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Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these ‘hypertension polypills’ were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.

Background and Objectives: Axillary tissue hypertrophy consists of ectopic breast tissue and occurs in up to six percent of women. Women complain of pain, interference with activity, and dissatisfaction with appearance. While it is recommended that accessory breast tissue be removed via surgical excision, there is lack of consensus on the best technique for the surgical management of axillary tissue hypertrophy. In this study, the senior authors (BC and NT) review outcomes and complications as they pertain to the surgical treatment of axillary tissue hypertrophy and axillary contouring. Materials and Methods: A retrospective review of all patients (n = 35), from two separate institutions, who presented with axillary tissue hypertrophy between December 2019 and August 2021 was conducted. All patients underwent a technique that included direct crescentic dermato-lipectomy and glandular excision with axillary crease obliteration. Tissue was sent for histological analysis after removal. During a six-month follow-up period, all patient outcomes were recorded. Results: The authors treated 35 women with axillary tissue hypertrophy. All patients complained of aesthetic deformity with significant discomfort leading to the desire for surgery. Histologically, all specimens contained benign breast and adipose tissue. Hypertrophic scarring, seroma, and axillary cording were noted complications. Conclusions: Detailed is the surgical management and optimal technique that can be used to treat both adipose and fibroglandular axillary tissue hypertrophy while simultaneously providing a favorable axillary aesthetic.

A first-of-its-kind, inductively driven micro-particle (Pellet) accelerator and injector have been developed and operated successfully in ADITYA-U circular plasma operations, which may ably address the critical need for a suitable disruption control mechanism in ITER and future tokamak. The device combines the principles of electromagnetic induction, pulse power technology, impact, and fracture dynamics. It is designed to operate in a variety of environments, including atmospheric pressure and ultra-high vacuum. It can also accommodate a wide range of pellet quantities, sizes, and materials and can adjust the pellets’ velocities over a coarse and fine range. The device has a modular design such that the maximum velocity can be increased by increasing the number of modules. A cluster of lithium titanate/carbonate (Li _2 TiO _3 /Li _2 CO _3 ) impurity particles with variable particle sizes, weighing ∼50–200 mg are injected with velocities of the order of ∼200 m s ^−1 during the current plateau in ADITYA-U tokamak. This leads to a complete collapse of the plasma current within ∼5–6 ms of triggering the injector. The current quench time is dependent on the amount of impurity injected as well as the compound, with Li _2 TiO _3 injection causing a faster current quench than Li _2 CO _3 injection, as more power is radiated in the case of Li _2 TiO _3 . The increase in radiation due to the macro-particle injection starts in the plasma core, while the soft x-ray emission indicates that the entire plasma core collapses at once.

The ADITYA upgrade (ADITYA-U), a medium-sized $\left( {{R_0} = 75{\text{ cm}},\,\,a = 25{\text{ cm}}} \right)$ conventional tokamak facility in India, has been consistently producing experiments findings by using circular and shaped-plasmas. Recognizing the plasma parameters aligning closely with the design parameters of circular limited plasmas, ADITYA-U shifted its focus toward exploring the operational regime for experimentation on saw-tooth and MHD phenomena. Moreover, ADITYA-U has made consistent advancements toward conducting preliminary plasma shaping experiments through the activation of top and bottom divertor coils utilizing hydrogen as well as deuterium fuels. Confinement is improved by a factor of ∼1.5 in ${D_2}$ plasmas when compared to H _2 plasmas of ADITYA-U. Further, ADITYA-U operations emphasize preventing disruptions and runaway electrons (REs) to ensure safe operations for future fusion devices. Significant suppression of REs has been achieved in ADITYA-U with the application of pulsed localized vertical magnetic field (LVF) perturbation, thereby establishing the technique’s independence from the tokamak device. The successful RE mitigation requires a critical threshold of LVF pulse magnitude, which is approximately 1% of the toroidal magnetic field, and a minimum duration of ∼5 ms. Apart from this, several novel findings have been achieved in the ADITYA-U experiments, including the modification of sawtooth duration through gas-puff, the emergence of MHD-induced geodesic acoustic mode-like oscillations, the propagation of fast heat pulses induced by MHD activity, the control of RE dynamics through Gas-puffs, the propagation of pinch-driven cold-pulses, the transport and core accumulations of argon impurities, the mass dependency of plasma toroidal rotation and the detection of ‘RICE’ scaling, as well as the characterization of edge plasma using wall conditioning methods, such as glow discharge cleaning using a combination of Ar -H _2 mixture, localized wall cleaning by electron cyclotron resonant plasma, and the development of machine learning-based disruption predictions, will be discussed in this paper.

