Comparison of rituximab efficacy in treatment-naive and refractory inflammatory myopathies: experiences from a tertiary care centre.

OBJECTIVES: To find out if Rituximab (RTX) is effective in "treatment naive" idiopathic inflammatory myopathies (IIM), and whether there could be differential treatment responses between the "treatment naive" and treatment "refractory" IIM. METHODS: Data obtained from a prospectively maintained database comprising patients with IIM treated with rituximab. Patient details were obtained at baseline, 3-months, 6-months intervals, and subsequent follow up visits. Treatment response was categorised as improved, worsening, or stable based on manual muscle testing (MMT8) scores, patient global and physician global improvement (PtGA and PGA) for skin and joint symptoms improvement and spirometry at 6 months. The time to clinical improvement and remission were noted and survival analysis curves were constructed. RESULTS: 60 patients with IIM (including 18 with anti-SRP myopathy) were included, out of which 33 who received RTX were treatment naïve. The remaining 27 were started on rituximab for refractory myopathy. Mean age was 39 years (SD12.58) in "treatment-naive" group and 43 years (SD 12.12) in "refractory" group. At 6 months of follow up, 48/55 (87%) patients showed response, 31/31 (100%) in "treatment-naive" and 17/24 (70%) in "refractory" cases, p 0.006*. In refractory group, 7 (29%) had stable disease. The mean changes in MMT8 were significantly more in the "treatment-naive" treatment group (13.41(SD 7.31) compared with "refractory" IIM 8.33 (SD 7.92) (p= 0.017*). Majority of patients were able to reduce dose below 5 mg/day before 6 months. No major adverse events were reported over the median follow-up of 24 (IQR 36) months. CONCLUSIONS: Rituximab is effective and safe across the spectrum of IIM. Early use in disease is associated with better outcomes.

Complement: Functions, location and implications.

The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra- and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location-based and tissue-specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement-independent functions, their effects at different locale, and their implication in disease settings.

Direct to implant reconstruction with adjustable permanent Becker implant expanders with ADM following de-epithelised skin reducing mastectomy in high-risk overweight and obese patients with severe ptosis.

Overweight and obese patients with severe ptosis undergoing mastectomy and reconstruction present a challenge to the oncoplastic breast surgeon. This paper investigates early-to medium-term outcome of high-risk overweight and obese women with severe ptosis undergoing de-epithelised skin reducing mastectomy and direct to implant reconstruction with Becker implant expanders. From Nov 2016 and April 2021, 20 Wise pattern skin reducing mastectomies (SRM) were performed, 18 with Adjustable Permanent Becker Implant expanders (APBI) and 2 with fixed volume implants. Median age was 48 years (27-73), and median FU was 21 months (4-49). There were 8 smokers and 7 patients needed radiation treatment. In the ABPI group, there was one infection, 3 patients had threatened wounds which needed revision, and one patient lost her implant. There was no locoregional recurrence or distant metastasis. There was 1 week delay in adjuvant chemotherapy for a patient with wound issues following reconstruction. One patient is awaiting autologous reconstruction following deformity subsequent to radiation treatment. In conclusion the use of APBI following de-epithelised skin reduction surgery in this high-risk group is an option with acceptable early-to medium-term outcome.

Recent advances in instrumental techniques for heavy metal quantification.

Heavy metals (HMs) are ubiquitous; they are found in soil, water, air, and all biological matrices. The toxicity, bioaccumulation potential, and deleterious effects of most of these metals on humans and the environment have been widely documented. Consequently, the detection and quantification of HMs in various environmental samples have become a pressing issue. The analysis of the concentrations of HMs is a vital component of environmental monitoring; hence, the selection of the most suitable analytical technique for their determination has become a topic of great interest in food, environment, and human health safety. Analytical techniques for the quantification of these metals have evolved. Presently, a broad range of HM analytical techniques are available with each having its outstanding merits as well as limitations. Most analytical scientists, therefore, adopt complementation of more than one method, with the choice influenced by the specific metal of interest, desired limits of detection and quantification, nature of the interference, level of sensitivity, and precision among others. Sequel to the above, this work comprehensively reviews the most recent advances in instrumental techniques for the determination of HMs. It gives a general overview of the concept of HMs, their sources, and why their accurate quantification is pertinent. It highlights various conventional and more advanced techniques for HM determination, and as one of its kind, it also gives special attention to the specific merits and demerits of the analytical techniques. Finally, it presents the most recent studies in this regard.

Immunolocalization of CD1a expressing dendritic cells in sinonasal polyposis.

