Association between Vitamin D Receptor Gene Polymorphism (Fok 1), Vitamin D Status and Autoimmune Thyroiditis.

Autoimmune thyroiditis gradually destroys the thyroid gland leading to hypothyroidism and may even lead to papillary thyroid carcinoma. Deficiency of Vitamin D has been linked to development of autoimmunity. Single nucleotide polymorphisms of the Vitamin D receptor gene have associated with autoimmune diseases in several studies. In this hospital based non interventional cross-sectional study Vitamin D receptor gene was studied for FokI (rs2228570) polymorphism from purified DNA in forty-eight adult cases and fifty age and sex matched healthy controls. This study was conducted in the department of Biochemistry, Calcutta National Medical College, Kolkata, West Bengal, India from January 2021 to July 2022. Their DNA was isolated using phenol chloroform method and were analysed for the related single nucleotide polymorphism by restriction digestion using appropriate restriction enzymes after amplification by PCR. Differences in allele frequencies between two groups were estimated by chi square and odds ratio test. Any potential association between the vitamin D anti TPO antibody and thyroid hormone status with polymorphic variations were assessed by post hoc ANOVA among the three genotypes. The distribution of FF genotype was significantly higher among the case group (Χ²=10.2788, p=0.006). The odds ratio for the allele F was significantly higher in case group for a range of 1.97 to 5.94 for 95 percent confidence interval (Χ²=13.9678, p=<0.001). The genotype FF group had significantly lowest Vitamin D (p=0.008) and highest Anti TPO ab (p=0.031) compared to Ff and ff genotypes. Thus, significant association was revealed between the VDR gene Fok1(rs2228570) polymorphism and autoimmune thyroiditis with the predominance of FF genotype being a strong susceptibility factor for autoimmune thyroiditis and Vitamin D deficiency in the studied population of Eastern India.

A Single-Institution Review of the Use of Radiation in the Adjuvant and Definitive Management of Keloids.

AIMS: Many individuals suffer from keloids that are refractory to standard treatment modalities, including surgical excision alone. Radiation therapy can be used to reduce the risk of recurrent keloids post-operatively, as well as be used as primary treatment for keloids not amenable to surgical resection. The purpose of this study was to review our institutional experience of radiation therapy for keloid management. MATERIALS AND METHODS: A retrospective review of patients treated with radiation therapy for keloids between 2014 and 2020 at our institution was performed. RESULTS: A total of 70 keloids in 41 patients were treated. For the 55 keloids treated with post-operative radiation therapy (16Gy delivered in 2 fractions), 82.5% (33/40) of evaluable lesions did not recur. Among the 15 keloids treated with definitive radiation therapy (24Gy delivered in 3 fractions), 78.6% (11/14) of evaluable keloids showed complete flattening, and 14.3% (2/14) had partial flattening. Both acute and late toxicities were mild, with only a single instance of grade 3 toxicity (dermatitis). CONCLUSION: Our study confirms that radiation therapy has a role in reducing the risk of keloid recurrence post-operatively, and plays an important role in the definitive management of unresectable keloids.

Short-course Palliative Hypofractionated Radiotherapy in Patients with Poor-prognosis High-grade Glioma: Survival and Quality of Life Outcomes from a Prospective Phase II Study.

AIMS: To report longitudinal quality of life (QoL) outcomes and survival in patients with poor-prognosis high-grade glioma (HGG) treated with palliative hypofractionated radiotherapy. MATERIALS AND METHODS: Patients with poor-prognosis HGG were accrued on a prospective study of short-course palliative hypofractionated radiotherapy (35 Gy/10 fractions/2 weeks). The European Organization for Research and Treatment of Cancer QoL core questionnaire (QLQ-C30) and brain cancer module (BN20) were used in English or validated Indian vernacular languages (Hindi and Marathi) for QoL assessment at baseline (before radiotherapy), the conclusion of radiotherapy, 1 month post-radiotherapy and subsequently at 3-monthly intervals until disease progression/death. Baseline QoL scores were compared with corresponding scores from a historical HGG cohort. Summary QoL scores were compared longitudinally over time by related samples Friedman's two-way test. Progression-free survival and overall survival were calculated using the Kaplan-Meier method and reported as 1-year estimates with 95% confidence intervals. RESULTS: Forty-nine (89%) of 55 patients completed the planned course of hypofractionated radiotherapy. Longitudinal QoL data were available in 42 (86%) of 49 patients completing radiotherapy, comprising the present cohort. The median age of included patients, comprised mainly of glioblastoma patients (81%), was 57 years, with an interquartile range (IQR) of 50-66 years and a median baseline Karnofsky score of 60 (IQR = 50-60). Baseline QoL scores were significantly worse for several domains compared with a historical institutional cohort of HGG patients treated previously with conventionally fractionated radiotherapy, indicating negative selection bias. QoL scores remained stable for most domains after palliative hypofractionated radiotherapy, with statistically significant improvements in fatigue (P = 0.032), dyspnoea (P = 0.042) and motor dysfunction (P = 0.036) over time. At a median follow-up of 8 months, Kaplan-Meier estimates of 1-year progression-free survival and overall survival were 33.3% (95% confidence interval 21.7-51.1%) and 38.1% (95% confidence interval 25.9-56%), respectively. CONCLUSION: Short-course palliative hypofractionated radiotherapy in patients with poor-prognosis HGG is associated with stable and/or improved QoL scores in several domains, making it a viable resource-sparing regimen.

