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Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Background: Medications for opioid use disorder (MOUD) reduce risks for overdose among correctional populations. Among other barriers, daily dosing requirements hinder treatment continuity post-release. Extended-release buprenorphine (XR-BUP) may therefore be beneficial. However, limited evidence exists. Objectives: To conduct a systematic review examining the feasibility and effectiveness of XR-BUP among correctional populations. Methods: Searches were carried out in Pubmed, Embase, and PsychINFO in October 2023. Ten studies reporting on feasibility or effectiveness of XR-BUP were included, representing n  = 819 total individuals (81.6% male). Data were extracted and narratively reported under the following main outcomes: 1) Feasibility; 2) Effectiveness; and 3) Barriers and Facilitators. Results: Studies were heterogeneous. Correctional populations were two times readier to try XR-BUP compared to non-correctional populations. XR-BUP was feasible and safe, with no diversion, overdoses, or deaths; several negative side effects were reported. Compared to other MOUD, XR-BUP significantly reduced drug use, resulted in similar or higher treatment retention rates, fewer re-incarcerations, and was cost-beneficial, with a lower overall monthly/yearly cost. Barriers to XR-BUP, such as side effects and a fear of needles, as well as facilitators, such as a lowered risk of opioid relapse, were also identified. Conclusion: XR-BUP appears to be a feasible and potentially effective alternative treatment option for correctional populations with OUD. XR-BUP may reduce community release-related risks, such as opioid use and overdose risk, as well as barriers to treatment retention. Efforts to expand access to and uptake of XR-BUP among correctional populations are warranted.

Background: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK., Methods: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG., Results: 132 pts were included. Median age was 56 years (28-91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5-6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts., Conclusion: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience., (© 2024. The Author(s).)

Sixteen percent of patients referred for cardiology evaluation are found to have no cause for palpitations. Studies show that hypertension intricately influences "heart rate" and "contractility,?" the key components of "palpitation." While the prevalence of hypertension is 22.4% in 18-39-year-olds, the relationship between palpitations and hypertension remains unknown in this age group. In our study, we assessed the incidence and prevalence of hypertension over 5 years in 18-40-year-olds referred for palpitations who had no known arrhythmic cause for palpitations between January 1, 206 and December 31, 2017. We found that over a period of 2.2 (0.7-4.1) years, an additional 56% patients were diagnosed with stage 1 (65/130) and stage 2 (28/130) hypertension, increasing the prevalence from 16% at the start of the study period to 72% at the end of the study period (p < .0001). Hypertensive patients were obese (BMI: 29 [24-36] kg/m 2 vs. 25 [22-31] kg/m 2 ; p = .03), used nonsteroidal anti-inflammatory drugs (NSAIDs) (62 vs. 35%; p = .04), had a stronger family history of hypertension (55 vs. 4%; p < .0001) and exhibited higher systolic (124[120-130] mmHg vs. 112[108-115] mmHg; p < .0001) and diastolic (80[76-83] mmHg vs. 72[69-75] mmHg; p < .0001) blood pressures. Hypertension is commonly diagnosed in 18-40-year-old predominantly white female patients referred for palpitations without a known arrhythmic cause. The possibility of untreated hypertension causing palpitations in this cohort needs further evaluation., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Purpose: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body radiation therapy (SBRT) has been increasingly used to treat localized lesions within a shorter timeframe. The purpose of this study is to examine the dosimetric difference between the step-and-shot intensity modulated radiation therapy (IMRT) plans on Elekta Unity and our clinical volumetric modulated arc therapy (VMAT) plans on Varian TrueBeam for HN SBRT., Method: Fourteen patients treated on TrueBeam sTx with VMAT treatment plans were re-planned in the Monaco treatment planning system for Elekta Unity MR-Linac (MRL). The plan qualities, including target coverage, conformity, homogeneity, nearby critical organ doses, gradient index and low dose bath volume, were compared between VMAT and Monaco IMRT plans. Additionally, we evaluated the Unity adaptive plans of adapt-to-position (ATP) and adapt-to-shape (ATS) workflows using simulated setup errors for five patients and assessed the outcomes of our treated patients., Results: Monaco IMRT plans achieved comparable results to VMAT plans in terms of target coverage, uniformity and homogeneity, with slightly higher target maximum and mean doses. The critical organ doses in Monaco IMRT plans all met clinical goals; however, the mean doses and low dose bath volumes were higher than in VMAT plans. The adaptive plans demonstrated that the ATP workflow may result in degraded target coverage and OAR doses for HN SBRT, while the ATS workflow can maintain the plan quality., Conclusion: The use of Monaco treatment planning and online adaptation can achieve dosimetric results comparable to VMAT plans, with the additional benefits of real-time tracking of target volume and nearby critical structures. This offers the potential to treat aggressive and variable tumors in HN SBRT and improve local control and treatment toxicity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

We propose a polarization sensitive terahertz time-domain spectrometer that can record orthogonally polarized terahertz fields simultaneously, using fibre-coupled photoconductive antennas and a scheme that modulated the emitter's polarization. The s and p channels of the multi-pixel terahertz emitter were modulated at different frequencies, thereby allowing orthogonal waveforms to be demultiplexed from the recorded signal in post-processing. The performance of the multi-pixel emitter used in this multiplexing scheme was comparable to that of a commercial single-polarization H-dipole antenna. The approach allowed two orthogonally polarized terahertz pulses to be recorded with good signal to noise (>1000:1) within half a second. We verified the capability of the spectrometer by characterizing a birefringent crystal and by imaging a polarization-sensitive metamaterial. This work has significant potential to improve the speed of terahertz polarization sensitive applications, such as ellipsometry and imaging.

Objective: Functional outcomes following facial and ocular trauma are time-sensitive and require prompt evaluation to minimise long-term vision loss, yet few studies have systematically evaluated disparities in the management of these cases. This study investigates whether a patient's race/ethnicity, primary language, insurance status, gender or age affects receipt of ophthalmology consultation for facial trauma., Methods and Analysis: This study was a retrospective cohort analysis of patients from the Elmhurst City Hospital Trauma Registry in Queens, New York who were seen for facial trauma including open globe injuries and orbital fractures between January 2014 and May 2016., Results: Of the 264 patients included, 43% reported as Hispanic, 23% white, 11% Asian, 8% black and 15% other/unknown. After controlling for confounding variables by multivariable logistic regression, neither race/ethnicity, gender, nor primary language were significantly associated with the likelihood of receiving an ophthalmology consult. However, patients with private insurance had 2.57 times greater odds of receiving an ophthalmology consultation than those with Medicaid or state corrections insurance (95% CI 1.37 to 4.95). As age increased, the likelihood of receiving an ophthalmology consultation decreased (p=0.009); patients 60 years of age and older had one-third the odds of ophthalmology consultation as younger patients (OR 0.33; 95% CI 0.16 to 0.68)., Conclusions: This study highlights that lack of ophthalmology consultation in patients with facial trauma is linked to age and underinsurance. Extra attention must be paid during primary assessments to ensure elderly patients and those with public insurance have equitable access to timely and appropriate care for facial trauma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study retrospectively reviewed data from men with localized prostate cancer treated with external beam radiotherapy (EBRT). We identified 359 men with localized prostate cancer treated with curative EBRT at the Cross Cancer Institute between 2010-2011. The volume of seminal vesicles (SVs) treated as well as dose values were extracted. These volumes were compared to gold standard contours drawn by a trained expert based on consensus European Society for Radiotherapy and Oncology (ESTRO) contouring guidelines. Patient and tumor characteristics were extracted for these patients. Memorial Sloan Kettering prostate cancer nomogram was used to assign a predicted risk of SV involvement for each patient based on baseline tumor characteristics. In patients with a predicted risk of SV involvement greater than 15% ( n = 184), 86.5% (SD = 18.6) of the base of the SVs were treated with EBRT, compared to 66.7% (SD = 32.6) for patients with a predicted risk of SV involvement less than 15% ( n = 175, p < 0.0001). Similarly, the mean percentage of proximal and total SV volumes treated with EBRT was 75.6% (SD = 24.4) and 68.7% (SD = 26.0) for patients with a predicted risk of SV involvement of greater than 15%, compared to 50.3% (SD = 31.0, p < 0.0001) and 41.0% (SD = 27.8, p < 0.0001) for patients with a risk of less than 15%. The results indicate that all parts of the SVs are more likely to be contoured in men with >15% risk of SV involvement than those with <15% risk. However, radiation oncologists still contour a high percentage of SVs in men with <15% risk of SV involvement, suggesting that there may be over-treatment of SVs that increases the risk of rectal or bladder toxicity.

