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BackgroundThe clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC).MethodsComprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized.ResultsTwenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women.ConclusionThe available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

INTRODUCTION: D-dimer tests were inappropriately overused in our emergency department as a result of bloods being taken before clinical assessment to help meet the '4-hour target'. We introduced a multifaceted intervention to reduce the number of inappropriate D-dimer tests. The secondary aim was to improve the diagnostic workup of suspected pulmonary embolism (PE). METHOD: Rate of D-dimer test and ventilation/perfusion scan requests were compared before, during and after a staggered intervention at two hospitals in one National Health Service Trust. Audits before and after the intervention were done to determine whether test use was appropriate and whether the diagnostic workup was complete. RESULTS: At hospital 1, D-dimer testing after the intervention was almost halved: ratio 0.59 (95% CI 0.55 to 0.63) (p<0.0001). There was also a small reduction at hospital 2 (control): rate 0.88 (95% CI 0.78 to 0.99) (p = 0.03). After the formal introduction of change at hospital 2, there was a further reduction in tests: ratio 0.67 (95% CI 0.58 to 0.76) (p<0.0001). In hospital 1, pretest probability assessment improved by 42% (p = 0.0004) and D-dimer test use was reduced by 12.5% (p = 0.04) between audits. Improvement in the use of D-dimer test according to the pathway was not significant (32.5%, p = 0.11), and there was no change in the proportion of patients with completion of their diagnostic workup for PE: 47.6% (95% CI 38.3% to 56%) before and 45.6% (95% CI 38.3% to 53.1%) after the intervention. CONCLUSION: Implementation of a multifaceted change program reduced the number of D-dimer test requests in both hospitals and may have improved the diagnostic workup for PE at hospital 1. Processes that speed patient transit through the emergency department may impact negatively on other aspects of patient care. This should be the subject of further studies. [ABSTRACT FROM AUTHOR]

This qualitative study, part of a larger study of resiliency, explores the impact of spirituality on runaway and/or homeless youth. Interviews with 19 former runaway and homeless youth were analyzed to explore their experience of spirituality as they coped with the adversity in their lives. Five themes related to spirituality emerged: a belief in divine intervention; having a personal relationship with a nonjudgmental higher power; use of prayer; participation in traditional and nontraditional religious practices; and finding meaning and purpose in life, including a desire to 'give back' to their community. Implications for social work practice and research are addressed. [ABSTRACT FROM AUTHOR]

This qualitative study, part of a larger study of resiliency, explores the impact of spirituality on runaway and/or homeless youth. Interviews with 19 former runaway and homeless youth were analyzed to explore their experience of spirituality as they coped with the adversity in their lives. Five themes related to spirituality emerged: a belief in divine intervention; having a personal relationship with a nonjudgmental higher power; use of prayer; participation in traditional and nontraditional religious practices; and finding meaning and purpose in life, including a desire to 'give back' to their community. Implications for social work practice and research are addressed. [ABSTRACT FROM AUTHOR]

Social work faculty and graduate students conducted focus groups with 52 burn-injured adolescents from three burn camps to explore perceptions of their camp experience. Three themes emerged from data analysis that suggest burn camps play an important role in participants' lives. Camp is a place where burn-injured adolescents: (1) feel 'normal' and accepted; (2) acquire insight in regard to self and meaning in life; and (3) gain confidence, increase self-esteem, and develop empathy. This project highlights how the use of qualitative research methods with grassroots organizations such as burn camps can serve as a link to greater social work involvement with this community. [ABSTRACT FROM AUTHOR]

Burn-injured people are confronted with enormous challenges in their recovery process on a physical, emotional, and spiritual level. Despite the magnitude of trauma, there has been a dearth of research exploring adult burn survivors' perception of their experiences. In this qualitative study, eight burn survivors were interviewed. Influences that impacted their experiences such as perceived memories, time, and age when burned were distinguished from the multiple themes of losses to identity, life style, relationships and physical functioning as well as themes of adaptation, coping and resiliency. Drawing from the burn survivors' stories of recovery can provide insights for social workers and other health care professionals in serving this compelling population more effectively. [ABSTRACT FROM AUTHOR]