Sinonasal polyps are benign projections of edematous nasal mucosa lined by respiratory epithelium. Langerhans cells (LCs) belonging to the dendritic cell family located in respiratory epithelium are involved in antigen presentation and maintenance of local immunological homeostasis. This study aims to elucidate the morphology and distribution of CD1a positive LCs in normal nasal mucosa and compare the same with polypoid nasal mucosa by immunohistochemistry. Normal nasal mucosa (n = 20) was obtained from patients who underwent septoplasty for deviated nasal septum. Polypoid nasal mucosa (n = 22) was obtained from patients with chronic rhinosinusitis (CRS) or allergic fungal rhinosinusitis who underwent excision of nasal polyps. The tissues obtained were processed for immunohistochemistry and stained with CD1a-EP80 Rabbit monoclonal antibody. In the tissues studied, CD1a positive LCs were observed in both the epithelium and lamina propria. Different morphological subtypes of LCs were noted in the epithelium. The cells were distributed adjacent to walls of subepithelial capillaries and cysts. The median number of CD1a positive LCs was significantly higher in polypoid category (13.5 per mm2) as compared with normal nasal mucosa (2.5per mm2) (p = .001). Presence of CD1a positive LCs in polypoid nasal mucosa hints at a critical immunological role in the etiopathogenesis of nasal polyps.

Recent advances in nanotechnology for remediation of heavy metals.

Heavy metal contamination of the environment has become an alarming environmental issue that has constituted serious threats to humans and the ecosystem. These metals have been identified as a priority class of pollutants due to their persistency in the environment and their potential to bioaccumulate in biological systems. Consequently, the remediation of heavy metals from various environmental matrices becomes a critical topic from the biological and environmental perspectives. To this end, various research interests have shifted to the need to put forward economically feasible and highly efficient approaches for mitigating these contaminants in the environment. Thus, numerous conventional approaches have reportedly been employed for the remediation of heavy metals, with each of the methods having its inherent limitations. More recently, studies have revealed that nanomaterials in their various forms show unique potential for the removal of various contaminants including heavy metals in comparison to their bulk counterparts making them a topic of importance to researchers in various fields. Also, various studies have documented specifically tailored nanomaterials that have been synthesized for the removal of heavy metals from various environmental matrices. This review provides up-to-date information on the application of nanotechnology for the remediation of heavy metals. It highlights various nanomaterials that have been employed for the remediation of heavy metals, current details on their methods of synthesis, factors affecting their adsorption processes, and the environmental and health impact of nanomaterials. Finally, it provides the challenges and future trends of nanomaterials for heavy metal removal.

The COVID-19 pandemic and its impact on mental health services: the provider perspective.

BACKGROUND: The impact of coronavirus disease 2019 on mental health of populations is in focus recently but few studies focus on service adaptations to ensure care provision for the mentally ill. In India, where community-based mental healthcare is led by non-government organizations (NGOs), this is a crucial time to gather evidence on how these organizations adapted to the challenges. METHODS: We explored provider perspectives in an NGO providing mental health services to communities using in-depth interviews and a focus group discussion to understand the impact on services and adaptations during the COVID 19 pandemic. RESULTS: Three elements of service provision were highlighted: established relationships with communities, responsiveness to the patient needs, and resilience in ensuring continuity. Responding to the end-to-end care needs of the clients and continual adaptations were vital for ensuring continued services. Telemedicine enabled expansion of service and clientele as well as efficiency, but there were issues of casualization of therapy and poor privacy. CONCLUSIONS: The study provides an understanding of adaptations to ensure continuity of care to mentally ill during disruptions. Insights from strategies are crucial to help plan for resilient community-based mental health care services.

Emergency remote learning in anatomy during the COVID-19 pandemic: A study evaluating academic factors contributing to anxiety among first year medical students.

BACKGROUND: 'Emergency remote learning' (ERL) has been undertaken as an emergency response globally to facilitate online shift of medical education due to COVID-19. Although medical students world-wide have reported an increased level of anxiety, factors in the academic setting during ERL that influenced anxiety levels have not been studied yet. The present study aimed to evaluate anxiety levels of first year medical students and its correlation with academic factors during ERL. METHODS: ERL for neuroanatomy was conducted for six weeks mainly by online small group teaching. At completion, feedback was collected from students (n = 97) which included a GAD-7 questionnaire for anxiety levels and a modified VARK analysis to record changes in learning styles. RESULTS: Of 97 students (M46, F51) 43.30% had minimal, 31.96% mild, 10.31% moderate and 14.43% severe anxiety. Academic exchanges such as student-teacher interaction (80.41%), tutor feedback (90.72%) and mentor meetings (81.44%) were reported to be advantageous. There was a significant (p = 0.0056) correlation between enjoyment of small group discussion and lower GAD-7 scores. There was significant change in perceived learning styles during ERL. Video calls (p = 0.018) and gaming (p = 0.022) were significant modes of stress relief. There was significant correlation (p = 0.022) between gaming and GAD-7 scores. CONCLUSION: About one-fourth of the students faced anxiety issues during ERL period. Small group interactions with focus on promoting connectedness and interaction, augmented by feedback, mentorship, familial and social support are important in reducing anxiety which should be kept in mind by educators while delivering such learning experiences.