High-dose salvage re-irradiation in recurrent/progressive adult diffuse gliomas: development of a novel prognostic scoring system.

PURPOSE: Over the past two decades, high-dose salvage re-irradiation (re-RT) has been used increasingly in the multimodality management of adults with recurrent/progressive diffuse glioma. Several factors that determine outcomes following re-RT have been incorporated into prognostic models to guide patient selection. We aimed to develop a novel four-tiered prognostic model incorporating relevant molecular markers from our single-institutional cohort of patients treated with high-dose salvage re-RT for recurrent/progressive diffuse glioma. MATERIAL AND METHODS: Various patient, disease, and treatment-related factors impacting upon survival following salvage re-RT were identified through univariate analysis. Each of these prognostic factors was further subdivided and assigned scores of 0 (low-risk), 1 (intermediate-risk), or 2 (high-risk). Scores from individual prognostic factors were added to derive the cumulative score (ranging from 0 to 16), with increasing scores indicating worsening prognosis. RESULTS: A total of 111 adults with recurrent/progressive diffuse glioma treated with salvage high-dose re-RT were included. We could assign patients into four prognostic subgroups (A=15 patients, score 0-3); (B=50 patients, score 4-7); (C=33 patients, score 8-10); and (D=13 patients, score 11-16) with completely non-overlapping survival curves suggesting the good discriminatory ability. Post-re-RT survival was significantly higher in Group A compared to groups B, C, and D, respectively (stratified log-rank p-value <0.0001). CONCLUSION: There exists a lack of universally acceptable 'standard-of-care' salvage therapy for recurrent/progressive diffuse glioma. A novel four-tiered prognostic scoring system incorporating traditional factors as well as relevant molecular markers is proposed for selecting patients appropriately for high-dose salvage re-RT that warrants validation in a non-overlapping cohort.

Enabling ultra-low-voltage switching in BaTiO3.

Single crystals of BaTiO3 exhibit small switching fields and energies, but thin-film performance is considerably worse, thus precluding their use in next-generation devices. Here, we demonstrate high-quality BaTiO3 thin films with nearly bulk-like properties. Thickness scaling provides access to the coercive voltages (<100 mV) and fields (<10 kV cm-1) required for future applications and results in a switching energy of <2 J cm-3 (corresponding to <2 aJ per bit in a 10 × 10 × 10 nm3 device). While reduction in film thickness reduces coercive voltage, it does so at the expense of remanent polarization. Depolarization fields impact polar state stability in thicker films but fortunately suppress the coercive field, thus driving a deviation from Janovec-Kay-Dunn scaling and enabling a constant coercive field for films <150 nm in thickness. Switching studies reveal fast speeds (switching times of ~2 ns for 25-nm-thick films with 5-µm-diameter capacitors) and a pathway to subnanosecond switching. Finally, integration of BaTiO3 thin films onto silicon substrates is shown. We also discuss what remains to be demonstrated to enable the use of these materials for next-generation devices.

Atoltivimab/maftivimab/odesivimab (Inmazeb) combination to treat infection caused by Zaire ebolavirus.