Red wine polyphenols (RWPPs) were obtained from red wine by absorption and elution from a resin column. Red wine (375 mL/d), white wine (375 mL/d), RWPPs (1 g/d, equivalent to 375 mL red wine/d) in capsules, RWPPs (1 g/d) dissolved in white wine, or a control alcoholic drink (40 g ethanol/d) was given to groups of 6-9 healthy men for 2 wk. Plasma LDL was separated by ultracentrifugation and desalted by dialyzing against a phosphate buffer without EDTA. In the copper-catalyzed peroxidation of LDL (copper-diene assay), the mean lag time increased by 17.8 min after red wine, 14.2 min after RWPP capsules, and 11.7 min after RWPPs in white wine. These groups also showed decreases in thiobarbituric acid-reactive substances, lipid peroxides, and conjugated dienes and increases in plasma and LDL polyphenols. The only change with white wine was an increase in thiobarbituric acid-reactive substances; there were no changes after the control drink. In a second study, RWPPs (1 and 2 g/d) and vitamin E [1000 IU (671 mg)/d] were given for 2 wk. In the copper-diene assay the addition of 10 micromol EDTA/L abolished the increased lag time of 17.7 min seen with 1 g RWPP/d and changed the increased lag time from 13.2 to 4.5 min seen with 2 g RWPP/d. Vitamin E increased lag time by 67.6 min with dialysis without EDTA and by 50.5 min with EDTA. When the column method was used for desalting LDL, all 3 treatments produced an increase in lag time. The failure of some authors to obtain antioxidant effects with the consumption of red wine may be due to the differing techniques. Copyright (c) 1998 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Treatment-resistant depression (TRD) is an epidemic with rising social, economic, and political costs. In a patient whose major depressive episode (MDE) persists through an adequate antidepressant trial, insurance companies often cover alternative treatments which may include repetitive transcranial magnetic stimulation (rTMS). RTMS is an FDA-cleared neuromodulation technique for TRD which is safe, efficacious, noninvasive, and well-tolerated. Recent developments in the optimization of rTMS algorithms and targeting have increased the efficacy of rTMS in treating depression, improved the clinical convenience of these treatments, and decreased the cost of a course of rTMS. In this opinion paper, we make a case for why conventional FDA-cleared rTMS should be considered as a first-line treatment for all adult MDEs. RTMS is compared to other first-line treatments including psychotherapy and SSRIs. These observations suggest that rTMS has similar efficacy, fewer side-effects, lower risk of serious adverse events, comparable compliance, the potential for more rapid relief, and cost-effectiveness. This suggestion, however, would be strengthened by further research with an emphasis on treatment-naive subjects in their first depressive episode, and trials directly contrasting rTMS with SSRIs or psychotherapy., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: The grim (<10% 5-year) survival rates for pancreatic ductal adenocarcinoma (PDAC) are attributed to its complex intrinsic biology and most often late-stage detection. The overlap of symptoms with benign gastrointestinal conditions in early stage further complicates timely detection. The suboptimal diagnostic performance of carbohydrate antigen (CA) 19-9 and elevation in benign hyperbilirubinaemia undermine its reliability, leaving a notable absence of accurate diagnostic biomarkers. Using a selected patient cohort with benign pancreatic and biliary tract conditions we aimed to develop a data analysis protocol leading to a biomarker signature capable of distinguishing patients with non-specific yet concerning clinical presentations, from those with PDAC., Methods: 539 patient serum samples collected under the Accelerated Diagnosis of neuro Endocrine and Pancreatic TumourS (ADEPTS) study (benign disease controls and PDACs) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, healthy controls) were screened using the Olink Oncology II panel, supplemented with five in-house markers. 