Intrinsic toroidal rotation velocity ( V _φ ) has been measured from the Doppler shift of C ^5+ carbon spectral lines (at 529.05 nm) in the edge region of the ADITYA-U tokamak without any auxiliary torque input in an ohmically heated pure hydrogen (H _2 ) plasma as well as in H _2 plasmas seeded with medium-Z (neon and argon) impurities . The toroidal rotation in the edge region is observed to reverse its direction from the counter-current to the co-current direction with an increase in plasma current beyond I _p ∼ 145–150 kA. Furthermore, a systematic decrease in the co-current V _φ has been observed with the edge density, which tends to decrease to almost zero velocity with an increase in the edge density. The injection of medium- Z (neon and argon) impurities is observed to influence the edge toroidal rotation significantly. In low I _p discharges, argon injection leads to a reversal of edge intrinsic rotation from the counter-current to the co-current direction. In high I _p discharges, both neon and argon seeding enhance the co-current rotation by about ∼5–10 km s ^−1 , at a constant I _p compared to pure H _2 discharges. Simultaneous measurements of the edge radial electric field, E _r , shows that the E _r × B _θ flow seems to be driving the edge toroidal rotation in ADITYA-U. With impurity injection, the E _r also gets modified, leading to an observed increase in the edge toroidal rotation.

The effect of impurity on the electrostatic microturbulence in ADITYA-U tokamak is assessed using global gyrokinetic simulations. The realistic geometry and experimental profiles of the ADITYA-U are used, before and after argon gas seeding, to perform the simulations. Before the impurity seeding, the simulations show the existence of the trapped electron mode (TEM) instability in three distinct regions on the radial-poloidal plane. The mode is identified by its linear eigenmode structure and its characteristic propagation in the electron diamagnetic direction. The simulations with Ar ^1+ impurity ions in the outer-core region show a significant reduction in the turbulence and transport due to a reduction in the linear instability drive, with respect to the case without impurity. A decrease in particle and heat transport in the outer-core region modifies the plasma density profile measured after the impurity seeding. It, thus, results in the stabilization of the TEM instability in the core region. Due to the reduced turbulence activity, the electron and ion temperatures in the central region increase by about 10%.

Effective control of impurities and precise regulation of the fueling gas are supreme prerequisites for optimal operation in any fusion device. Conventional wall-conditioning methods fall short of achieving optimal wall conditioning. Conventional wall-conditioning methods, such as vessel baking and H _2 /(D _2 )-fueled glow discharge cleaning (GDC), are generally required to remove wall-absorbed impurities in bulk after vessel venting. The excess amount of hydrogen, injected during H _2 GDC, can be reduced by helium (He)-fueled GDC. However, He removal from the vessel is more challenging due to its low molecular mass, very low condensation temperature, and inert characteristics. In ADITYA-U, optimal wall conditioning cannot be achieved using H _2 followed by He-fueled GDC when applied for extended periods spanning hours or days. A GDC with a mixture of argon and hydrogen (Ar–H _2 ) is introduced in the ADITYA-U tokamak to obtain better wall conditioning than H _2 followed by He GDC. In Ar–H _2 GDC, long-lived ArH ^+ ions are formed in sufficient numbers and accelerated toward the vessel wall with high momentum. This results in the breaking of high energy bonds of impurities with the wall/plasma facing components, which is not possible by H ^+ , H _2 ^+, H _3 ^+ ions in H _2 GDC due to their lower momentum. An optimal blend ratio of Ar to H _2 is established at 15%–20% for the mixture. This composition ensures that the introduction of high- Z Ar does not adversely affect tokamak plasma operations. The C- and O-containing impurities are reduced beyond the limit of the prolonged operation of H _2 GDC. Relative low pressures of dominant impurities such as CO, CH _4 , and H _2 O are obtained due to the Ar–H _2 GDC compared to routinely operated H _2 GDC. A comparison study of H _2 GDC and the developed Ar–H _2 GDC is performed in terms of wall conditioning and tokamak plasma operation. The encouraging results of the Ar–H _2 GDC are obtained in both wall cleaning and tokamak operation scenarios in the midsize tokamak ADITYA-U. This development and application of Ar–H _2 GDC are beneficial for large-sized fusion devices, leading to improved impurity reduction, reduced operational fuel consumption (H _2 /D _2 /He), and enhanced control over fuel recycling/extraction.

