived from our ERX-11 oligobenzamide (that was rationally designed to target ERα) for anti-proliferative activity in TNBC cell lines. Identified leads were then validated in multiple TNBC cell lines. In vitro activity was tested using Cell titer glo, MTT, matrigel invasion, and apoptosis assays. Mechanistic studies were conducted using Western blot, reporter gene assays, CRISPR/Cas9 KO and RNA-seq analysis. Xenograft, patient derived xenograft (PDX), patient derived explant (PDE) and xenograft derived explant (XDE) TNBC models were used for preclinical evaluation and toxicity. Results: We have identified a first-in-class drug (ERX-41) that has potent activity (IC50 = 50-250nM) against all six molecular subtypes of TNBC. Systematic evaluation using CRISPR/Cas9 KO screen and overexpression screen comprising 48 NRs identified TLX as a preferred target of ERX-41. Analyses of primary breast tumors revealed TLX was highly expressed in TNBC. Further, TLX was amplified in nearly 50% of TNBC xenografts (cbioportal.org). Modelling, mechanistic and biochemical studies showed that ERX-41 interact with TLX and selectively blocks its interactions with coregulators. Gene expression analyses revealed both significant reduction of TLX-activated genes (CCND1, WNT7A) and significant activation of TLX-repressed genes (p21) upon treatment with ERX-41 in TNBC models. Gene ontogeny pathway analyses of RNA-seq data in TNBC cells showed that ERX-41 treatment positively correlated with apoptosis. Our ultrastructural studies indicated that ERX-41 enhances endoplasmic reticulum stress in TNBC inducing autophagic flux and subsequent apoptosis. ERX-41 has significant potency against multiple TNBC xenografts and PDXs in vivo, PDEs and XDEs ex vivo, indicating its potential for clinical translation. Pharmacologically, ERX-41 exhibited high oral bioavailability and associated with minimal toxicity upon oral gavage for up to 120 days in animal studies. Conclusions: We believe that the ability of ERX-41 to block NR signaling and target a critical molecular vulnerability in TNBC and its ability to enhance endoplasmic reticulum stress in TNBC, will revolutionize the therapeutic landscape of TNBC. ERX-41 is oral bioavailable, potent against multiple TNBC molecular subtypes, and is associated with minimal systemic side effects. (supported by NIH grant RO1 CA223828-01) Citation Format: Liu X, Viswanadhapalli S, Ma S, Lee T-K, Sareddy GR, Ekoue DN, Blatt EM, Zhou M, Li M, Tekmal RR, Ahn J-m, Vadlamudi RK, Raj GV. A small molecule inhibitor (ERX-41) induces endoplasmic reticulum stress in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-01.