16 specialized base-learner classifiers were stacked to select and enhance biomarker performances and robustness in blinded samples. Each base-learner was constructed through cross-validation and recursive feature elimination in a discovery set comprising approximately two thirds of the ADEPTS and UKCTOCS samples and contrasted specific diagnosis with PDAC., Results: The signature which was developed using diagnosis-specific ensemble learning demonstrated predictive capabilities outperforming CA19-9, the only biomarker currently accepted by the FDA and the National Comprehensive Cancer Network guidelines for pancreatic cancer, and other individual biomarkers and combinations in both discovery and held-out validation sets. An AUC of 0.98 (95% CI 0.98-0.99) and sensitivity of 0.99 (95% CI 0.98-1) at 90% specificity was achieved with the ensemble method, which was significantly larger than the AUC of 0.79 (95% CI 0.66-0.91) and sensitivity 0.67 (95% CI 0.50-0.83), also at 90% specificity, for CA19-9, in the discovery set (p = 0.0016 and p = 0.00050, respectively). During ensemble signature validation in the held-out set, an AUC of 0.95 (95% CI 0.91-0.99), sensitivity 0.86 (95% CI 0.68-1), was attained compared to an AUC of 0.80 (95% CI 0.66-0.93), sensitivity 0.65 (95% CI 0.48-0.56) at 90% specificity for CA19-9 alone (p = 0.0082 and p = 0.024, respectively). When validated only on the benign disease controls and PDACs collected from ADEPTS, the diagnostic-specific signature achieved an AUC of 0.96 (95% CI 0.92-0.99), sensitivity 0.82 (95% CI 0.64-0.95) at 90% specificity, which was still significantly higher than the performance for CA19-9 taken as a single predictor, AUC of 0.79 (95% CI 0.64-0.93) and sensitivity of 0.18 (95% CI 0.03-0.69) (p = 0.013 and p = 0.0055, respectively)., Conclusion: Our ensemble modelling technique outperformed CA19-9, individual biomarkers and indices developed with prevailing algorithms in distinguishing patients with non-specific but concerning symptoms from those with PDAC, with implications for improving its early detection in individuals at risk., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: UM reports stock ownership in Abcodia UK between 2011 and 2021; UM has received grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), the India Alliance, NIHR Biomedical Research Centre at University College London Hospital, and The Eve Appeal; UM currently has research collaborations with iLOF, RNA Guardian and Micronoma, with funding paid to UCL; UM holds patent number EP10178345.4 for Breast Cancer Diagnostics; AG currently has research collaborations with Micronoma and iLoF, with the research funding awarded to UCL. The other authors have declared that no competing interests exist., (Copyright: © 2024 Ney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Morel-Lavallee lesions are uncommon injuries and there is a lack of data to support what the most effective management is. In the case of a young athlete with a small lesion, we propose that conservative treatment with rest and close follow up is appropriate., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Understanding the interplay of interaction and disorder in quantum transport poses long-standing scientific challenges for theory and experiment. While highly controlled ultracold atomic platforms combining atomic interactions with spatially disordered lattices have led to remarkable advances, the extension of such controlled studies to phenomena in high-dimensional disordered systems, such as the three-dimensional Anderson metal-insulator transition has been limited. Kicked quantum gases provide an alternate experimental platform that captures the Anderson model in momentum space and features dynamical localization as the analog of Anderson localization. Here, we utilize a momentum space lattice platform using quasiperiodically kicked ultracold atomic gases to experimentally investigate interaction effects on the three-dimensional dynamical Anderson metal-insulator transition. We observe interaction-driven subdiffusion and a divergence of delocalization onset time on approaching the phase boundary. Mean-field numerical simulations show qualitative agreement with experimental observations, but with significant quantitative deviations.