The recently developed AlphaFold2 (AF2) algorithm predicts proteins' 3D structures from amino acid sequences. The open AlphaFold protein structure database covers the complete human proteome. Using an industry-leading molecular docking method (Glide), we investigated the virtual screening performance of 37 common drug targets, each with an AF2 structure and known holo and apo structures from the DUD-E data set. In a subset of 27 targets where the AF2 structures are suitable for refinement, the AF2 structures show comparable early enrichment of known active compounds (avg. EF 1%: 13.0) to apo structures (avg. EF 1%: 11.4) while falling behind early enrichment of the holo structures (avg. EF 1%: 24.2). With an induced-fit protocol (IFD-MD), we can refine the AF2 structures using an aligned known binding ligand as the template to improve the performance in structure-based virtual screening (avg. EF 1%: 18.9). Glide-generated docking poses of known binding ligands can also be used as templates for IFD-MD, achieving similar improvements (avg. EF 1% 18.0). Thus, with proper preparation and refinement, AF2 structures show considerable promise for in silico hit identification.

Competing Interests: Intérêts concurrents: Ari Cuperfain indique avoir reçu la bourse John Renner Award de l’American Association of Addiction Psychiatry. Aucun autre intérêt concurrent n’a été déclaré.

Many factors may trigger intervertebral disc (IVD) structural failure (intervertebral disc degeneration (IDD) and endplate changes), including inflammation, infection, dysbiosis, and the downstream effects of chemical factors. Of these, microbial diversity in the IVD and elsewhere in the body has been considered as one of the potential reasons for disc structural failure. The exact relationships between microbial colonization and IVD structural failure are not well understood. This meta-analysis aimed to investigate the impact of microbial colonization and its location (such as skin, IVD, muscle, soft tissues, and blood) on IVD structural failure and corresponding low back pain (LBP) if any. We searched four online databases for potential studies. The potential relationships between microbial colonization in different sample sources (such as skin, IVD, muscle, soft tissues, and blood) and IDD and endplate change were considered as primary outcomes. Odds ratio (OR) and 95% confidence intervals (CI) for direct comparisons were reported. Grading of Recommendations Assessment, Development and Evaluation (GRADE) scale was used to assess the quality of evidence. Twenty-five cohort studies met the selection criteria. Overall pooled prevalence of microbial colonization in 2419 patients with LBP was 33.2% (23.6%-43.6%). The pooled prevalence of microbial colonization in 2901 samples was 29.6% (21.0%-38.9%). Compared with the patients without endplate change, the patients with endplate changes had higher rates of microbial colonization of disc (OR = 2.83; 95% CI = 1.93-4.14; I 2  = 37.6%; p  = 0.108). The primary pathogen was Cutibacterium acnes which was present in 22.2% of cases (95% CI = 13.3%-32.5%; I 2  = 96.6%; p  = 0.000). This meta-analysis and systematic review found low-quality grade evidence for an association between microbial colonization of disc with endplate changes. The primary pathogen was C. acnes . Due to lack of enough high-quality studies and methodological limitations of this review, further studies are required to improve our understanding of the potential relationships and mechanisms of microbiota, dysbiosis, IVD colonization and IVD structural failure., Competing Interests: Ashish Diwan is an Editorial Board member of JOR Spine and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication. [Correction added on 22 June 2023, after first online publication: Conflict of Interest statement was revised], (© 2023 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Objective: Whilst microdiscectomy is an excellent reliever of pain for recalcitrant lumbar disc herniation (LDH), it has a high failure rate over time due to the ensuing reduction in mechanical stabilization and support of the spine. One option is to clear the disc and replace it with a nonhygroscopic elastomer. Here, we present the evaluation of biomechanical and biological behavior of a novel elastomeric nucleus device (Kunovus disc device [KDD]), consisting of a silicone jacket and a two-part in situ curing silicone polymer filler., Materials and Methods: ISO 10993 and American Society for Testing and Materials (ASTM) standards were used to evaluate the biocompatibility and mechanics of KDD. Sensitization, intracutaneous reactivity, acute systemic toxicity, genotoxicity, muscle implantation study, direct contact matrix toxicity assay, and cell growth inhibition assay were performed. Fatigue test, static compression creep testing, expulsion testing, swell testing, shock testing, and aged fatigue testing were conducted to characterize the mechanical and wear behavior of the device. Cadaveric studies to develop a surgical manual and evaluate feasibility were conducted. Finally, a first-in-human implantation was conducted to complete the proof of principle., Results: The KDD demonstrated exceptional biocompatibility and biodurability. Mechanical tests showed no Barium-containing particles in fatigue test, no fracture of nucleus in static compression creep testing, no extrusion and swelling, and no material failure in shock and aged fatigue testing. Cadaver training sessions showed that KDD was deemed implantable during microdiscectomy procedures in a minimally invasive manner. Following IRB approval, the first implantation in a human showed no intraoperative vascular and neurological complications and demonstrated feasibility. This successfully completed Phase 1 development of the device., Conclusion: The elastomeric nucleus device may mimic native disc behavior in mechanical tests, offering an effective way for treating LDH by way of Phase 2 and subsequent clinical trials or postmarket surveillance in the future., Competing Interests: This work is an Australian Government supported small medium company start‐up project, that is expected to work closely with academia for high‐quality research with a risky commercial prospect, while building work‐force capacity. Xiaolong Chen, Divya Bhargav, Johnathon Choi, Senori Perera, Cameron Dean, and Esther Apos are either employed or supported by Kunovus Technologies. Ashish D. Diwan conflicts as inventor are declared to IRB and he may receive possible royalties related to device for replacing nucleus and regenerating nucleus. Divya Bhargav is a shareholder. Saeed Kohan serves as a consultant in an honorary role till now and may receive consulting or research fees in the future. Richard Appleyard's institution receives MRFF support via Kunovus Technologies for Human Cadaveric Research., (© 2023 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Purpose: To investigate the usefulness and effectiveness of a dual beam-current transformer (BCTs) design to monitor and record the beam dosimetry output and energy of pulsed electron FLASH (eFLASH) beams in real-time, and to inform on the usefulness of this design for future eFLASH beam control., Methods: Two BCTs are integrated into the head of a FLASH Mobetron system, one located after the primary scattering foil and the other downstream of the secondary scattering foil. The response of the BCTs was evaluated individually to monitor beam output as a function of dose, scattering conditions, and ability to capture physical beam parameters such as pulse width (PW), pulse repetition frequency (PRF), and dose per pulse (DPP), and in combination to determine beam energy using the ratio of the lower-to-upper BCT signal., Results: A linear relationship was observed between the absorbed dose measured on Gafchromic film and the BCT signals for both the upper and lower BCT (R 2  > 0.99). A linear relationship was also observed in the BCT signals as a function of the number of pulses delivered regardless of the PW, DPP, or PRF (R 2  > 0.99). The lower-to-upper BCT ratio was found to correlate strongly with the energy of the eFLASH beam due to differential beam attenuation caused by the secondary scattering foil. The BCTs were also able to provide accurate information about the PW, PRF, energy, and DPP for each individual pulse delivered in real-time., Conclusion: The dual BCT system integrated within the FLASH Mobetron was shown to be a reliable monitoring system able to quantify accelerator performance and capture all essential physical beam parameters on a pulse-by-pulse basis, and the ratio between the two BCTs was strongly correlated with beam energy. The fast signal readout and processing enables the BCTs to provide real-time information on beam output and energy and is proposed as a system suitable for accurate beam monitoring and control of eFLASH beams., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Competing Interests: Competing interests: Ari Cuperfain reports receiving the American Association of Addiction Psychiatry John Renner Award. No other competing interests were declared.