Background: Leukemia inhibitory factor (LIF) and its receptor LIFR are over-expressed in multiple solid tumors and play a key role in tumor growth, progression, and resistance to standard anti-cancer treatments. Triple-negative breast cancer (TNBC) lacks targeted therapies and represents a disproportional share of breast cancer (BCa) mortality. TNBC exhibits autocrine stimulation of the LIF/LIFR axis and overexpression of LIF is associated with poorer relapse-free survival in BCa patients. LIF signaling also promotes maintenance of stem cells. Therefore, targeting the LIF/LIFR axis may have therapeutic utility in TNBC. Methods: We rationally designed a small organic molecule (EC359) that emulates the LIF/LIFR binding site and functions as a LIFR inhibitor from a library of compounds. In silico docking studies were used to identify the putative interaction of the EC359 and LIF/LIFR complex. Direct binding of EC359 to LIFR was confirmed using surface plasmon resonance (SPR) and microscale thermophoresis technique (MST) assays. In vitro activity was tested using Cell-Titer Glo, MTT, invasion, and apoptosis assays. Mechanistic studies were conducted using Western blot, reporter gene assays, and RNA-seq analysis. Xenograft, patient-derived xenograft (PDX), and patient-derived explant (PDEX) models were used for preclinical evaluation and toxicity. Results: Molecular docking studies showed that EC359 interacts at the LIF/LIFR binding interface. SPR and MST studies confirmed direct interaction of EC359 to LIFR. EC359 reduced the growth of TNBC cells with high potency (IC50 50-100nM) and promoted apoptosis. Further, EC359 treatment reduced invasion and stemness of TNBC cells. EC359 activity is dependent on the expression levels of LIFR and showed little or no activity on TNBC cells that have low levels of LIFR or ER+ve BCa cells. Further, EC359 significantly reduced the viability of cisplatin and taxane-resistant TNBC cells and enhanced the efficacy of HDAC inhibitors. Mechanistic and biochemical studies showed that EC359 interacts with LIFR and effectively blocking LIF/LIFR interactions. EC359 also blocked LIFR interactions with other LIFR ligands such as oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1. EC359 treatment attenuated the activation of LIF/LIFR driven pathways including STAT3, mTOR, AKT, and MAPK. RNA-seq analysis identified regulation of apoptosis as one of the important pathway modulated by EC359. In TNBC xenograft and PDX assays, EC359 significantly reduced tumor progression. Further, using human primary BCa PDEX cultures, we demonstrated that EC359 has the potential to substantially reduce the proliferation of human BCa. Pharmacologically, EC359 exhibited high oral bioavailability and long half-life with a wide therapeutic window. Conclusions: EC359 is a novel targeted therapeutic agent that inhibits LIF/LIFR oncogenic signaling in TNBC via a unique mechanism of action. EC359 has the distinct pharmacologic advantages of oral bioavailability, in vivo stability, and is associated with minimal systemic side effects. (DOD BCRP grant #BC170312) Citation Format: Viswanadhapalli S, Luo Y, Sareddy GR, Santhamma B, Zhou M, Li M, Pratap UP, Altwegg KA, Li X, Srinivasan U, Ma S, Chang A, Riveros AC, Zhang KY, Dileep KV, Pan X, Murali R, Bajda M, Raj G, Brenner A, Manthati V, Rao M, Tekmal RR, Nair HB, Nickisch KJ, Vadlamudi RK. Development of a first-in-class small molecule inhibitor (EC359) targeting oncogenic LIF/LIFR signaling for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-02.

The present research effort was undertaken to develop a new generation of SiC fiber-reinforced engineered ceramic matrix composites (E-CMCs). In contrast to traditional CMCs with a brittle SiC matrix, an E-CMC is designed to consist of a matrix engineered to possess sufficient high temperature plasticity to minimize crack propagation, relatively high fracture toughness, and self-healing capabilities to prevent oxygen ingress to the BN-coated fibers through surface-connected cracks. The present paper discusses the bend strength, isothermal oxidation, microstructures and self-healing properties of several silicide-behaved engineered matrices. Based on the oxidation tests, where it was observed that some of the matrices exhibited either catastrophic oxidation ("pesting") or spalling of the oxide scale, two engineered matrices, CrSi2/SiC/Si3N4 and CrMoSi/SiC/Si3N4, were down-selected for further investigation. Four-point bend tests were conducted on these two engineered matrices between room temperature and 1698 degrees Kelvin. Although these matrices were brittle at low temperatures, it was observed that the bend strengths and bend ductility increased at high temperatures as the silicide particles became more ductile, which was qualitatively consistent with the theoretically expected behavior that crack blunting at these particles should increase the matrix strength. Additional studies were conducted to study the effects of different additives on the self-healing properties of the engineered matrices, which helped to identify the most effective additives.