Background: Institutional academic productivity varies on an individual level. This study aims to analyze the research output of adult reconstruction and arthroplasty fellowship programs in the United States., Methods: The American Association of Hip and Knee Surgeons Fellowship Directory was used to evaluate 112 adult reconstruction and arthroplasty fellowships in the United States. Publication data and Hirsch index (h-index) were collected from the Scopus Database. All of each author's total publications were analyzed with their current institution, regardless of their affiliation at the time of publication. Multivariate logistic regressions were performed to determine the effect of program size on research productivity., Results: The total number of publications per institution ranged from 2 to 3743, with a mean of 289 and a median of 135. The h-index of individual faculty members ranged from 0 to 103, with a mean of 16 and a median of 11. The number of faculty ( P < .001) and number of fellows ( P  = .003) per program had a significant effect on the total number of publications. The number of faculty did not have a significant effect on the median number of publications ( P  = .12) or the median h-index ( P  = .31). The number of fellows had a significant effect on the median number of publications ( P < .001) and the median h-index ( P < .001)., Conclusions: Academic productivity in adult reconstruction and arthroplasty fellowships within the United States varies widely, with the top few institutions responsible for a majority of the overall output.

SNT is a high-dose accelerated intermittent theta-burst stimulation (iTBS) protocol coupled with functional-connectivity-guided targeting that is an efficacious and rapid-acting therapy for treatment-resistant depression (TRD). We used resting-state functional MRI (fMRI) data from a double-blinded sham-controlled randomized controlled trial 1 to reveal the neural correlates of SNT-based symptom improvement. Neurobehavioral data were acquired at baseline, post-treatment, and 1-month follow-up. Our primary analytic objective was to investigate changes in seed-based functional connectivity (FC) following SNT and hypothesized that FC changes between the treatment target and the sgACC, DMN, and CEN would ensue following active SNT but not sham. We also investigated the durability of post-treatment observed FC changes at a 1-month follow-up. Study participants included transcranial magnetic stimulation (TMS)-naive adults with a primary diagnosis of moderate-to-severe TRD. Fifty-four participants were screened, 32 were randomized, and 29 received active or sham SNT. An additional 5 participants were excluded due to imaging artifacts, resulting in 12 participants per group (Sham: 5F; SNT: 5F). Although we did not observe any significant group × time effects on the FC between the individualized stimulation target (L-DLPFC) and the CEN or sgACC, we report an increased magnitude of negative FC between the target site and the DMN post-treatment in the active as compared to sham SNT group. This change in FC was sustained at the 1-month follow-up. Further, the degree of change in FC was correlated with improvements in depressive symptoms. Our results provide initial evidence for the putative changes in the functional organization of the brain post-SNT., (© 2024. The Author(s).)

In clinical practice, theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial magnetic stimulation (rTMS), as it allows for the delivery of more stimuli in less time and at similar intensities. To date, accelerated treatment plans according to various continuous (cTBS) and intermittent TBS (iTBS) protocols for depression have been proposed. To investigate which of the TBS protocols provided a favorable risk-benefit balance for individuals with depression, this systematic review and random-effects model network meta-analysis was conducted. The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence of switch to mania, and incidence of headache/discomfort at treatment site. In this meta-analysis, a total of 23 randomized controlled trials (n = 960, mean age = 41.88 years, with 60.78% females) were included. Approximately 69.57% of the trials included individuals with an exclusive diagnosis of major depressive disorder. The following six TBS protocols (target) were evaluated: cTBS (right-dorsolateral prefrontal cortex [R-DLPFC]), cTBS (R-DLPFC) + iTBS (left-DLPFC [L-DLPFC]), iTBS (L-DLPFC), iTBS (L-DLPFC) + iTBS (R-DLPFC), iTBS (left-dorsomedial prefrontal cortex) + iTBS (right-dorsomedial prefrontal cortex), and iTBS (occipital lobe). Compared to sham, cTBS (R-DLPFC) + iTBS (L-DLPFC), iTBS (L-DLPFC), and iTBS (occipital lobe) had a higher response rate (k = 23); cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) dominated in the depression symptom improvement (k = 23); and iTBS (L-DLPFC) had a higher remission rate (k = 15). No significant differences were found for all-cause discontinuation rate (k = 17), incidence of switch to mania (k = 7), and incidence of headache/discomfort at treatment site (k = 10) between any TBS protocols and sham. Thus, cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) demonstrate favorable risk-benefit balance for the treatment of depression., (© 2024. The Author(s).)

Background: Efforts to improve recovery after radical cystectomy (RC) are needed., Objective: To investigate wrist-worn wearable activity trackers in RC participants., Design, Setting, and Participants: An observational cohort study was conducted within the iROC randomised trial., Intervention: Patients undergoing RC at nine cancer centres wore wrist-based trackers for 7 days (d) at intervals before and after surgery., Outcome Measurements and Statistical Analysis: Step counts were compared with participant and operative features, and recovery outcomes., Results and Limitations: Of 308 participants, 284 (92.2%) returned digital activity data at baseline (median 17 d [interquartile range: 8-32] before RC), and postoperatively (5 [5-6] d) and at weeks 5 (43 [38-43] d), 12 (94 [87-106] d), and 26 (192 [181-205] d) after RC. Compliance was affected by the time from surgery and a coronavirus disease 2019 pandemic lockdown (return rates fell to 0-7%, chi-square p < 0.001). Step counts dropped after surgery (mean of 28% of baseline), before recovering at 5 weeks (wk) (71% of baseline) and 12 wk (95% of baseline; all analysis of variance [ANOVA] p < 0.001). Baseline step counts were not associated with postoperative recovery or death. Patients with extended hospital stays had reduced postoperative step counts, with a difference of 2.2 d (95% confidence interval: 0.856-3.482 d) between the lowest third and highest two-third tertiles (linear regression analysis; p < 0.001). Additionally, they spent less time out of the hospital within 90 d of RC (80.3 vs 74.3 d, p = 0.013). Lower step counts at 5, 12, and 26 wk were seen in those seeking medical help and needing readmission (ANOVA p ≤ 0.002)., Conclusions: Baseline step counts were not associated with recovery. Lower postoperative step counts were associated with longer length of stay at the hospital and postdischarge readmissions. Studies are required to determine whether low step counts can identify patients at a risk of developing complications., Patient Summary: Postoperative step counts appear to be a promising tool to identify patients in the community needing medical help or readmission. More work is needed to understand which measures are most useful and how best to collect these., (Copyright © 2023. Published by Elsevier B.V.)