Change in dysphagia and laryngeal function after radical radiotherapy in laryngo pharyngeal malignancies - a prospective observational study.

BACKGROUND: Intensity modulated radiotherapy (IMRT) has the perceived advantage of function preservation by reduction of toxicities in the treatment of laryngo-pharyngeal malignancies. The aim of the study was to assess changes in dysphagia from baseline (i.e. prior to start of treatment) at three and six months post treatment in patients with laryngo-pharyngeal malignancies treated with radical radiotherapy ± chemotherapy. Functional assessment of other structures involved in swallowing was also studied. MATERIALS AND METHODS: 40 patients were sampled consecutively. 33 were available for final analysis. Dysphagia, laryngeal edema, xerostomia and voice of patients were assessed at baseline and at three and six months after treatment. Radiation was delivered with simultaneous integrated boost (SIB) using volumetric modulated radiation therapy (VMAT). Concurrent chemotherapy was three weekly cisplatin 100 mg/m2. RESULTS: Proportion of patients with dysphagia rose significantly from 45.5% before the start of treatment to 57.6% at three months and 60.6% at six months post treatment (p = 0.019). 67% patients received chemotherapy and addition of chemotherapy had a significant correlation with dysphagia (p = 0.05, r = -0.336). Severity of dysphagia at three and six months correlated significantly with the mean dose received by the superior constrictors (p = 0.003, r = 0.508 and p = 0.024, r = 0.391) and oral cavity (p = 0.001, r = 0.558 and p = 0.003, r = 0.501). There was a significant worsening in laryngeal edema at three and six months post treatment (p < 0.01) when compared to the pre-treatment examination findings with 60.6% of patients having grade two edema at six months. Significant fall in the mean spoken fundamental frequency from baseline was seen at 6 months (p = 0.04), mean fall was 21.3 Hz (95% CI: 1.5-41 Hz) with significant increase in roughness of voice post treatment (p = 0.01). CONCLUSION: There was progressive worsening in dysphagia, laryngeal edema and voice in laryngo-pharyngeal malignancies post radical radiotherapy ± chemotherapy.

Proposal of a timing strategy for cholesteatoma surgery during the COVID-19 pandemic.

PURPOSE: The COVID-19 infection is an aggressive viral illness with high risk of transmission during otolaryngology examination and surgery. Cholesteatoma is known for its potential to cause complications and scheduling of surgery during the pandemic must be done carefully. The majority of otological surgeries may be classified as elective and postponed at this time (e.g., stapedotomy, tympanoplasty); whereas, others are emergencies (e.g., complicated acute otitis media, complicated cholesteatoma with cerebral or Bezold's abscess, meningitis, sinus thrombosis) and require immediate intervention. What is the ideal time for the surgical management of Cholesteatoma during the COVID-19 pandemic? METHODS: Senior otologic surgeons from six teaching hospitals from various countries affected by the COVID-19 from around the world met remotely to make recommendations on reorganizing schedules for the treatment of cholesteatoma which has a risk of severe morbidity and mortality. The recommendations are based on their experiences and on available literature. RESULTS: Due to the high risk of infecting the surgical staff it is prudent to stop all elective ear surgeries and plan cholesteatoma surgery after careful selection of patients, based on the extent of the disease and available resources. Specific precautions including use of appropriate personal protection equipment should be followed when operating on all patients during the pandemic. To facilitate the decision-making in the management of cholesteatoma, timing for surgery can be divided into two categories with 3 and 2 sub-groups based on disease severity. CONCLUSIONS: Evidence on the timing of surgery of patients with cholesteatoma during the COVID-19 pandemic is lacking. This manuscript contains practical tips on how cholesteatoma surgery can be reorganized during this pandemic.

A descriptive pilot study of mitochondrial mutations & clinical phenotype in fibromyalgia syndrome.