Zaire ebolavirus has been responsible for several catastrophic outbreaks with a high mortality rate. Unfortunately, there were no approved therapies or vaccines to treat or prevent infections caused by Ebola virus (EBOV) or other filoviruses. Atoltivimab/ maftivimab/odesivimab (Inmazeb) is the first Food and Drug Administration (FDA)-approved treatment for Zaire ebolavirus infection in adult and pediatric patients, including neonates born to a mother who is reverse transcription polymerase chain reaction (RT-PCR)-positive for Zaire ebolavirus infection. The efficacy of Inmazeb has been established in vivo and it has successfully completed a phase I clinical trial in healthy individuals with no drug-related adverse effects. Additionally, Inmazeb has displayed significant reduction in mortality in the PALM (PAmoja tuLinde Maisha) trial, when compared with the control arm receiving ZMapp. Inmazeb has received orphan drug designation from both the U.S. FDA and the European Medicines Agency (EMA).

Association of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Ureaplasma species infection and organism load with cervicitis in north Indian population.

Cervicitis is predominantly caused by Neisseria gonorrhoeae and Chlamydia trachomatis, which accounts for almost half of all the cases of cervicitis. The role of newer organisms like Mycoplasma genitalium and Ureaplasma sp. and association of bacterial load with cervicitis are also not well established. So the study aimed to determine the relative frequency of these organisms and their load in association with cervicitis cases from north India. A case-control study involving 300 women was conducted using quantitative real-time PCR from endocervical swabs for identification of organisms and quantification of bacterial load. Among 150 cervicitis cases, C. trachomatis, N. gonorrhoeae, M. genitalium and Ureaplasma parvum were detected in 5 (3·3%), 10 (6·6%), 37(24·6%) and 47 (31·3%) respectively. Old age (<0·001, chi-squared test) and irregular menstrual cycles (<0·001, chi-squared test) were significantly associated with cervicitis. M genitalium was the only organism to be associated significantly with cervicitis with regard to age (<0·031) and symptoms like discharge (P < 0·033, chi-squared test) and dysuria (P < 0·044, chi-squared test) in multivariate analysis. Our finding suggests that the bacterial load of these organisms is not significantly associated with cervicitis. However, we found significant association of M. genitalium infection with clinical characteristics of cervicitis cases.

Update on nifurtimox for treatment of Chagas disease.

Chagas disease is a vector-borne neglected tropical disease caused by Trypanosoma cruzi. It is a systemic and chronic parasitic infection which is endemic in 21 countries with 10 million cases worldwide and 12,000 annual deaths. Around 70 million people in the Americas are at risk of contracting this disease, and less than 1% of infected people are treated due to low disease awareness and limited access to treatment. The current treatment for Chagas disease consists of benznidazole and nifurtimox under the World Health Organization (WHO) authorization protocol. The current treatment has limitations in terms of efficacy against the chronic phase of infection and side effects associated with prolonged therapy. This review provides an update on nifurtimox progress over the years and its recent approval by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of Chagas disease in pediatric patients under 18 years of age.

Pretomanid for the treatment of pulmonary tuberculosis.

Discovering novel drugs active against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is currently one of the most unmet medical needs. In this context, pretomanid (PA-824), a novel nitroimidazole prodrug that targets both replicating and nonreplicating cells, is being developed by TB Alliance under license from Novartis. In replicating Mtb, pretomanid inhibits mycolic acid biosynthesis, which is an important building block of Mtb cell wall. Under nonreplicating conditions, pretomanid is reduced by deazaflavin-dependent nitroreductase, leading to generation of reactive nitrogen species exhibiting potent antimycobacterial activity. The U.S. Food and Drug Administration (FDA) has approved pretomanid under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD pathway) for treatment of adult patients with treatment-intolerant or nonresponsive multidrug-resistant TB and extensively drug-resistant TB in combination with bedaquiline and linezolid as part of the oral.

Levonadifloxacin arginine salt to treat acute bacterial skin and skin structure infection due to S. aureus including MRSA.

Acute bacterial skin and skin structure infections (ABSSSIs) are one of the most common types of infections due to methicillin-resistant Staphylococcus aureus (MRSA). The standard of care for ABSSSI includes glycopeptides such as vancomycin, teicoplanin, oxazolidinones and fluoroquinolones, which are potent broad-spectrum antibacterial agents. Unfortunately, due to indiscriminate utilization, resistance to these agents is rising and identification of novel agents is an urgent unmet medical need. In this context, levonadifloxacin (WCK-771) is a novel, hydrate arginine salt of nadifloxacin with improved bactericidal activity against MRSA as well as fluoroquinolone-resistant S. aureus by targeting bacterial DNA supercoiling enzymes DNA gyrase and topoisomerase IV. Levonadifloxacin displays a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria, atypical bacteria, anaerobic bacteria and bioterror pathogens with a very low frequency of mutation. Levonadifloxacin also displays improved activity under low pH biofilm environments. The drug has successfully completed phase I, phase II and phase III clinical trials in India. The U.S. Food and Drug Administration (FDA) granted a Qualified Infectious Disease Product (QIDP) designation to levonadifloxacin for the treatment of MRSA infections in August 2014.