Theta burst stimulation (TBS) is a noninvasive brain stimulation technique that can be used to modulate neural networks underlying psychiatric and neurological disorders. TBS can be delivered intermittently or continuously. The conventional intermittent TBS protocol is approved by the U.S. Food and Drug Administration to treat otherwise treatment-resistant depression, but the 6-week duration limits the applicability of this therapy. Accelerated TBS protocols present an opportunity to deliver higher pulse doses in shorter periods of time, thus resulting in faster and potentially more clinically effective treatment. However, the acceleration of TBS delivery raises questions regarding the relative safety, efficacy, and durability compared with conventional TBS protocols. In this review paper, we present the data from accelerated TBS trials to date that support the safety and effectiveness of accelerated protocols while acknowledging the need for more durability data. We discuss the stimulation parameters that seem to be important for the efficacy of accelerated TBS protocols and possible avenues for further optimization., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Åsberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (P corrected  < 0.001, Cohen's d = 0.74) and 1 month (P corrected  < 0.001, d = 2.20) after treatment and in PTSD (P corrected  < 0.001, d = 2.54), depression (P corrected  < 0.001, d = 2.80) and anxiety (P corrected  < 0.001, d = 2.13) at 1 month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 ., (© 2024. The Author(s).)

Treatment-resistant obsessive-compulsive disorder (OCD) occurs in approximately one-third of OCD patients. Obsessions may fluctuate over time but often occur or worsen in the presence of internal (emotional state and thoughts) and external (visual and tactile) triggering stimuli. Obsessive thoughts and related compulsive urges fluctuate (are episodic) and so may respond well to a time-locked brain stimulation strategy sensitive and responsive to these symptom fluctuations. Early evidence suggests that neural activity can be captured from ventral striatal regions implicated in OCD to guide such a closed-loop approach. Here, we report on a first-in-human application of responsive deep brain stimulation (rDBS) of the ventral striatum for a treatment-refractory OCD individual who also had comorbid epilepsy. Self-reported obsessive symptoms and provoked OCD-related distress correlated with ventral striatal electrophysiology. rDBS detected the time-domain area-based feature from invasive electroencephalography low-frequency oscillatory power fluctuations that triggered bursts of stimulation to ameliorate OCD symptoms in a closed-loop fashion. rDBS provided rapid, robust, and durable improvement in obsessions and compulsions. These results provide proof of concept for a personalized, physiologically guided DBS strategy for OCD., Competing Interests: Declaration of interests No funding from NeuroPace was received for this study nor were data analyses reported here conducted by NeuroPace employees. C.H.H., R.S.S., and C.E.R. have patents related to sensing and brain stimulation for the treatment of neuropsychiatric disorders. C.H.H. is a consultant for Boston Scientific and Insightec and receives honoraria for educational lectures., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; he has served on scientific advisory boards for Otsuka, NeuraWell, Nooma, and Halo Neuroscience; and he has equity/stock options in Magnus Medical, NeuraWell, and Nooma. Dr. Feyder and Dr. Bentzley are employees of Magnus Medical and hold equity in Magnus Medical. Dr Batail has served as a scientific consultant for Magnus Medical.

Competing Interests: All other investigators declare no conflicts of interest.