Twinkle is a mitochondrial replicative helicase which can self-load onto and unwind mitochondrial DNA. Nearly 60 mutations on Twinkle have been linked to human mitochondrial diseases. Using cryo-electron microscopy (cryo-EM) and high-speed atomic force microscopy (HS-AFM), we obtained the atomic-resolution structure of a vertebrate Twinkle homolog with DNA and captured in real-time how Twinkle is self-loaded onto DNA. Our data highlight the important role of the non-catalytic N-terminal domain of Twinkle. The N-terminal domain directly contacts the C-terminal helicase domain, and the contact interface is a hotspot for disease-related mutations. Mutations at the interface destabilize Twinkle hexamer and reduce helicase activity. With HS-AFM, we observed that a highly dynamic Twinkle domain, which is likely to be the N-terminal domain, can protrude ∼5 nm to transiently capture nearby DNA and initialize Twinkle loading onto DNA. Moreover, structural analysis and subunit doping experiments suggest that Twinkle hydrolyzes ATP stochastically, which is distinct from related helicases from bacteriophages., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Outcomes following catheter ablation (CA) for atrial fibrillation (AF) improve as the diagnosis-to-ablation time (DAT) shortens. Use of a protocol-based integrated care model through a dedicated atrial fibrillation clinic (AFC) may serve to standardize treatment pathways and decrease DAT., Objective: To evaluate the DAT and clinical characteristics of patients with AF referred from an AFC vs a conventional electrophysiology clinic (EC)., Methods: Retrospective analysis was completed in consecutive patients undergoing index AF ablation at Riverside Methodist Hospital in 2019 with minimum 1 year follow-up. Patients were categorized based off their CA referral source (AFC vs EC) and where the initial visit following index diagnosis of AF occurred (AFC vs EC)., Results: A total of 182 patients (mean age 65 years, 64% male) were reviewed. Patients referred from an AFC (21%) had a median DAT of 342 days (interquartile range [IQR], 125-855 days) compared to patients referred from EC (79%) with a median DAT of 813 days (IQR, 241-1444 days; P = .01). Patients with their index visit following AF diagnosis occurring in the AFC (9%) had significantly shorter median DAT (127 days [IQR, 95-188 days]) compared to EC (91%) (789 days [IQR, 253-1503 days]; P = .002). Patients with DAT <1 year had lower AF recurrence than patients with DAT >1 year (P = .04, hazard ratio = 0.58, 95% confidence interval 0.3418-1.000)., Conclusion: DAT is a modifiable factor that may affect CA outcomes. Significant reductions in DAT were observed in patients evaluated through a dedicated AF clinic., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Objective: This study examines comprehensive patient and process factors that influence breast milk use in the NICU setting., Study Design: We examined the association of maternal, neonatal, and family factors and lactation support systems to identify gaps in breast milk use in a retrospective study of 865 infants born in 23-41 weeks gestation admitted to the NICU., Results: Breast milk at discharge for all infants was 89.3%, for extremely preterm 82.3%, moderately preterm 91.4%, late preterm 86.5%, and term 92.7%. Prematurity (OR 0.31 [0.17-0.56]), low birth weight, morbidities, Black maternal race (OR 0.20 [0.07-0.57]) and public insurance (OR 0.54 [0.34-0.85]) were associated with decreased breast milk use. Early initiation of feeds was associated with increased breast milk use., Conclusions: There is a need to increase social as well as hospital support systems to address gaps in breast milk use in the NICU., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Dofetilide suppresses atrial fibrillation (AF) in a dose-dependent fashion. The protective effect of AF against QT c prolongation induced torsades de pointe and transient post-cardioversion QT c prolongation may result in dofetilide under-dosing during initiation. Thus, the optimal timing of cardioversion for AF patients undergoing dofetilide initiation to optimize discharge dose remains unknown as does the longitudinal stability of QT c . The purpose of this study was to evaluate the impact of baseline rhythm on dofetilide dosing during initiation and assess the longitudinal stability of QT c-all (Bazzett, Fridericia, Framingham, and Hodges) over time., Methods: Medical records of patients who underwent preplanned dofetilide loading at a tertiary care center between January 2016 and 2019 were reviewed., Results: A total of 198 patients (66 ± 10 years, 32% female, CHADS 2 -Vasc 3 [2-4]) presented for dofetilide loading in either AF (59%) or sinus rhythm (SR) (41%). Neither presenting rhythm, nor spontaneous conversion to SR impacted discharge dose. The cumulative dofetilide dose before cardioversion moderately correlated (r = .36; p = .0001) with discharge dose. Postcardioversion QT c-all prolongation (p < .0001) prompted discharge dose reduction (890 ± 224 mcg vs. 552 ± 199 mcg; p < .0001) in 30% patients. QT c-all in SR prolonged significantly during loading (p < .0001). All patients displayed QT c-all reduction (p < .0001) from discharge to short-term (46 [34-65] days) that continued at long-term (360 [296-414] days) follow-ups. The extent of QT c-all reduction over time moderately correlated with discharge QT c-all (r = .54-0.65; p < .0001)., Conclusion: Dofetilide initiation before cardioversion is equivalent to initiation during SR. Significant QT c reduction proportional to discharge QT c is seen over time in all dofetilide-treated patients. QT c returns to preloading baseline during follow-up in patients initiated in SR., (© 2022 Wiley Periodicals LLC.)