OBJECTIVES To compare outcomes after surgical treatment of Pipkin I and II femoral head fractures treated with either a surgical dislocation (SD) or a direct anterior approach (the modified Heuter approach). STUDY DESIGN Retrospective, multicentre. SETTING Three Level I trauma care centers. PATIENTS Fourty-nine patients operated for Pipkin types I or II femoral head fractures. Twenty-seven using SD and 22 using the modified Heuter approach. INTERVENTIONS Initial closed reduction of the joint followed by open reduction and internal fixation of the fracture/fragment excision. Fixation was performed using headless or countersunk mini fragment screws. OUTCOME MEASUREMENTS The 2 groups were compared for (1) perioperative measures: blood loss, surgical time, pain [visual analog scale (VAS)], and length of hospital stay; (2) radiological outcome in terms of fracture union, occurrence of posttraumatic hip arthritis, and femoral head osteonecrosis; and (3) functional outcome using the modified Merle d' Aubigne score and Oxford hip scores. RESULTS Surgical time, blood loss, and VAS at 24 hours were significantly lower in the modified Heuter group. The VAS at discharge and length of stay were similar in both groups. All fractures had united. No cases of osteonecrosis were observed. Functional outcome and complications were similar in both groups. CONCLUSIONS Both SD and the modified Heuter approach are effective in treating patients with Pipkin I and II femoral head fractures with comparable radiological and functional outcomes. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Estrogen receptor-positive (ER+) breast cancer is the most commonly diagnosed form of this malignancy. Aromatase inhibitors and selective estrogen receptor modulators or degraders (SERMS, SERDs) can be highly effective in treating ER+ breast cancer, but de novo and acquired resistance to these interventions is a persistent clinical problem. Endocrine therapy resistant breast cancer cells rewire their metabolism to support cellular demands associated with rapid proliferation and/or increased invasion and metastasis. An important feature of this metabolic flexibility is conversion of glutamine to glutamate, an amino acid integral to protection of cells from oxidative stress. Consistent with this, we show multiple cellular models of ER+, endocrine resistant breast cancer cells markedly increase glutamate release and upregulate expression of essential glutamine/glutamate metabolic enzymes and transporters, including the glutamate/cystine antiporter xCT, glutamate dehydrogenase (GLUD1/2), and/or the glutamine importer SLC1A5. Riluzole (RIL) is FDA-approved for the treatment of amyotrophic lateral sclerosis (ALS), and has several proposed mechanisms of action, including suppression of glutamate release and increased glutamate uptake. We show ER+, endocrine responsive and resistant breast cancer cells are growth-inhibited by RIL. This is due to an increase in cell death, particularly in endocrine resistant breast cancer cells, and cell cycle arrest. Interestingly, histologic subtype confers a different cell cycle arrest profile, with invasive ductal cancer (IDC) models arresting in G1 but invasive lobular cancer (ILC) models arresting in G2/M. Isobologram analysis of RIL plus SERMs or SERDs shows additive-to-synergistic activity in a subset of ER+ cell line models, and preliminary studies show combination activity in patient-derived explants (PDEs). Mechanistically, we tested whether signaling through metabotropic glutamate receptors (mGluRs, GRMs) and/or cystine import contribute to RIL’s growth-inhibitory phenotype. Antagonists of mGluRs/GRMs don’t phenocopy the effects of RIL, suggesting extracellular glutamate signaling through these receptors is not a key mechanism. Rescue experiments with β-mercaptoethanol to promote cystine uptake through transporters other than xCT show partial reversal of RIL-mediated cell cycle arrest in some cells, suggesting xCT may contribute to RIL-induced growth inhibition. In summary, we show RIL may be a viable addition to endocrine therapy in ER+ breast cancer. Ongoing studies will test additional mechanism(s) by which RIL may attenuate the growth of ER+ breast cancer models in vitro, including inhibition of protein kinase C and casein kinase 1 delta. We are further testing RIL efficacy alone and in combination with a SERD in primary tumors and lung metastases in a ER+ patient-derived xenograft (PDX) model.