Background: The role of multiparametric magnetic resonance imaging (MRI) for detecting recurrent prostate cancer after radiotherapy is unclear., Objective: To evaluate MRI and MRI-targeted biopsies for detecting intraprostatic cancer recurrence and planning for salvage focal ablation., Design, Setting, and Participants: FOcal RECurrent Assessment and Salvage Treatment (FORECAST; NCT01883128) was a prospective cohort diagnostic study that recruited 181 patients with suspected radiorecurrence at six UK centres (2014 to 2018); 144 were included here., Intervention: All patients underwent MRI with 5 mm transperineal template mapping biopsies; 84 had additional MRI-targeted biopsies. MRI scans with Likert scores of 3 to 5 were deemed suspicious., Outcome Measurements and Statistical Analysis: First, the diagnostic accuracy of MRI was calculated. Second, the pathological characteristics of MRI-detected and MRI-undetected tumours were compared using the Wilcoxon rank sum test and chi-square test for trend. Third, four biopsy strategies involving an MRI-targeted biopsy alone and with systematic biopsies of one to two other quadrants were studied. Fisher's exact test was used to compare MRI-targeted biopsy alone with the best other strategy for the number of patients with missed cancer and the number of patients with cancer harbouring additional tumours in unsampled quadrants. Analyses focused primarily on detecting cancer of any grade or length. Last, eligibility for focal therapy was evaluated for men with localised (≤T3bN0M0) radiorecurrent disease., Results and Limitations: Of 144 patients, 111 (77%) had cancer detected on biopsy. MRI sensitivity and specificity at the patient level were 0.95 (95% confidence interval [CI] 0.92 to 0.99) and 0.21 (95% CI 0.07 to 0.35), respectively. At the prostate quadrant level, 258/576 (45%) quadrants had cancer detected on biopsy. Sensitivity and specificity were 0.66 (95% CI 0.59 to 0.73) and 0.54 (95% CI 0.46 to 0.62), respectively. At the quadrant level, compared with MRI-undetected tumours, MRI-detected tumours had longer maximum cancer core length (median difference 3 mm [7 vs 4 mm]; 95% CI 1 to 4 mm, p < 0.001) and a higher grade group (p = 0.002). Of the 84 men who also underwent an MRI-targeted biopsy, 73 (87%) had recurrent cancer diagnosed. Performing an MRI-targeted biopsy alone missed cancer in 5/73 patients (7%; 95% CI 3 to 15%); with additional systematic sampling of the other ipsilateral and contralateral posterior quadrants (strategy 4), 2/73 patients (3%; 95% CI 0 to 10%) would have had cancer missed (difference 4%; 95% CI -3 to 11%, p = 0.4). If an MRI-targeted biopsy alone was performed, 43/73 (59%; 95% CI 47 to 69%) patients with cancer would have harboured undetected additional tumours in unsampled quadrants. This reduced but only to 7/73 patients (10%; 95% CI 4 to 19%) with strategy 4 (difference 49%; 95% CI 36 to 62%, p < 0.0001). Of 73 patients, 43 (59%; 95% CI 47 to 69%) had localised radiorecurrent cancer suitable for a form of focal ablation., Conclusions: For patients with recurrent prostate cancer after radiotherapy, MRI and MRI-targeted biopsy, with or without perilesional sampling, will diagnose cancer in the majority where present. MRI-undetected cancers, defined as Likert scores of 1 to 2, were found to be smaller and of lower grade. However, if salvage focal ablation is planned, an MRI-targeted biopsy alone is insufficient for prostate mapping; approximately three of five patients with recurrent cancer found on an MRI-targeted biopsy alone harboured further tumours in unsampled quadrants. Systematic sampling of the whole gland should be considered in addition to an MRI-targeted biopsy to capture both MRI-detected and MRI-undetected disease., Patient Summary: After radiotherapy, magnetic resonance imaging (MRI) is accurate for detecting recurrent prostate cancer, with missed cancer being smaller and of lower grade. Targeting a biopsy to suspicious areas on MRI results in a diagnosis of cancer in most patients. However, for every five men who have recurrent cancer, this targeted approach would miss cancers elsewhere in the prostate in three of these men. If further focal treatment of the prostate is planned, random biopsies covering the whole prostate in addition to targeted biopsies should be considered so that tumours are not missed., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have therapeutic clinical effects when applied in serial-sessions. The present study sought to preliminarily determine whether serial-sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD., Methods: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, two-sessions-per-visit, two-visits-per-week, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up., Results: There were no significant differences in craving between conditions. Participants who received active-rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham-rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p=0.14). Participants who received active-rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period than those receiving sham-rTMS (Active vs. Sham: -0.72; Z=-2.33, p=0.02)., Conclusions: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period., Competing Interests: Declaration of Competing Interest GLS has collaborated with MagVenture and MECTA as part of investigator-initiated trials. He additionally consults for and has equity in the company Trial Catalyst. TJF is employed by Magnus Medical and holds stock/equity options. NRW is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; he has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and he has equity/stock options in Magnus Medical, NeuraWell, and Nooma. EBS is a paid consultant for Neuronetics and is an equity holder of Bodhi Neurotech. MSG has the following disclosures; Babystrong (patent co-holder), Brainsway (unpaid consultant, research grant, donated equipment for research trials), Magnus Medical (unpaid scientific Advisor), Magstim (unpaid consultant, donated equipment for research trials), MECTA (unpaid consultant, research grant, donated equipment for research grant), Microtransponder (DSMB member), Neuronetics (unpaid consultant, research grant, donated equipment for research), NeoSync (unpaid consultant, DSMB member), Neuralief (scientific advisory board, research grant, and Sooma (scientific advisory board), and he is an editor of the Elsevier journal Brain Stimulation. ALM has received research support from PleoPharma. None of the other authors have any relevant conflicts to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Breast cancer is a multifactorial disease that affects millions of women worldwide. Recent work has shown intriguing connections between microorganisms and breast cancer, which might have implications for prevention and treatment. This article analyzed 117 relevant breast cancer clinical studies listed on ClinicalTrials.gov selected using a bespoke set of 38 search terms focused on bacteria, viruses, and fungi. This was supplemented with 20 studies found from a search of PubMed. The resulting 137 studies were described by their characteristics such as geographic distribution, interventions used, start date and status, etc. The studies were then collated into thematic groups for a descriptive analysis to identify knowledge gaps and emerging trends.