Runaway electron (RE) deconfinement and subsequent suppression is of prime importance for successful long-term operation of any tokamak. In this work, to deconfine and mitigate REs, the efficacy of local vertical field (LVF) perturbation has been explored numerically. LVF perturbation-assisted RE loss studies are carried out by simulating the drift orbits of the REs in magnetostatic perturbed fields and estimating the resulting orbit losses for different initial energies and magnitudes of LVF perturbation. To this end, the pre-existing PARTICLE code has been extended to the relativistic full-orbit-following code PARTICLE-3D (P3D) integrated with the magnetic field calculation code EFFI and plasma equilibrium field calculation code IPREQ to include the required fields for studying particle dynamics in general; this is then used to numerically model LVF perturbation-assisted RE deconfinement experiments conducted in the ADITYA tokamak. Simulation results show a significant (∼90%) deconfinement of REs with the application of LVF perturbation of a suitable amplitude (∼0.1% of the total magnetic field) in a preferred direction. The existence of a threshold magnitude of the applied field is also established, which is observed to be dependent on the energy of the REs. The simulation results reproduce all the experimental observations and reveal other interesting features of RE mitigation using LVF perturbation. The temporal map of orbiting time of REs shows that REs originating from the inboard side edge region ( $\psi $ _N > 0.5) of the plasma are relatively more prone to be lost with the application of suitable LVF perturbation than those originating from the plasma core. Interestingly, the simulation results demonstrate the existence of strong correlation between the safety factor ( q ) profile in the plasma edge region ( $\psi $ _N > 0.7) and the level of RE deconfinement using LVF perturbation.

Author(s): Shaji A. Manuel [1]; Dhara B. Tanna (corresponding author) [1]; Heena K. Patel [1]; Neeta Bose [1] INTRODUCTION Cardiopulmonary resuscitation (CPR) is a necessary life-saving skill for all medical [...], Background and Aims: Medical professionals must be able to perform life-saving skills like cardiopulmonary resuscitation (CPR) during emergency situations, even outside the hospital. The foundation course for the first-year medical students includes first aid and CPR training. This quasi-experimental study was conducted to assess the effectiveness of basic cardiac life support (BCLS) training based on Indian guidelines, on the self-confidence and knowledge regarding CPR of first-year medical students. Methods: This study was conducted during the foundation course for first-year medical students. The training included a common lecture for all the students followed by a 4 day long practical training in groups of 45-46 students, each day. BCLS training was carried out in three skill stations - airway, chest compressions and full sequence CPR. Students&apos; skills were recorded real time on a skill assessment manikin after completion of the hands-on training. The students were asked to fill a questionnaire regarding knowledge and self-confidence, before and after the training. The outcome measures were the difference in knowledge and self-confidence with regard to CPR before and after the training. Results: Out of the 199 students, 181 were included in the analysis. There was significant improvement in the knowledge score (pre-test - 1.46 versus post-test - 8.27, P < 0.001). The overall confidence regarding first aid skills, BCLS knowledge and self-confidence for performing BCLS improved significantly. Conclusion: There is improvement in knowledge and self-confidence regarding CPR and the students develop an acceptable level of skills after the training. Keywords: Cardiopulmonary resuscitation, emergency treatment, foundation course, simulation training, undergraduate medical education

BackgroundXpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF.MethodsWe searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394.FindingsOur search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68-1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65-1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60-0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I2

Description of the subject. According to Regulation (EC) No 2073/2005, Escherichia coli must be enumerated in raw milk butter before sales. Hygiene of batches is acceptable when a maximum of two samples out of five have levels of E. coli between 10 and 100 cfu·g-1. E. coli is still a threat to the safety of raw milk butter. Objectives. This study aimed to identify sources of E. coli in six farms facing recurrent contaminations in butter. Method. Farms were visited three times between March and May 2021. Surface samples and dairy products samples were collected throughout the process for E. coli enumeration and assessment of potential correlations between equipment contamination and hygienic quality of food products. Results. Two major sources of contamination were identified: the lack of efficacy of cleaning and disinfection practices on milk pipelines, junctions and cream separators, and absence of milk cooling in case of time-lapse of more than 2 h between milking and skimming. The use of lactic acid starters could be a helpful way to control E. coli during cream maturation, in association to adequate good manufacturing practices. Conclusions. Levels of E. coli in the considered raw milk butter batches were really high. A new decision tree is proposed that could help manufacturers and food controllers to improve hygienic quality of raw milk butter.

Introduction Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain.Research design and methods We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components.Results HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60–90, 45–59, and 30–44 mL/min/1.73 m2, overall HbA1c (canagliflozin vs placebo) decreased by −0.24%, −0.14%, and −0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control.Conclusions The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22

BackgroundDigital therapeutic platforms facilitate health care through patient-centered strategies based on multidisciplinary teams and shared decision-making. Such platforms can be used for developing a dynamic model of diabetes care delivery, which can help in improving glycemic control by promoting long-term behavior changes in people with diabetes. ObjectiveThis study aims to evaluate the real-world effectiveness of the Fitterfly Diabetes CGM digital therapeutics program for improving glycemic control in people with type 2 diabetes mellitus (T2DM) after the completion of 90 days in the program. MethodsWe analyzed deidentified data of 109 participants in the Fitterfly Diabetes CGM program. This program was delivered through the Fitterfly mobile app coupled with continuous glucose monitoring (CGM) technology. This program consists of 3 phases: the first phase is observation, wherein the patient’s CGM readings are observed for 7 days (week 1); the second phase is the intervention; and the third phase aims at sustaining the lifestyle modification introduced during the second phase. The primary outcome of our study was the change in the participants’ hemoglobin A1c (HbA1c) levels after program completion. We also evaluated the changes in participant weight and BMI after the program, changes in the CGM metrics in the initial 2 weeks of the program, and the effects of participant engagement in the program on improving their clinical outcomes. ResultsAt the end of the 90 days of the program, the mean HbA1c levels, weight, and BMI of the participants were significantly reduced by 1.2% (SD 1.6%), 2.05 (SD 2.84) kg, and 0.74 (SD 1.02) kg/m2 from baseline values of 8.4% (SD 1.7%), 74.45 (SD 14.96) kg, and 27.44 (SD 4.69) kg/m2 in week 1, respectively (P