BACKGROUND & OBJECTIVES: : Fibromyalgia syndrome (FMS) is one of the most common chronic pain conditions of unknown aetiology. Mitochondrial dysfunction has been reported in FMS with some studies reporting the presence of mitochondrial mutation namely A3243G, which also causes mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. This pilot study was conducted to assess this mutation and also detect large deletions in mitochondrial DNA (mtDNA) in patients with FMS. METHODS: : Thirty female patients with FMS participated and 30 matched controls were included. Genomic DNA was subjected to polymerase chain reaction (PCR) amplification using specific primers followed by restriction digestion with Apa I enzyme to detect the specific A3243G mtDNA mutation. Long-range PCR was done in two sets to detect the large deletions in the mtDNA. Biochemical parameters including thyroid-stimulating hormone and vitamin D levels were also looked at. RESULTS: : None of the patients were found to carry the common mutation or large deletions. Low vitamin D level was a common finding. Hypothyroidism was found in a few patients. INTERPRETATION & CONCLUSIONS: : Although the common mutation or large mtDNA deletions were not detected in blood mtDNA in the FMS patients, mutations in the muscle and sequence variation in mtDNA remained a possibility. Future studies in both blood and muscle tissue including mtDNA sequencing are warranted in such patients to determine if a subset of FMS patients have mitochondrial myopathy.

Pharmacological Targeting of KCa Channels to Improve Endothelial Function in the Spontaneously Hypertensive Rat.

Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2-0.3 µM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology.

Addition of second-line steroid sparing immunosuppressants like mycophenolate mofetil improves outcome of Immunoglobulin G4-related disease (IgG4-RD): a series from a tertiary care teaching hospital in South India.

IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease. This disease may be associated with elevated serum and tissue IgG4 levels. Early treatment prevents fibrosis and organ damage. We retrospectively studied the clinicopathologic correlation and outcome of treatment in IgG4-RD. This single-center retrospective study was done using electronic records of patients subjected to assay of serum IgG4 levels in our laboratory by nephelometry. There were 473 patients with suspected IgG4-RD. Of them, 41 patients fulfilled comprehensive diagnostic criteria for IgG4-RD and 432 had diseases other than IgG4-RD. Clinical and histopathological data including tissue IgG4/IgG ratio, other relevant laboratory findings as well as management data of 41 patients with IgG4-RD were analyzed. There were 29 males and 12 females with mean age of 44.1 ± 2.19 years. Thirteen patients had definite, 19 had probable and 9 had possible IgG4-RD. Male predominance, multiple organ involvement and IgG4 responder Index were significantly higher in definite IgG4-RD as compared to probable and possible IgG4-RD. Serum IgG4 level was elevated in 37 patients (90.2%). Glucocorticoids were used in 35 patients (85.4%) and second-line immunosuppressive agent in 23 patients (65.7%). Of the 21 patients on follow-up, 19 (90.7%) had clinical improvement at the first follow-up visit. Nine (90%) out of the ten patients who were assessed by IgG4 responder index, also had shown improved score with treatment. Patients with IgG4-RD in our series showed favorable responses to treatment with glucocorticoids and addition of steroid sparing immunosuppressive agents (mainly mycophenolate mofetil) helped successful tapering of steroids, while maintaining the improvement.

Antinuclear antibodies in scrub typhus: Transient occurrence during acute illness.

BACKGROUND & OBJECTIVES: The pathological hallmark of scrub typhus infection is focal or disseminated vasculitis. As with other infections, antinuclear antibodies (ANA) have been previously described in scrub typhus. However, the underlying mechanisms and implications of this immunological phenomenon is not well understood. In the present work it was assessed whether ANA is associated with illness severity and outcomes. METHODS: In this prospective study spanning one year, patients fulfilling the diagnostic criteria for scrub typhus were recruited. Patients with other acute infective febrile illnesses were taken as controls. ANA positivity was compared between the cases and controls. ANA in scrub typhus was assessed for correlation with disease severity, organ dysfunction and outcomes. RESULTS: The cohort comprised of 149 patients (scrub 89; controls 60) with mean age 46.5 (SD=16.9) yr; 48.3% were female. ANA was detected in 48 (53.9%) patients with scrub typhus and 9(15%) controls (p < 0.001). The ANA pattern was predominantly speckled (93.8%) in both scrub typhus patients and controls. In patients with scrub typhus, ANA positivity was associated with increasing APACHE-III score [Odds ratio (OR) 1.01; 95% CI 0.99-1.03; p = 0.09]. On bivariate analysis, ANA tended to be correlated with acute respiratory distress syndrome (OR 2.32; 95% CI 0.98-5.46; p = 0.06), hepatic dysfunction (OR 2.25; 95% CI 0.94-5.39, p = 0.06) and aseptic meningitis (OR 6.83; 95% CI 0.80-58.05, p = 0.08). The presence of these antibodies did not correlate with duration of hospitalization or mortality. Convalescent sera on 31 ANA positive scrub typhus patients demonstrated persistence of ANA in only 5 (16.1%) patients. INTERPRETATION & CONCLUSION: The disappearance of ANA during the convalescent phase suggests that ANA is expressed during the acute phase of scrub typhus infection. Its association with organ dysfunction warrants further study of the mechanisms and impact of autoantibody formation in scrub typhus.