Concerns regarding students' difficulties with the concept of energy date back to the 1970s. They become particularly apparent for systems involving adenosine triphosphate (ATP), which plays a central role in maintaining the nonequilibrium state of biological systems and in driving energetically unfavorable processes. One of the most well-documented misconceptions related to ATP is the idea that breaking bonds releases energy, when the opposite is true. This misconception is often attributed to language used in biology referring to the "high-energy bonds" in ATP. We interviewed chemistry, biology, and biochemistry instructors to learn how they think about and teach the mechanism(s) by which ATP is used as an energy source in biological systems. Across 15 interviews, we found that instructors relied primarily on two mechanisms to explain the role of ATP: 1) energy release, focused on ATP hydrolysis and bond energies; and/or 2) energy transfer, focused on phosphorylation and common intermediates. Many instructors shared negative and uncomfortable experiences related to teaching ATP and energy release. Based on these findings, we suggest instructional strategies that: 1) aim to ease the concerns expressed by introductory biology instructors, and 2) emphasize the role of ATP so as to support students' understanding of molecular mechanisms.

Tibial spine avulsion fractures occur predominantly in children and young adults and are an uncommon type of knee injury. To ensure knee stability and preserve range of motion with minimal knee laxity, it is essential to restore anterior cruciate ligament length through surgical reduction and fixation of the fracture. Achieving anatomic reduction of tibial spine avulsion fractures with an arthroscopic approach is a technically complex procedure. In this Technical Note and accompanying video, we describe a unique fixation repair of tibial spine avulsion fractures using Arthrex FiberRing sutures and an Arthrex ACL Repair TightRope. The technique presented is an effective method to reduce tibial spine avulsion fractures to anatomic position with a variable tensioning system that allows for a strong and secure fixation method., (© 2023 The Authors.)

Introduction: Triple negative breast cancer (TNBC) is a subtype of breast cancer characterised by its high tumourigenic, invasive, and immunosuppressive nature. Photodynamic therapy (PDT) is a focal therapy that uses light to activate a photosensitizing agent and induce a cytotoxic effect. 5-aza-2'-deoxycytidine (5-ADC) is a clinically approved immunomodulatory chemotherapy agent. The mechanism of the combination therapy using PDT and 5-ADC in evoking an anti-tumour response is not fully understood., Methods: The present study examined whether a single dose of 5-ADC enhances the cytotoxic and anti-tumour immune effect of low dose PDT with verteporfin as the photosensitiser in a TNBC orthotopic syngeneic murine model, using the triple negative murine mammary tumour cell line 4T1. Histopathology analysis, digital pathology and immunohistochemistry of treated tumours and distant sites were assessed. Flow cytometry of splenic and breast tissue was used to identify T cell populations. Bioinformatics were used to identify tumour immune microenvironments related to TNBC patients., Results: Functional experiments showed that PDT was most effective when used in combination with 5-ADC to optimize its efficacy. 5-ADC/PDT combination therapy elicited a synergistic effect in vitro and was significantly more cytotoxic than monotherapies on 4T1 tumour cells. For tumour therapy, all types of treatments demonstrated histopathologically defined margins of necrosis, increased T cell expression in the spleen with absence of metastases or distant tissue destruction. Flow cytometry and digital pathology results showed significant increases in CD8 expressing cells with all treatments, whereas only the 5-ADC/PDT combination therapy showed increase in CD4 expression. Bioinformatics analysis of in silico publicly available TNBC data identified BCL3 and BCL2 as well as the following anti-tumour immune response biomarkers as significantly altered in TNBC compared to other breast cancer subtypes: GZMA, PRF1, CXCL1, CCL2, CCL4, and CCL5. Interestingly, molecular biomarker assays showed increase in anti-tumour response genes after treatment. The results showed concomitant increase in BCL3, with decrease in BCL2 expression in TNBC treatment. In addition, the treatments showed decrease in PRF1, CCL2, CCL4, and CCL5 genes with 5-ADC and 5-ADC/PDT treatment in both spleen and breast tissue, with the latter showing the most decrease., Discussion: To our knowledge, this is the first study that shows which of the innate and adaptive immune biomarkers are activated during PDT related treatment of the TNBC 4T1 mouse models. The results also indicate that some of the immune response biomarkers can be used to monitor the effectiveness of PDT treatment in TNBC murine model warranting further investigation in human subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Banerjee, Acedo, El Sheikh, Harati, Meecham, Williams, Gerard, Keshtgar, MacRobert and Hamoudi.)