The treatment and management of prostate cancer continues to evolve; newer classes of agents and combination therapies are being developed and some are being investigated in early phase clinical trials.We discuss investigational hormonal agents for the treatment of prostate cancer and focus primarily on luteinizing hormone releasing hormone (LHRH) agonists in early stage trials. We look at agents that target the hormonal axis, including anti-androgens, gonadotropins, estrogenic agents and progestogenic agents and other non-hormonal agents often used in combination with LHRH agonists. We review these candidates in the specific clinical niche in which they might find utility.Of all candidate compounds being evaluated in clinical trials, very few will receive FDA approval. Few, if any of the investigational agents discussed here will be used routinely in clinical practice for treating prostate cancer. Recognizing the reasons for the failure of agents to advance to later stage trials is important. Furthermore, a thorough understanding of the mechanisms underlying prostate cancer pathogenesis, including various points in the HGPA and parallel pathways, will help identify potentially actionable targets.

In recent years latent heat energy storage (LHES) has received a worldwide focus in the area of solar still applications. Among various techniques available to improve the productivity of solar stills, heat storage is one of the proverbial areas in the present scenario. LHES surpasses sensible heat energy storage (SHES) in solar still applications owing to its properties like latent heat, thermal conductivity, etc. Focus has to be given in the selection of suitable LHES material since its properties are very significant during the performance and operation of solar stills. Though previous reviews on LHES in solar stills focus only on the productivity enhancement, this paper presents an up to date comprehensive review exclusively about LHES in solar stills focusing on its productivity, properties of LHES materials and the mechanisms behind the variation in properties of LHES materials. Further, in addition to this, a detailed analysis is also presented in this paper by employing analytical hierarchy process (AHP) which enable the researchers to prioritize the properties during the selection of LHES in solar still applications. Besides AHP analysis, we also evaluate the relative efficiency of the available LHES materials for solar still application by data envelopment analysis (DEA) to find the frontier LHES materials thereby suggesting the methods to augment the properties of the frontier material (identified through DEA analysis). Thus, this paper may be a reference guide in the near future for the academicians, researchers to get an overview about the various LHES materials used in solar stills and significance of their properties for improving the yield in solar still applications.

A new series of high near-infrared (NIR) reflecting pigments with colors ranging from yellow to red by tuning the Bi2Ce2O7 with rare earth ion substitutions on both A and B sites were synthesized by a solid state reaction method. The resulting colorants were evaluated for their structural and optical properties. The absorption edge is gradiently red shifted on substitution from Y to Tb resulting colors yellow to red. The XPS analysis surmises the presence of the elements with trends of reduction in Ce3+ concentration on both substitutions. These results suggest that the color shift is mainly due to charge transfer band shift of the O2− to Ce4+ (4f-5d) and deep red shift is due to the introduction of additional energy level by terbium ions. A brilliant yellow hue was obtained for Bi1.75Y0.25Ce2O7 (b∗ = 51.4), whereas Bi2Ce1.50Tb0.50O7 (a∗ = 15.0) exhibited a red color. High NIR solar reflectance of 93% and 88% were obtained for Bi0.5Y1.5Ce2O7 yellow and Bi2Ce1.50Tb0.50O7 red pigments respectively. The application study of these selected pigments was investigated in the polymer matrix which demonstrates their coloring performance for various potential applications. These results demonstrate the synthesized pigments as potential near infrared reflective candidates for cool roof applications.