Predictive mechanistic model for single-layered pressure-sensitive adhesive (PSA) joints : Part I: Uniaxial tensile stress-strain response.

Modeling the deformation of structures containing pressure-sensitive adhesive (PSA) joints can be a challenging task because of the dependence of the deformation mechanism on a) PSA adhesive properties and b) the bonding substrate's surface properties, such as surface energy and surface roughness. These parameters have significant and unique effects on the mechanical response of the joint. This paper is part of a two-part series, where a mechanism-based predictive modeling approach, supported by empirical observations, is presented for modeling the uniaxial tensile mechanical behavior of single-layered PSA joints based on acrylic PSA materials. This paper (Part I) addresses the stress-strain response, while Part II of this series will address the creep behavior. The underlying model is based on multiple mechanisms: i) cavity nucleation and growth in the bulk adhesive material of the PSA system, as well as at the interfaces between the PSA and the substrate; ii) fibrillation of the cavitated adhesive layer and iii) interfacial slippage between the adhesive and the bonding substrate; iv) PSA delamination from the substrate. This predictive model can be used as a virtual testing tool to generate stress-strain curves for constitutive models of PSA joints under different tensile loading conditions.

Focal Leptomeningeal Disease with Perivascular Invasion in EGFR-Mutant Non-Small-Cell Lung Cancer.

We report a previously undescribed pattern of brain metastases in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer treated with tyrosine kinase inhibitors and radiation therapy. These highly distinct lesions appear to spread focally within the leptomeninges, with invasion along the perivascular spaces (FLIP). The survival of patients with FLIP was significantly better compared with patients with classic leptomeningeal disease (median survival, 21 versus 3 months; P = .003). It is unclear whether this pattern of growth is unique to epidermal growth factor receptor-mutated non-small-cell lung cancer.

Lascufloxacin hydrochloride to treat bacterial infection.

Lascufloxacin hydrochloride (AM-1977) is a novel 8-methoxy fluoroquinolone antibacterial agent with a unique pharmacophore at the 1st and 7th positions of the quinoline nucleus developed by Kyorin Pharmaceutical Co., Ltd. (Tokyo, Japan). It has been approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for treatment of respiratory tract and ear, nose and throat infections including community-acquired pneumonia and otorhinolaryngological infections, and shows great promise against fluoroquinolone-resistant strains of major pathogens which infect the respiratory tract. It is suitable for treating infections caused by Staphylococcus, Streptococcus, Pneumococcus, Moraxella (Branhamella) catarrhalis, Klebsiella, Enterobacter, Haemophilus influenzae, Legionella pneumophila, Prevotella and Mycoplasma pneumoniae that are sensitive to this drug.

Imipenem/cilastatin sodium/relebactam fixed combination to treat urinary infections and complicated intra-abdominal bacterial infections.

Imipenem/cilastatin sodium/relebactam is a combination of imipenem/cilastatin, a U.S. Food and Drug Administration (FDA)-approved antibiotic, and ß-lactamase inhibitor relebactam which has been developed for the treatment of complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) due to drug-resistant bacterial pathogens. The combination (Recarbrio) has been designated as a qualified infectious disease product (QIDP) and obtained FDA approval in 2019 for the treatment of cUTI and cIAI caused by susceptible Gram-negative microorganisms in adult patients with limited or no alternative treatment options. The product was also approved by the European Medicines Agency (EMA) in 2020 for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.

Mechanochemical symmetry breaking during morphogenesis of lateral-line sensory organs.

Actively regulated symmetry breaking, which is ubiquitous in biological cells, underlies phenomena such as directed cellular movement and morphological polarization. Here we investigate how an organ-level polarity pattern emerges through symmetry breaking at the cellular level during the formation of a mechanosensory organ. Combining theory, genetic perturbations, and in vivo imaging, we study the development and regeneration of the fluid-motion sensors in the zebrafish's lateral line. We find that two interacting symmetry-breaking events - one mediated by biochemical signaling and the other by cellular mechanics - give rise to precise rotations of cell pairs, which produce a mirror-symmetric polarity pattern in the receptor organ.