Alcohol use disorder and gastric bypass surgery are highly comorbid. Alcohol withdrawal syndrome (AWS) is a common and potentially life-threatening event, requiring nuanced and individually tailored management depending on various clinical factors including patient history, alcohol consumption, comorbidities, and timeline of use. Although increasingly common, the literature for managing alcohol withdrawal in the gastric bypass population is quite limited. We present the case of a 45-year-old woman with a past history of Roux-en-Y gastric bypass admitted for alcohol withdrawal at a psychiatric hospital who experienced a complicated withdrawal despite adhering to standard management guidelines. She had been consuming 8 to 12 standard drinks daily, and she was therefore monitored on a Clinical Institute Withdrawal Assessment for Alcohol. She experienced only minimal withdrawal symptoms up to 48 hours following cessation of alcohol consumption. At 70 hours postcessation, she experienced a witnessed tonic-clonic seizure with associated head trauma with internal bleeding, requiring acute medical intervention. This timeline of withdrawal symptoms is atypical, yet perhaps understood in the context of her past medical history which included gastric bypass surgery. We discuss the potential complicating factors inherent in individuals who have received Roux-en-Y gastric bypass in the past with respect to alcohol metabolism. We discuss the similar considerations with respect to altered metabolism of therapeutics commonly used in managing this condition. Lastly, we include a review of the extent literature on this topic and propose possible considerations for managing this unique but increasingly prevalent clinical scenario., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

Purpose: Low back pain (LBP), a widely prevalent and costly disease around the world, is mainly caused by intervertebral disc (IVD) degeneration (IDD). Although numerous factors may trigger this degenerative process, microbiome dysbiosis has recently been implicated as one of the likely causes. However, the exact relationship between the microbiome and IDD is not well understood. This review summarizes the potential mechanisms and discusses microbiome dysbiosis's possible influence on IDD and LBP., Methods: Prospective literature review., Results: Alterations in microbiome composition and host responses to the microbiota causing pathological bone development and involution, led to the concept of gut-bone marrow axis and gut-bone axis. Moreover, the concept of the gut-disc axis was also proposed to explain the microbiome's role in IDD and LBP. According to the existing evidence, the microbiome could be an important factor for inducing and aggravating IDD through changing or regulating the outside and inside microenvironment of the IVD. Three potential mechanisms by which the gut microbiota can induce IVD and cause LBP are: (1) translocation of the bacteria across the gut epithelial barrier and into the IVD, (2) regulation of the mucosal and systemic immune system, and (3) regulation of nutrient absorption and metabolites formation at the gut epithelium and its diffusion into the IVD. Furthermore, to investigate whether IVD is initiated by pathogenic bacteria and establish the correlation between the presence of certain microbial groups with the disease in question, microbiome diversity analysis based on16S rRNA data can be used to characterise stool/blood microbiota from IVD patients., Conclusion: Future studies on microbiome, fungi and viruses in IDD is necessary to revolutionize our thinking about their possible role in the development of IVD diseases. Furthermore, we believe that inflammation inhibition and interruption of amplification of cascade reaction in IVD by targeting the gut and IVD microbiome is worthwhile for the treatment of IDD and LBP., Level of Evidence I: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding., (© 2022. The Author(s).)

The 20S proteasome (20S) facilitates turnover of most eukaryotic proteins. Substrate entry into the 20S first requires opening of gating loops through binding of HbYX motifs that are present at the C-termini of certain proteasome activators (PAs). The HbYX motif has been predominantly characterized in the archaeal 20S, whereas little is known about the sequence preferences of the human 20S (h20S). Here, we synthesize and screen ~120 HbYX-like peptides, revealing unexpected differences from the archaeal system and defining the h20S recognition sequence as the Y-F/Y (YФ) motif. To gain further insight, we create a functional chimera of the optimized sequence, NLSYYT, fused to the model activator, PA26 E102A . A cryo-EM structure of PA26 E102A -h20S is used to identify key interactions, including non-canonical contacts and gate-opening mechanisms. Finally, we demonstrate that the YФ sequence preferences are tuned by valency, allowing multivalent PAs to sample greater sequence space. These results expand the model for termini-mediated gating and provide a template for the design of h20S activators., (© 2022. The Author(s).)