Objectives To determine the implications of different prostate sampling schemes on the diagnosis of clinically significant prostate cancer (csPCA, ISUP group 2–5) and clinically insignificant prostate cancer (ciPCA, ISUP group 1) in men with abnormal multiparametric magnetic resonance imaging (mpMRI) undergoing MRI-transrectal ulrasound fusion targeted biopsies. Materials and Methods This is a retrospective analysis of a cohort including all men who had a single lesion on mpMRI of the prostate performed between January 2016 and June 2017. All men underwent an MRI-transrectal ulrasound fusion biopsy and systematic (SBx) sampling of the prostate, which combined and were considered the standard of reference. The hypothetical 3 biopsy sampling schemes were defined as follows: Targeted biopsy only (TBx), TBx + ipsilateral SBx (ipsi-SBx) and TBx + contralateral SBx (contra-SBx) and were evaluated for the detection of csPCA and ciPCA. Sensitivity and 95% intervals were calculated, McNemar test was used to compare sensitivities between the various sampling schemes. Results TBx + SBx detected csPCa in 47% (55 of 116) of the 116 men who met eligibility criteria. Sensitivity and 95% confidence intervals for csPCa detection was 85.5% (73.3%–93.5%), 96.4% (87.5%–99.6%), and 92.7 (82.4%–98%) for TBx alone, TBx + ipsi-SBx and TBx + contra-SBx, respectively. csPCa detection rates were higher for both TBx + ipsi-SBx and TBx + contra-SBx compared to TBx alone. Clinically insignificant cancers alone were detected in 7.7% (9 of 116), 10.3% (12 of 116), and 14.6% (17 of 116) of the cohort by TBx only and TBx + ipsi-SBx, and TBx + contra-SBx, respectively. Conclusions TBx + ipsi-SBx may increase the detection of csPCa while limiting overdiagnosis of indolent cancers.

Objective. Methods for separating the forward–backward components from blood pulse waves rely on simultaneously measured pressure and flow velocity from a target artery site. Modelling approaches for flow velocity simplify the wave separation analysis (WSA), providing a methodological and instrumentational advantage over the former; however, current methods are limited to the aortic site. In this work, a multi-Gaussian decomposition (MGD) modelled WSA (MGDWSA) is developed for a non-aortic site such as the carotid artery. While the model is an adaptation of the existing wave separation theory, it does not rely on the information of measured or modelled flow velocity. Approach. The proposed model decomposes the arterial pressure waveform using weighted and shifted multi-Gaussians, which are then uniquely combined to yield the forward (P F(t)) and backward (P B(t)) pressure wave. A study using the database of healthy (virtual) subjects was used to evaluate the performance of MGDWSA at the carotid artery and was compared against reference flow-based WSA methods. Main results. The MGD modelled pressure waveform yielded a root-mean-square error (RMSE) P F(t) and P B(t) were obtained. When compared with the reference counterparts, the pulse pressures (ΔP F and ΔP B), as well as reflection quantification indices, showed a statistically significant strong correlation (r > 0.96, p r > 0.83, p p > 0.05) bias. Significance. This study reports WSA for carotid pressure waveforms without assumptions on flow conditions. The proposed method has the potential to adapt and widen the vascular health assessment techniques incorporating pulse wave dynamics.

Background: Mucormycosis is an uncommon but a fatal fungal infection that usually affects patients with altered immunity. Mucormycosis is proven to be a life-threatening condition. This occurred in the delta variant epidemic of coronavirus in India. This prompted us to conduct a systematic review of deaths in mucormycosis to know its temporal associations in relation to comorbidities, association with drugs being used in COVID-19 and overall characteristics of patients with its outcome.Methods: This retrospective study was conducted over 21 deaths out of 140 mucormycosis patients in the tertiary care centre between time period from May 2021 to July 2021. Based on the detailed history, clinical examination, endoscopic examination, blood investigations and radiological investigations, data was collected and analysed. Results: In the study 19 patients were post covid and 2 were COVID positive at the time of admission to the hospital. 13 patients were having random blood sugars above 300 and 8 were having below 300 mg/dl. 13 patients had diabetic ketoacidosis. The maximum C-reactive protein (CRP) values was 200 and declined on treatment. The prothrombin time international normalized ratio (PT INR) values range between 0.99 and 1.3. Serum electrolytes were found to be normal in most of the patients. In the present study, 3 patients had electrolyte imbalance not responding to treatment. According to computed tomography/magnetic resonance imaging (CT/MRI) findings,12 had pansinusitis, 3 had pansinusitis with orbital cellulitis, 5 had pansinusitis with cavernous sinus thrombosis and 1 had pansinusitis with mandibular osteomyelitis.Conclusions: Early diagnosis, prompt treatment of comorbidities and immediate surgical debridement prevents death in mucormycosis patients.