PurposeTo describe the earliest features of ABCA4-associated retinopathy.DesignCase series.ParticipantsChildren with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy.MethodsThe retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO). Sequencing of the ABCA4 gene was performed in all patients.Main outcome measuresVisual acuity, OCT, FAF, electroretinography, and AOSLO results.ResultsEight children with ABCA4-associated retinopathy without macular atrophy were identified. Biallelic variants in ABCA4 were identified in all patients. Four children were asymptomatic, and 4 reported loss of VA. Patients were young (median age, 8.5 years; interquartile range, 6.8 years) with good visual acuity (median, 0.155 logarithm of the minimum angle of resolution [logMAR]; interquartile range, 0.29 logMAR). At presentation, the macula appeared normal (n = 3), had a subtly altered foveal reflex (n = 4), or demonstrated manifest fine yellow dots (n = 1). Fundus autofluorescence identified hyperautofluorescent dots in the central macula in 3 patients, 2 of whom showed a normal fundus appearance. Only 1 child had widespread hyperautofluorescent retinal flecks at presentation. OCT imaging identified hyperreflectivity at the base of the outer nuclear layer in all 8 patients. Where loss of outer nuclear volume was evident, this appeared to occur preferentially at a perifoveal locus. Longitudinal split-detector AOSLO imaging in 2 individuals confirmed that the greatest change in cone spacing occurred in the perifoveal, and not foveolar, photoreceptors. Electroretinography showed a reduced B-wave-to-A-wave ratio in 3 of 5 patients tested; in 2 children, recordings clearly showed electronegative results.ConclusionsIn childhood-onset ABCA4-associated retinopathy, the earliest stages of macular atrophy involve the parafovea and spare the foveola. In some cases, these changes are predated by tiny, foveal, yellow, hyperautofluorescent dots. Hyperreflectivity at the base of the outer nuclear layer, previously described as thickening of the external limiting membrane, is likely to represent a structural change at the level of the foveal cone nuclei. Electroretinography suggests that the initial site of retinal dysfunction may occur after phototransduction.

Thomas Bradbury,1 Gian Luca Di Tanna,1 Anish Scaria,1 Allison Martin,1 Fu-Qiang Wen,2 Nan-Shan Zhong,3 Jin-Ping Zheng,3 Peter J Barnes,4 Bartolome Celli,5 Norbert Berend,1 Christine R Jenkins1 On behalf of the TASCS Investigators1Respiratory Group, The George Institute for Global Health, Sydney, NSW 2042, Australia; 2West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 4National Heart & Lung Institute, Imperial College, London, UK; 5Pulmonary and Critical Care Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USACorrespondence: Thomas BradburyRespiratory Group, The George Institute for Global Health, Level 5, 1 King St, Newtown, Sydney, NSW 2042, Australia, Tel +61 2 8052 4413, Email tbradbury@georgeinstitute.org.auBackground and Objectives: The burden of chronic obstructive pulmonary disease (COPD) disproportionately affects patients in low to middle-income countries. Although the Theophylline and Steroids in COPD Study (TASCS) showed no clinical benefit from administering low-dose theophylline and prednisone in COPD patients compared to placebo, it was hypothesized that those with elevated blood eosinophil counts would receive clinical benefit from the intervention.Methods: This was a post-hoc analysis of the TASCS dataset – a double-blinded, placebo-controlled trial conducted in patients with moderate–severe COPD in China. Participants were allocated 1:1:1 to low-dose oral theophylline (100mg bd) and prednisone (5mg qd; PrT), theophylline (100mg bd) and prednisone-matched placebo (TP), or double-matched placebo (DP) groups and followed-up for 48 weeks. A baseline count of ≥ 300 eosinophils/μL blood was categorized as elevated/eosinophilic, and the primary outcome was the annualized moderate-severe exacerbation rate.Results: Of 1487 participants eligible for analysis, 325 (22%) were eosinophilic. These participants were predominantly male (82%), had a mean (SD) age of 64 (± 8) years and a predicted forced expiratory volume in 1s (FEV1) of 43% (± 16). The annualized moderate–severe exacerbation rate was significantly higher in the PrT group compared to the pooled results of the TP and DP groups (incidence rate ratio = 1.6; ([95% CI 1.06– 1.76]) p = 0.016). Changes in spirometry values and reported disease impact scores (St. George’s Respiratory Questionnaire and COPD Assessment Test) at week 48 were not significantly different between groups.Conclusion: Combination low-dose theophylline and prednisone was associated with a significant increase in the annual moderate-severe exacerbation rate in participants with a blood eosinophil count ≥ 300 cells/μL compared to placebo.Keywords: eosinophil, COPD, clinical trial, China, theophylline, prednisone