Background  Peer physical examination learning is commonly practiced in medical schools during preclinical curricula and has been shown to improve empathy for patients. While there is literature regarding medical student attitudes toward peer physical exam learning, no studies to date have specifically examined student attitudes toward fundoscopy and dilation of the eyes for the purposes of learning fundoscopy. This study evaluates medical student preferences with regards to learning fundoscopy on peers and explores attitudes toward alternate approaches. Methods  First year medical students at the Icahn School of Medicine at Mount Sinai participated in a 2-hour fundoscopy skills workshop in March 2020. Following the session, the authors administered a voluntary survey querying students on attitudes toward peer physical exam learning and its use in learning peer fundoscopy. Primary study endpoints evaluated (1) student attitudes toward the use of peer physical exam learning, (2) learning benefit of the session, including student comfort with conducting the fundoscopy exam, and (3) empathy toward patients experiencing dilation. Secondary endpoints focused on alternative teaching methods and preferences for nonmydriatic fundoscopy. Analysis of survey data was performed using nonparametric Spearman's correlations, chi-square tests, t -tests, and Mann-Whitney U tests. Results  A total of 51/138 (37%) students completed the survey, with 78% indicating they felt peer physical exam learning was a helpful instructional method, including for the fundoscopic exam. The session led to improved self-rated fundoscopy skills and empathy for patients. However, when considering learning with dilation versus alternative nonmydriatic techniques, 96% of students indicated a preference for using alternative nonmydriatic techniques. Conclusion  This study found that students' attitudes toward fundoscopy generally aligned with their overall peer physical exam preferences. However, they preferred not using dilation and learning with nonmydriatic fundoscopic techniques. Assessing student learning preferences and incorporating novel instructional tools can help facilitate more successful fundoscopy skills acquisition. These considerations are particularly important in the context of COVID-19 and with advances in teleophthalmology., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration., Competing Interests: In the last 3 years, the following authors had no conflict of interest: Drs. de Leon, Schoretsanitis, Molden, Smith, Solismaa, Švancer, Olmos, Ricciardi, Iglesias-Garcia, Iglesias-Alonso, Spina, Ruan, Chuan-Yue Wang, Gang Wang, Tang, Lin, Lane, Rajkumar, González-Esquivel, Jung-Cook, Baptista, Rohde, Nielsen, Verdoux, Quiles, Sanz, De las Cuevas, Cohen, Schulte, Chopra, McCollum, Shelton, Kaithi, Farooq, McGrane, Lana, Arrojo-Romero, Rădulescu, Every-Palmer, Bebawi, Bhattacharya, Otsuka, Lazary, Torres, Yecora, Motuca, Chan, Zolezzi, Ouanes, De Berardis, Grover, Kirilochev, Soloviev, Ayub, Silva, Bonelli, Temmingh, Decloedt, Pedro, Pacheco Palha, LLerena, Fernandez-Egea, Siskind, Masmoudi, Mohd Saffian, Leung and Buckley. In the last 3 years several authors report conflicts of interests. Dr. Seppälä is permanent medical advisor, received lecture fees and is an advisory board member from Viatris that markets clozapine in Finland and other European countries. Dr. Kopeček participated in speakers/advisory boards and lectured with the support of Angelini, Janssen Pharmaceuticals, Lundbeck and Richter Gedeon. Dr. Yong Sik Kim received grants, research support and honoraria from Janssen, Otsuka, Whan in Pharm and Bukwang Pharm (Sumitomo Dannipon Pharma). Dr. Se Hyun Kim received research grants from and/or served as a lecturer for Janssen, Eli Lilly, and Dongwha. Dr. Ertuğrul has received speaker’s honoraria from Abdi İbrahim Otsuka. Dr. Anıl Yağcıoğlu has received speaker’s honoraria and consulting fees from Janssen and Abdi İbrahim Otsuka. Dr. Cotes has received research funding from Otsuka, Lundbeck, Roche, Alkermes, and is a consultant for Saladax Biomedical. Dr. Kane reports personal fees from Alkermes, personal fees from Allergan, personal fees from Bristol-Myers Squibb, personal fees from IntraCellular Therapies, Janssen, Lundbeck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Sunovion, Takeda, Teva, outside-the-submitted work from LB Pharma, MedAvante and The Vanguard Research Group. Dr. Ng had served as consultant for Grunbiotics, Lundbeck, Servier, and Janssen-Cilag, and received research speaker honoraria from Servier, Janssen-Cilag and Pfizer.IMcG received royalties from Hogrefe Publishing Corp. T.L. Dr. Bilbily is supported by the National Institute on Drug Abuse training grant 5T32DA007261-30 (MPI). Dr. Hiemke received speaker’s honoraria from Otsuka. Dr. López-Jaramillo reports financial support for research from Financial support from the National Institute of Mental Health, USA, MinCiencias, Colombia and the Universidad de Antioquia, Colombia. Dr. Eap received honoraria for conferences or teaching CME courses from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Vifor-Pharma, and Zeller. Dr. Seifritz has received honoraria from Schwabe GmbH for educational lectures. He has further received educational grants and consulting fees from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Recordati, Vifor, Sunovion, and Mepha. Dr. Bousman is a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Pharmacogene Variation Consortium (PharmVar). Dr. Kelly has served as a consultant for Alkermes, Lyndra and Sunovion. Dr. Procyshyn has been on the speaker's bureau and attended advisory board meetings for Janssen, Lundbeck, and Otsuka. Dr. Adebayo was on the advisory board of Janssen for a Long Acting Injectable Paliperidone palmitate in Nigeria. Janssen is not involved in Clozapine in Nigeria. Dr. Fountoulakis has received grants in the past, served as consultant, advisor or CME speaker, or received support to attend congresses by the following entities: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Pfizer, the Pfizer Foundation, Sanofi-Aventis, Servier, Shire and others. Since January 2020 he has been the director of Cochrane Greece and completely free from any conflict of interest. Dr. Wilkowska has received research support from Angelini, Biogen, Eli Lilly and Company, Janssen-Cilag, Lundbeck, Polpharma, Sanofi and Valeant. Dr. Cubała has received research support from Alkermes, Allergan, Auspex, Biogen, Celon, Ferrier, Forest Laboratories, Janssen, Otsuka, and Sanofi; he has served on speaker bureaus for Angelini, Celon, Janssen, and Sanofi, and he has served as a consultant for GW Pharmaceuticals, Janssen, Celon and Sanofi. Dr. Villagrán-Moreno has received speakerʼs honoraria from Janssen and have developed lectures and presented clozapine lectures for Adamed, which sells clozapine in Spain; he has participated in advisory boards for Rovi and in research projects for Otsuka. Dr. Crespo-Facorro has received funding unrelated to the present work for research projects and/or honoraria as a consultant or speaker from the following entities: Angelini, Janssen-Cilag, Lundbeck, Otsuka, Mylan, Sanofi-Aventis, ADAMED, Agencia Española de Investigacion, Instituto de Salud Carlos III, the EU Seventh Framework Program and Horizon 2020. Dr. Takeuchi has received speaker’s fees from EA Pharma, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, Takeda, and Yoshitomiyakuhin. Dr. Tsukahara has received speaker's honoraria from Eisai Inc. Dr. Gründer has served as a consultant for Allergan (Dublin, Ireland), Boehringer Ingelheim (Ingelheim, Germany), Institute for Quality and Efficiency in Health Care (IQWiG, Cologne, Germany), Janssen-Cilag (Neuss, Germany), Lundbeck (Copenhagen, Denmark), Otsuka (Chiyoda, Japan), Recordati (Milan, Italy), Sage (Cambridge, USA), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Gedeon Richter (Budapest, Hungary), Janssen Cilag, Lundbeck, Otsuka, Recordati. He has received grant support from Boehringer Ingelheim, Lundbeck and Saladax (Bethlehem, USA). He is co-founder and/or shareholder of Mind and Brain Institute GmbH (Zornheim, Germany), Brainfoods GmbH (Zornheim, Germany), OVID Health Systems GmbH (Berlin, Germany) and MIND Foundation gGmbH (Berlin, Germany). Dr. Sagud participated in lectures for the following companies: Alkaloid, Belupo, Elli Lilly, Gedeon Richter, Jadran Galenski Laboratorij, Johnson / Johnson, Lundbeck, Makpharm, Pliva, Stada and participated in the clinical trial: Eli Lilly, Krka and Gedeon Richter. Dr. Celofiga received speaker’s honoraria from Ely Lilly, Lundbeck, Richter Gedeon, Krka, Lek, Pliva, Angelini Pharma and participated in advisory boards for Janssen Pharmaceuticals and Lundbeck. Dr. Ignjatovic Ristic developed and presented clozapine lectures with the support of Mylan, received speakerʼs honoraria from Mylan, Teva Serbia, Pharm Swiss, Krka and Janssen. Dr. Ortiz has been a consultant and has received honoraria from Janssen-Cilag. Dr. Elkis received research grants from the São Paulo Research Support Foundation (FAPESP) and honoraria for participation as a member of advisory boards, speaker, or travel support from the following pharmaceutical companies: Aché, Cristalia, Daiichi-Sankyo, Janssen, Mantecorp-Hypera, Sandoz, and Teva. Dr. Weizman received speakerʼs honoraria from Lundbeck, Lilly, Teva, Trima, Jansen, Medison, Novartis and AstraZeneca. These activities were unrelated to the current study. Dr Marder reports consultation fees from Roche, Sunovion, Merck, Boehringer Ingelheim and Otsuka. He reports research support from Boehringer-Ingelheim, and GW Pharma. Dr. Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: AbbVie, Acadia, Alexza, Alkermes, Allergan, Angelini, Astellas, AstraZeneca, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Bristol-Myers Squibb, Cadent Therapeutics, Eisai, Eli Lilly, Forum, Genentech, Impel, Indivior, Intra-Cellular Therapies, Janssen, Jazz, Karuna, Lundbeck, Luye, Lyndra, Medavante-Prophase, Meiji, Merck, Medivation, Mylan, Neurocrine, NeuroRx, Novartis, Noven, Osmotica, Otsuka, Pfizer, Reckitt Benckiser, Relmada, Reviva, Sage, Shire, Sunovion, Takeda, Teva, University of Arizona, Valeant, Vanda, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research. Dr. Freudenreich has the following financial relationship with a commercial interest to disclose (recipient SELF; content area SCHIZOPHRENIA): Alkermes – Research grant (to institution), consultant honoraria (Advisory Board); Avanir – Research grant (to institution); Janssen – Research grant (to institution), consultant honoraria (Advisory Board); Integral - Consultant honoraria; Neurocrine – Consultant honoraria (Advisory Board); Novartis – Consultant honoraria; Otsuka – Research grant (to institution); Roche – Consultant honoraria; Springer Verlag – Royalties (medical writer); Elsevier – Honoraria (medical editing); Global Medical Education – Honoraria (CME speaker and content developer); Medscape – Honoraria (CME speaker); American Psychiatric Association – Consultant honoraria (SMI Adviser); Wolters-Kluwer – Royalties (content developer); UpToDate – Royalties, honoraria (content developer and editor, including for a chapter on clozapine). Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Damitsa, Gedeon Richter, Hikma, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of LB Pharma. Dr. Müller reports he has been a co-investigator for two pharmacogenetic studies where genetic test kits were provided as an in-kind contribution by Myriad Neuroscience. He did not receive any payments or any equity, stocks, or options from any pharmacogenetic companies. He is also a co-inventor of two patents assessing risk for antipsychotic-induced weight gain (pending)., (Thieme. All rights reserved.)