Sarecycline hydrochloride for the treatment of acne vulgaris.

Sarecycline hydrochloride (Seysara) is a novel, narrow-spectrum tetracycline derivative approved by the U.S. Food and Drug Administration (FDA) in October 2018 for the treatment of inflammatory non-nodular moderate to severe acne vulgaris. It was initially developed by Paratek Pharmaceuticals, Inc. (U.S.) and Allergan plc (U.S.), which later was acquired by Almirall S.A. (Barcelona, Spain). Almirall S.A. obtained U.S. FDA approval of oral sarecycline tablets under the trade name Seysara. Sarecycline exhibits antibacterial activity against important skin/soft tissue pathogens with targeted activity against Cutibacterium acnes--an anaerobic Gram-positive bacterium linked with acne lesions--and also exerts anti-inflammatory effects as do other tetracyclines used in the treatment of acne vulgaris. Interestingly, unlike the broad-spectrum tetracyclines, sarecycline is less potent against aerobic Gram-negative bacilli and anaerobic bacteria associated with endogenous intestinal microbial flora. This provides it with a more specific antibacterial spectra with lower chances of adverse off-target antibacterial effects, thus making it a promising choice of treatment over others in its class. It has also demonstrated low propensity to resistance as compared with other tetracyclines and is also active against tetracycline-resistant Staphylococcus aureus as well as erythromycin- and clindamycin-resistant C. acnes strains. Sarecycline has successfully undergone numerous phase I, phase II and three phase III studies establishing it as a well-tolerated once-daily oral drug available as a tablet for the treatment of patients 9 years of age or above.

Management of multidrug-resistant tuberculosis in the 21st century.

The spread of drug-resistant tuberculosis (TB) continues to be a global health crisis with increasing cases of multidrug-resistant TB (MDR-TB) being diagnosed worldwide. The identification and clinical management of MDR-TB is associated with additional problems related to resistance, diagnosis and treatment as compared to drug-susceptible TB. Treatment of MDR-TB usually involves therapy with long regimens of second-line drugs up to 24 months resulting in higher risks of serious adverse effects, lack of compliance and heightened economic burden on the patients. Issues such as increasing transmission of drug-resistant strains, poor diagnostic coverage and lengthy, toxic treatments need to be overcome by innovative approaches such as quick diagnostic tools and shorter drug regimens as already recommended by the World Health Organization (WHO) in its 2018 Global Tuberculosis Report. This review highlights the challenges being faced by clinicians worldwide in the diagnosis and treatment of MDR-TB.

Triclabendazole for the treatment of fascioliasis.

Fascioliasis is a neglected tropical disease that is commonly caused by flatworms affecting both domestic ruminants and humans. Fascioliasis currently affects roughly 17 million people globally with additional 180 million people at risk of developing infection. Despite the gigantic patient pool, clinicians typically have very few treatment options available. In this context, triclabendazole (Fasinex, Egaten) is the only medication approved by the Food and Drug Administration (FDA) for the treatment of fascioliasis. The FDA approval has been granted in 2019 although the drug was already utilized in the veterinary setting. Recently, three hits from the Pathogen Box have been identified in vitro as exhibiting potent anti-fascioliasis activity in an effort to identify other drugs active against fascioliasis.

Delafloxacin meglumine for the treatment of acute bacterial skin and skin structure infections (ABSSSI).

Delafloxacin meglumine (Baxdela, WQ-3034, ABT-492, RX-3341; Melinta Therapeutics) was approved by the U.S. Food and Drug Administration (FDA) in June 2017 for the treatment of acute bacterial skin and skin structure infections on the basis of data from two phase III trials. Delafloxacin is a broad-spectrum anionic fluoroquinolone and its distinct chemical structure increases its potency in acidic environments. It is known to inhibit DNA replication and repair by targeting DNA gyrase and topoisomerase IV. Delafloxacin is administered via both oral and parenteral routes. It has potent activity against methicillin-resistant Staphylococcus aureus and Streptococci, and is also effective against Enterobacteriaceae and Pseudomonas aeruginosa. Delafloxacin is currently in phase III evaluation for treatment of community-acquired pneumonia and was classified as a qualified infectious disease product by the U.S. FDA in its approval.