Myopericytoma-An Alternate Cause of Persistent Knee Pain in Rheumatoid Arthritis.

Rheumatoid Arthritis can present with consistent pain over peripheral joints. The manner of presentation of a subcutaneous tumour such as Myopericytoma may be very similar to that of an inflamed joint leading to the high frequency of it being overlooked and inadequately treated. Knowing the radiological and pathological differences will direct us in the right road to timely and adequate treatment.

The vascular endothelium: A regulator of arterial tone and interface for the immune system.

As the primary interface between the blood and various tissues of the body, the vascular endothelium exhibits a diverse range of roles and activities, all of which contribute to the overall health and function of the cardiovascular system. In this focused review, we discuss several key aspects of endothelial function, how this may be compromised and subsequent consequences. Specifically, we examine the dynamic regulation of arterial contractility and distribution of blood flow through the generation of chemical and electrical signaling events that impinge upon vascular smooth muscle. The endothelium can generate a diverse range of vasoactive compounds and signals, most of which act locally to adjust blood flow in a dynamic fashion to match tissue metabolism. Disruption of these vascular signaling processes (e.g. reduced nitric oxide bioavailability) is typically referred to as endothelial dysfunction, which is a recognized risk factor for cardiovascular disease in patients and occurs early in the development and progression of hypertension, atherosclerosis and tissue ischemia. Endothelial dysfunction is also associated with type-2 Diabetes and aging and increased mechanistic knowledge of the cellular changes contributing to these effects may provide important clues for interventional strategies. The endothelium also serves as the initial site of interaction for immune cells entering tissues in response to damage and acts to facilitate the actions of both the innate and acquired immune systems to interact with the vascular wall. In addition to representing the main cell type responsible for the formation of new blood vessels (i.e. angiogenesis) within the vasculature, the endothelium is also emerging as a source of extracellular vesicle or microparticles for the transport of signaling molecules and other cellular materials to nearby, or remote, sites in the body. The characteristics of released microparticles appear to change with the functional status of the endothelium; thus, these microparticles may represent novel biomarkers of endothelial health and more serious cardiovascular disease.

Nanoscale Electromechanics To Measure Thermal Conductivity, Expansion, and Interfacial Losses.

We study the effect of localized Joule heating on the mechanical properties of doubly clamped nanowires under tensile stress. Local heating results in systematic variation of the resonant frequency; these frequency changes result from thermal stresses that depend on temperature dependent thermal conductivity and expansion coefficient. The change in sign of the linear expansion coefficient of InAs is reflected in the resonant response of the system near a bath temperature of 20 K. Using finite element simulations to model the experimentally observed frequency shifts, we show that the thermal conductivity of a nanowire can be approximated in the 10-60 K temperature range by the empirical form κ = bT W/mK, where the value of b for a nanowire was found to be b = 0.035 W/mK(2), significantly lower than bulk values. Also, local heating allows us to independently vary the temperature of the nanowire relative to the clamping points pinned to the bath temperature. We suggest a loss mechanism (dissipation ~10(-4)-10(-5)) originating from the interfacial clamping losses between the metal and the semiconductor nanostructure.

Carrier transport in high mobility InAs nanowire junctionless transistors.

The ability to understand and model the performance limits of nanowire transistors is the key to the design of next generation devices. Here, we report studies on high-mobility junctionless gate-all-around nanowire field effect transistor with carrier mobility reaching 2000 cm(2)/V·s at room temperature. Temperature-dependent transport measurements reveal activated transport at low temperatures due to surface donors, while at room temperature the transport shows a diffusive behavior. From the conductivity data, the extracted value of sound velocity in InAs nanowires is found to be an order less than the bulk. This low sound velocity is attributed to the extended crystal defects that ubiquitously appear in these nanowires. Analyzing the temperature-dependent mobility data, we identify the key scattering mechanisms limiting the carrier transport in these nanowires. Finally, using these scattering models, we perform drift-diffusion based transport simulations of a nanowire field-effect transistor and compare the device performances with experimental measurements. Our device modeling provides insight into performance limits of InAs nanowire transistors and can be used as a predictive methodology for nanowire-based integrated circuits.