The use of BReast CAncer (BRCA) mutations as biomarkers for sensitivity to DNA damage response (DDR) targeted drugs and platinum agents is well documented in breast and gynaecological cancers. More recently the successful use DDR targeted therapies including poly (ADP-ribose) polymerases (PARP) inhibitors has been shown to extend to other germline and somatic deficiencies within the homologous recombination (HR) pathway (Farmer et al., 2005; Turner et al., 2019; Li and Heyer, 2008). Gastrointestinal (GI) cancers are lagging behind other tumour types when it comes to personalising treatment with targeted therapies. Current methods of identifying PARP-inhibitor sensitivity in gastrointestinal cancers are based on analogies from other cancer types despite there being a lack of uniformity in determining HR status between tumour types. There is an urgent clinical need to better understand the treatment implications of DDR alterations in gastrointestinal cancers. We have reviewed PARP-inhibitor use in pancreatic, gastroesophageal, hepatobiliary and colorectal cancers and explored HRD as a biomarker for sensitivity to PARP-inhibitors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: Hodgkin lymphoma is a malignant proliferation of lymphatic system which when advanced can involve the bone marrow. It is usually indolent and responds to chemotherapy. However the prediction of rapidly progressive disease is often dependent on lot of clinicopathological parameters. Serum ferritin may act as a marker for disease activity in these patients. But the prior studies have failed to establish its role or group the patients into prognostic categories., Aims: To study the status of serum ferritin at time of admission and after completion of chemotherapy and also iron overload induced organ involvement in the form of hepatic, cardiovascular and thyroid dysfunction in nine patients admitted in our ward with Hodgkin lymphoma and receiving treatment in the form of chemotherapy., Methodology: A spectrum of clinicopathological variables were tested at baseline and after treatment liver function test, thyroid function test, 2D echocardiography, Ultrasound abdomen, PET scan and serum ferritin level., Conclusion: Serum ferritin at baseline statistically correlated with disease activity however the final ferritin values reduced to significant values in patient that underwent remission, and hence grouping of patients based on serum ferritin values can serve as better outcome predictors. Although transfusion requirement was very rare in the patients the levels of serum ferritin correlated with disease activity. Serum ferritin level may act as a predictor of disease activity and remission., Competing Interests: None., (AJBR Copyright © 2022.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) Aβ 1-42 and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3'-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins/genes. MiR-20b-5p, a miRNA that downregulated APP, was paradoxically associated with an increased risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of "pathogenic" Aβ, the molecular etiology of AD is likely to not just be a disease of "excess" but a disruption of delicate homeostasis., (© 2021. The Author(s).)

Manufacturing has been the key factor limiting rollout of vaccination during the COVID-19 pandemic, requiring rapid development and large-scale implementation of novel manufacturing technologies. ChAdOx1 nCoV-19 (AZD1222, Vaxzevria) is an efficacious vaccine against SARS-CoV-2, based upon an adenovirus vector. We describe the development of a process for the production of this vaccine and others based upon the same platform, including novel features to facilitate very large-scale production. We discuss the process economics and the "distributed manufacturing" approach we have taken to provide the vaccine at globally-relevant scale and with international security of supply. Together, these approaches have enabled the largest viral vector manufacturing campaign to date, providing a substantial proportion of global COVID-19 vaccine supply at low cost., (© 2021 The Authors. Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause-effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest., (© 2021 by the authors.)

Direct encapsulation of graphene shells on noble metal nanoparticles via chemical vapor deposition (CVD) has been recently reported as a unique way to design and fabricate new plasmonic heterostructures. But currently, the fundamental nature of the growth mechanism of graphene layers on metal nanostructures is still unknown. Herein, we report a systematic investigation on the CVD growth of graphene-encapsulated Au nanoparticles (Au@G) by combining an experimental parameter study and theoretical modeling. We studied the effect of growth temperature, duration, hydrocarbon precursor concentration, and extent of reducing (H 2 ) environment on the morphology of the products. In addition, the influence of plasma oxidation conditions for the surface oxidation of gold nanoparticles on the graphene shell growth is evaluated in combination with thermodynamic calculations. We find that these parameters critically aid in the evolution of graphene shells around gold nanoparticles and allow for controlling shell thickness, graphene shell quality and morphology, and hybrid nanoparticle diameter. An optimized condition including the growth temperature of ∼675 °C, duration of 30 min, and xylene feed rate of ∼10 mL/h with 10% H 2 /Ar carrier gas was finally obtained for the best morphology evolution. We further performed finite-element analysis (FEA) simulations to understand the equivalent von Mises stress distribution and discrete dipolar approximation (DDA) calculation to reveal the optical properties of such new core-shell heterostructures. This study brings new insight to the nature of CVD mechanism of Au@G and might help guiding their controlled growth and future design and application in plasmonic applications.

Background: An RFA lesion quality indicator, Surpoint Tag Index ® (TI) incorporates key factors: power, time, and contact force, impacting lesion quality. TI accurately estimates lesion depth in animal studies. However, the relationship between TI and in-vivo atrial wall thickness in patients exhibiting bidirectional block remains unknown., Objective: To describe the relationship between atrial wall thickness and TI in CTI exhibiting bidirectional block., Methods: Data from 492 RFA lesions from 25 patients undergoing PVI and CTI ablations in SR with point-by-point RF lesions (<45 W) utilizing a Thermocool Smarttouch ®  SF ablation catheter and CARTO-3 mapping were retrospectively analyzed. Operators were blinded to TI data and CTI thickness. CTI thickness was obtained using ICE images on Cartosound pre-ablation. Durable lesions were defined as part of a lesion set exhibiting bidirectional block of >30 min., Results: In lesions exhibiting bidirectional block, the thinnest (1-2 mm; 5% lesions) and thickest (8-10 mm; 6% lesions) portions of the CTI correlated with the lowest (429 ± 75) and highest (516 ± 64) TI. The bulk of thickness (2-6 mm; 80%) correlated with a TI of 455 ± 72 ( p  = 0.001). There was a weak but positive correlation between TI and CTI thickness ( r  = 0.2; p  ≤ 0.01). Examined in sectors, the anterior 1/3 rd CTI was the thickest (4.8 ± 1.9 mm) but correlated with a similar TI value (479 ± 75 vs. 471 ± 70; p  = 0.34) as the thinner middle 1/3 rd (3.8 ± 1.7 mm; p  ≤ 0.0001)., Conclusion: A mean TI value of 455 correlates with bidirectional block across the bulk of CTI with lower and higher values needed for the thinner and thicker portions, respectively. Tissue composition, aside from wall thickness, influences TI values for the creation of the bidirectional block., Competing Interests: None., (© 2021 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

An increased mortality risk was observed in patients with cancer during the first wave of COVID-19. Here, we describe determinants of mortality in patients with solid cancer comparing the first and second waves of COVID-19. A retrospective analysis encompassing two waves of COVID-19 (March-May 2020; December 2020-February 2021) was performed. 207 patients with cancer were matched to 452 patients without cancer. Patient demographics and oncological variables such as cancer subtype, staging and anti-cancer treatment were evaluated for association with COVID-19 mortality. Overall mortality was lower in wave two compared to wave one, HR 0.41 (95% CI: 0.30-0.56). In patients with cancer, mortality was 43.6% in wave one and 15.9% in wave two. In hospitalized patients, after adjusting for age, ethnicity and co-morbidities, a history of cancer was associated with increased mortality in wave one but not wave two. In summary, the second UK wave of COVID-19 is associated with lower mortality in hospitalized patients. A history of solid cancer was not associated with increased mortality despite the dominance of the more transmissible B.1.1.7 SARS-CoV-2 variant. In both waves, metastatic disease and systemic anti-cancer treatment appeared to be independent risk factors for death within the combined cancer cohort.