Background: Hypokalemia is one of the most common electrolyte disturbances seen in clinical practice and in patients receiving liposomal-amphotericin B (L-AMB). The aim of this retrospective study was to examine the prevalence of hypokalemia in patients of post COVID-19 mucormycosis receiving L-AMB and to evaluate common presenting symptoms of hypokalemia in them.Methods: The present study was conducted as a retrospective study on 100 patients of post COVID-19 mucormycosis who received L-AMB for 1st time between May 2021 and August 2021 at department of otorhinolaryngology and head and neck surgery, Netaji Subhash Chandra Bose medical college and hospital, Jabalpur, Madhya Pradesh, India. Results: In the present study, hypokalemia of varying grades occurred in 23% of the patients, making it an adverse event that requires attention and correction. Hypokalemia is reported in middle aged adults, more in males compared to females and at doses less than 2 gm of L-AMB. Majority (91.30%) of the patients of mucormycosis who developed hypokalemia presented with generalized weakness, anorexia and muscle cramps followed by nausea which is seen in 82.60% patients. Constipation, bloating and abdominal pain being other presenting symptoms in them seen in 56.50%, 56.50% and 52.20% patients respectively.Conclusions: Hypokalemia is a common electrolyte disorder occurring in patients receiving L-AMB which if undetected can be life threatening. Adequate medical management of these patients not only requires proper antifungal administration but also management of electrolyte imbalances related to the administration. L-AMB is a life-saving drug provided it is used judicially and with utmost care.

T cell–replete post-transplant cyclophosphamide (PTCy)-based protocols have led to increasing use of haploidentical allogeneic hematopoietic cell transplantation (haploHCT). With this approach, bidirectional alloreactivity causing nonengraftment or severe graft-versus-host disease (GVHD) is no a longer major barrier to haploHCT. PTCy eliminates alloreactive lymphocytes but spares CD34+ stem cells and regulatory T lymphocytes, resulting in reliable hematopoietic recovery with relatively low incidence of GVHD. The immediate post-haploHCT course, usually before PTCy administration, is often complicated by cytokine release syndrome (CRS). The predictors of CRS and its effect on outcomes post-transplant have not been fully ascertained. We analyzed the outcomes of 66 patients who received haploHCT at our institution. Using published CRS criteria we identified 48 patients who developed CRS. In multivariate analysis peripheral blood grafts were significantly associated with grade ≥ 2 CRS, compared with bone marrow. Grade ≥ 2 CRS (compared with grade

In this work, we synthesized and characterized a narrow band red emitting Gd3Zn2Nb3O14:Eu3+ phosphor in order to improve the color qualities of warm white light emitting diodes. The phosphors were synthesized via conventional solid state reaction method and investigated the evolution of emission spectra with partial occupation of Zn2+ ions on both A and B site of the fergusonite type structure. The structural and luminescence property analysis corroborates the occupancy of Eu3+ ions in the Gd3+/Zn2+ ion site (A site). The developed phosphor exhibits a strong red emission peaking at 613 nm with a fwhm of merely ∼3.50 nm under the 392 nm excitation. These compounds produce narrow emissions in the visible red spectral regions that are highly professed by human eye and lead to outstanding chromatic saturation of the red spectra. The enhanced electric dipole transition intensity arises from the symmetry distortion of Eu3+ ions caused by the introduction of Zn2+ ions in the lattice. The distortion of the A site symmetry and the red shift of the charge transfer energy leads to an intense 5D0 – 7F2 hypersensitive electric dipole transition under 392 nm excitation. The relative emission intensity was found to be maximum at x = 0.40 and is 3.9 times higher than that of the commercial red phosphor under the 392 nm excitation. These phosphors with remarkable CIE chromaticity coordinates (0.64, 0.35), good CCT values along with high color purity (94.2%) might have significant applications in display devices and evidence as an efficient red phosphor.