Purpose: Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using BRAF -mutated myeloma as a model for resistance to precision medicine we investigated if BRAF- mutated cancer cells have the ability to ensure their survival by rapidly adapting to BRAF inhibitor treatment., Experimental Design: Full-length single-cell RNA (scRNA) sequencing (scRNA-seq) was conducted on 3 patients with BRAF -mutated myeloma and 1 healthy donor. We sequenced 1,495 cells before, after 1 week, and at clinical relapse to BRAF/MEK inhibitor treatment. We developed an in vitro model of dabrafenib resistance using genetically homogeneous single-cell clones from two cell lines with established BRAF mutations (U266, DP6). Transcriptional and epigenetic adaptation in resistant cells were defined by RNA-seq and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). Mitochondrial metabolism was characterized by metabolic flux analysis., Results: Profiling by scRNA-seq revealed rapid cellular state changes in response to BRAF/MEK inhibition in patients with myeloma and cell lines. Transcriptional adaptation preceded detectable outgrowth of genetically discernible drug-resistant clones and was associated with widespread enhancer remodeling. As a dominant vulnerability, dependency on oxidative phosphorylation (OxPhos) was induced. In treated individuals, OxPhos was activated at the time of relapse and showed inverse correlation to MAPK activation. Metabolic flux analysis confirmed OxPhos as a preferential energetic resource of drug-persistent myeloma cells., Conclusions: This study demonstrates that cancer cells have the ability to rapidly adapt to precision treatments through transcriptional state changes, epigenetic adaptation, and metabolic rewiring, thus facilitating the development of refractory disease while simultaneously exposing novel vulnerabilities., (©2021 American Association for Cancer Research.)

Background: Cancer patients are at higher risk of COVID-19 complications and mortality than the rest of the population. Breast cancer patients seem to have better prognosis when infected by SARS-CoV-2 than other cancer patients., Methods: We report a subanalysis of the OnCovid study providing more detailed information in the breast cancer population., Results: We included 495 breast cancer patients with a SARS-CoV-2 infection. Mean age was 62.6 years; 31.5% presented more than one comorbidity. The most frequent breast cancer subtype was luminal-like ( n  = 245, 49.5%) and 177 (35.8%) had metastatic disease. A total of 332 (67.1%) patients were receiving active treatment, with radical intent in 232 (47.6%) of them. Hospitalization rate was 58.2% and all-cause mortality rate was 20.3%. One hundred twenty-nine (26.1%) patients developed one COVID-19 complication, being acute respiratory failure the most common ( n  = 74, 15.0%). In the multivariable analysis, age older than 70 years, presence of COVID-19 complications, and metastatic disease were factors correlated with worse outcomes, while ongoing anticancer therapy at time of COVID-19 diagnosis appeared to be a protective factor. No particular oncological treatment was related to higher risk of complications. In the context of SARS-CoV-2 infection, 73 (18.3%) patients had some kind of modification on their oncologic treatment. At the first oncological reassessment (median time: 46.9 days ± 36.7), 255 (51.6%) patients reported to be fully recovered from the infection. There were 39 patients (7.9%) with long-term SARS-CoV-2-related complications., Conclusion: In the context of COVID-19, our data confirm that breast cancer patients appear to have lower complications and mortality rate than expected in other cancer populations. Most breast cancer patients can be safely treated for their neoplasm during SARS-CoV-2 pandemic. Oncological treatment has no impact on the risk of SARS-CoV-2 complications, and, especially in the curative setting, the treatment should be modified as little as possible., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.J. Pinato reports personal fees from BMS (travel fees, grant to institution, and lecture fees), Eisai (consultancy, lecture fees, and occasional advisory board), H3B (consultancy and occasional advisory board), Astrazeneca (consultancy and occasional advisory board), MiNa therapeutics (consultancy), Roche (lecture fees), Viiv Healthcare (lecture fees), Bayer Healthcare (lecture fees), and Falk Foundation (lecture fees). A. Zambelli reports personal fees from Lilly (occasional advisory board and travel fees), Novartis (occasional advisory board and travel fees), Pfizer (occasional advisory board), Astrazeneca (occasional advisory board), and Roche (occasional advisory board). M. Bower reports personal fees from Gilead (lecture fees), ViiV (lecture fees), BMS (lecture fees), MSD (lecture fees), and Janssen (lecture fees). M. Lambertini reports personal fees from Roche (consultancy and travel fees), Novartis (consultancy and travel fees), Lilly (consultancy and travel fees), Astrazeneca (consultancy), Pfizer (travel fees), Sandoz (travel fees), and Takeda (travel fees). E. Felip reports personal fees from Pfizer (grant to institution) and Instituto Carlos III (research grant). A. Cortellini reports personal fees from BMS (consultancy), MSD (consultancy), Astrazeneca (consultancy and lecture fees), Roche (consultancy), Astellas (lecture fees), and Novartis (Lecture fees). F. Mazzoni reports personal fees from Roche (lecture fees), Takeda (lecture fees), MSD (lecture fees), BMS (lecture fees), Lilly (lecture fees), and Boehringer (lecture fees). M. Romeo reports personal fees from MSD (consultancy), Pfizer (travel fees), and GSK (occasional advisory board). A. Gennari reports personal fees from Astrazeneca (lecture fees), Lilly (lecture fees), Eisai (lecture fees), Pfizer (lecture fees), Novartis (lecture fees), Teva (lecture fees), and Daiichi Sankyo (lecture fees)., (© The Author(s), 2021.)

Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy., (© 2020. The Author(s).)

Background: Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres., Methods: From the OnCovid repository ( N  = 1318), we analysed cancer patients aged ⩾18 diagnosed with COVID-19 between 26 February and 22 June 2020 who had complete specialist palliative care team data (SPCT+ referred; SPCT- not referred)., Results: Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 years (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had ⩾1 co-morbidity. Two hundred and six patients received SPCT input for symptom control (80.1%), psychological support (54.4%) and/or advance care planning (51%). SPCT+ patients had more 'Do not attempt cardio-pulmonary resuscitation' orders completed prior to (12.6% versus 3.7%) and during admission (50% versus 22.1%, p  < 0.001), with more SPCT+ patients deemed suitable for treatment escalation (50% versus 22.1%, p  < 0.001). SPCT involvement was associated with higher discharge rates from hospital for end-of-life care (9.7% versus 0%, p  < 0.001). End-of-life anticipatory prescribing was higher in SPCT+ patients, with opioids (96.3% versus 47.1%) and benzodiazepines (82.9% versus 41.2%) being used frequently for symptom control., Conclusion: SPCT referral facilitated symptom control, emergency care and discharge planning, as well as high rates of referral for psychological support than previously reported. Our study highlighted the critical need of SPCTs for patients with cancer during the pandemic and should inform service planning for this population., Competing Interests: Conflict of interest statement: DJP received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and Astra Zeneca; received research funding (to institution) from MSD and BMS. AP has declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations, and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb. TND has declared consulting/advisory role for Amgen, Bayer, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Roche, and Takeda; speaker fees from AstraZeneca, MSD, Roche, Takeda; and travel, accommodations and expenses paid by AstraZenca, BMS, Boehringer Ingelheim, Lilly, MSD, Otsuka, Roche, and Takeda. JB has declared consulting/advisory role for MSD and Astra Zeneca. PPS has declared consulting/advisory role for Sanofi and Abbvie. AP has declared consulting/advisory role for Takeda and Sanofi. MP has declared consulting/advisory role for Gilead and Bayer. AG has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speaker’s bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. LR reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Sanofi; lecture fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, and Sanofi; travel fees from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, and Roche. No potential conflicts of interest were disclosed by other authors., (© The Author(s), 2021.)

Background: "Kangaroo mother care," a type of newborn care involving skin-to-skin contact with the mother or other caregiver, reduces mortality in infants with low birth weight (<2.0 kg) when initiated after stabilization, but the majority of deaths occur before stabilization. The safety and efficacy of kangaroo mother care initiated soon after birth among infants with low birth weight are uncertain., Methods: We conducted a randomized, controlled trial in five hospitals in Ghana, India, Malawi, Nigeria, and Tanzania involving infants with a birth weight between 1.0 and 1.799 kg who were assigned to receive immediate kangaroo mother care (intervention) or conventional care in an incubator or a radiant warmer until their condition stabilized and kangaroo mother care thereafter (control). The primary outcomes were death in the neonatal period (the first 28 days of life) and in the first 72 hours of life., Results: A total of 3211 infants and their mothers were randomly assigned to the intervention group (1609 infants with their mothers) or the control group (1602 infants with their mothers). The median daily duration of skin-to-skin contact in the neonatal intensive care unit was 16.9 hours (interquartile range, 13.0 to 19.7) in the intervention group and 1.5 hours (interquartile range, 0.3 to 3.3) in the control group. Neonatal death occurred in the first 28 days in 191 infants in the intervention group (12.0%) and in 249 infants in the control group (15.7%) (relative risk of death, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P = 0.001); neonatal death in the first 72 hours of life occurred in 74 infants in the intervention group (4.6%) and in 92 infants in the control group (5.8%) (relative risk of death, 0.77; 95% CI, 0.58 to 1.04; P = 0.09). The trial was stopped early on the recommendation of the data and safety monitoring board owing to the finding of reduced mortality among infants receiving immediate kangaroo mother care., Conclusions: Among infants with a birth weight between 1.0 and 1.799 kg, those who received immediate kangaroo mother care had lower mortality at 28 days than those who received conventional care with kangaroo mother care initiated after stabilization; the between-group difference favoring immediate kangaroo mother care at 72 hours was not significant. (Funded by the Bill and Melinda Gates Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12618001880235; Clinical Trials Registry-India number, CTRI/2018/08/015369.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study., Methods: In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets., Results: We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p<0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p<0.001) and shorter median overall survival in the training and validation sets (p<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611)., Conclusions: Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer., Competing Interests: Competing interests: DJP received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and Astra Zeneca; research funding (to institution) from MSD and BMS. AP has declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations, and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb. TND has declared consulting/advisory role for Amgen, Bayer, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Roche, and Takeda; speakers fees from AstraZeneca, MSD, Roche, Takeda; and travel, accommodations and expenses paid by AstraZenca, BMS, Boehringer Ingelheim, Lilly, MSD, Otsuka, Roche, and Takeda. JB has declared consulting/advisory role for MSD and Astra Zeneca. PPS has declared consulting/advisory role for Sanofi and Abbvie. AP has declared consulting/advisory role for Takeda and Sanofi. MP has declared consulting/advisory role for Gilead and Bayer. AG has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. LR reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Sanofi; lectures fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, and Sanofi; travel fees from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, and Roche. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Pulmonary tuberculosis (TB) may present in the form of parenchymal disease or extraparenchymal disease. Patients with TB as a primary cause of respiratory failure requiring mechanical ventilation have been reported to have mortality rates ranging between 47% and 80%. However, acute respiratory distress syndrome (ARDS) as a presentation of TB is rarely reported. We describe two cases of immunocompetent women presenting with ARDS. They were initially worked up for viral aetiologies in view of the ongoing COVID-19 pandemic but were later diagnosed to have microbiologically proven parenchymal pulmonary TB. One of our patients succumbed to nosocomial pneumonia, while the other was discharged to follow-up., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Late Onset Alzheimer's Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aβ40 (p = 001) and Aβ42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aβ levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aβ40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aβ precursor protein-α (sAPPα) levels, suggesting the decrease in Aβ did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aβ deposition.

Background: Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients., Methods: We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized., Results: Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20])., Conclusions: In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

A variable proportion of patients develop persistent/prolonged symptoms of Coronavirus Disease 2019 (COVID-19) infection (long COVID). We aimed to study the clinical predictors of persistent symptoms in patients with mild COVID-19 at 30 days post discharge (long COVID-19). We also tried to identify symptom clusters among mild COVID-19 patients. Fifty-seven patients admitted at a tertiary care centre after a positive RT-PCR report over a period of 2 months, were enrolled in the study. Details of presentation, history of illness, laboratory investigations and disease outcomes were recorded from documented medical records and discharge slip. The patients were contacted (telephonically) at 30 days after discharge and enquired regarding persistent symptoms, if any. Follow up data at 30 days post-discharge was available for 53 patients. Among them, the most common persistent symptom was fatigue (22.6%), followed by cough (9.4%) and myalgias (7.5%). There was a significant association of persistent symptoms with diarrhoea at presentation [OR 14.26 (95% CI 2.30-142.47; p = 0.009] and gap between symptom onset and admission [OR 1.40 (95% CI 1.08-1.93; p = 0.020] on multivariate logistic regression analysis. On cluster analysis, three phenotypes of mild COVID-19 were identified, which may have implications on monitoring and management. There appears to be a positive association of diarrhoea as a presenting manifestation and gap between symptom onset and admission with the persistence of symptoms classified as long COVID-19, even in mild illness. We also identified multiple phenotypes of mild COVID-19 illness, which warrant further exploration.

Female genital tuberculosis (FGTB) is a common cause of infertility in India but its diagnosis remains elusive due to paucibacillary nature of disease. Traditional methods of diagnosis include demonstration of acid fast bacilli on endometrial or peritoneal biopsy or epithelioid granuloma on the biopsy or positive gene Xpert on the biopsy, but they are positive in small percentage of cases only missing diagnosis in many cases. Positive polymerase chain reaction (PCR) alone is not taken for diagnosis due to high false positivity. Diagnostic laparoscopy and hysteroscopy can detect many cases by direct demonstration of TB lesions. Composite reference standard is a useful method to diagnose FGTB. This review discusses various diagnostic modalities including endometrial or peritoneal biopsy to detect acid fast bacilli on microscopic or culture or epithelioid granuloma, role of PCR, role of radiological imaging (hysterosalpingography, ultrasound, CT scan, MRI and PET-CT scan) and role of endoscopic techniques (laparoscopy and hysteroscopy) in diagnosis of FGTB including role of composite reference standard. The International and National studies highlight the role of composite reference standard and its components like demonstration of AFB on microscopy or culture of endometrial or peritoneal biopsy or epithelioid granuloma or gene Xpert or PCR or latest tests like loop-mediated isothermal amplification (TB-LAMP) test and other newer molecular methods like Xpert Ultra for diagnosis of FGTB. It also detects role of endoscopy in FGTB and role of diagnostic algorithm for diagnosis of FGTB. Treatment is with four primary drugs (rifampicin, isoniazid, ethambutol and pyrazinamide) for two months followed by three drugs (rifampicin, isoniazid and ethambutol) daily orally for 4 months for drug sensitive FGTB. Shorter Multidrug-resistant TB (MDR-TB) regimen is given for Rifampicin resistant (RR)/MDR confined to only FGTB while longer all oral regimen is given for RR/MDR with or without additional drug resistance, HIV seropositives with FGTB or involvement of other sites or pulmonary TB (PTB) along with FGTB. Composite reference standard which combines various diagnostic modalities is a useful strategy to diagnose FGTB., Competing Interests: Conflicts of interest All authors have none to declare., (Copyright © 2020 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)