Objectives: To externally validate a published model predicting failure within 2 years after salvage focal ablation in men with localised radiorecurrent prostate cancer using a prospective, UK multicentre dataset., Patients and Methods: Patients with biopsy-confirmed ≤T3bN0M0 cancer after previous external beam radiotherapy or brachytherapy were included from the FOcal RECurrent Assessment and Salvage Treatment (FORECAST) trial (NCT01883128; 2014-2018; six centres), and from the high-intensity focussed ultrasound (HIFU) Evaluation and Assessment of Treatment (HEAT) and International Cryotherapy Evaluation (ICE) UK-based registries (2006-2022; nine centres). Eligible patients underwent either salvage focal HIFU or cryotherapy, with the choice based predominantly on anatomical factors. Per the original multivariable Cox regression model, the predicted outcome was a composite failure outcome. Model performance was assessed at 2 years post-salvage with discrimination (concordance index [C-index]), calibration (calibration curve and slope), and decision curve analysis. For the latter, two clinically-reasonable risk threshold ranges of 0.14-0.52 and 0.26-0.36 were considered, corresponding to previously published pooled 2-year recurrence-free survival rates for salvage local treatments., Results: A total of 168 patients were included, of whom 84/168 (50%) experienced the primary outcome in all follow-ups, and 72/168 (43%) within 2 years. The C-index was 0.65 (95% confidence interval 0.58-0.71). On graphical inspection, there was close agreement between predicted and observed failure. The calibration slope was 1.01. In decision curve analysis, there was incremental net benefit vs a 'treat all' strategy at risk thresholds of ≥0.23. The net benefit was therefore higher across the majority of the 0.14-0.52 risk threshold range, and all of the 0.26-0.36 range., Conclusion: In external validation using prospective, multicentre data, this model demonstrated modest discrimination but good calibration and clinical utility for predicting failure of salvage focal ablation within 2 years. This model could be reasonably used to improve selection of appropriate treatment candidates for salvage focal ablation, and its use should be considered when discussing salvage options with patients. Further validation in larger, international cohorts with longer follow-up is recommended., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Pakistan faces tremendous challenges in providing healthcare due to a lack of consistent policymaking, increasing expenditure and exponential growth in population since its inception in 1947. These challenges are not just driven by politics, policy and allocation of resources but also by healthcare, environment and characteristics of the population biology. Clinical trials provide the best way to find population-specific, cost-effective treatments that do not merely mimic those used in wealthier nations. This article analyzes all clinical studies conducted with at least one site in Pakistan listed on ClinicalTrials.gov, combined with a short overview that considers new therapeutic approaches that can be investigated in future clinical trials. Therapies using repurposed medicines are of particular interest as they use affordable drugs that are already widely available.

Unprecedented knowledge of the brain is inevitably contributing to the convergence of neurology and psychiatry. However, clinical training continues to follow a divergent approach established in the 19th century. An etiological approach will continue to shift more psychiatric patients to the care of neurologists who are untrained in psychiatric management. At the same time, this new era of diagnostic biomarkers and neuroscience-based precision treatments requires skills not readily available to those trained in psychiatry. The challenges in training the next generation of doctors include establishing competence involving aspects of the whole brain, fostering the subspecialized expertise needed to remain current, and developing programs that are feasible in duration and practical in implementation. A new 4-year residency training program proposed in this article could replace existing residency programs. The program includes 2 years of common and urgent training in various aspects of neurology and psychiatry followed by 2 years of elective subspecialty tracks. The concept is similar to internal medicine residencies and fellowships. No changes to existing departmental structures are necessary. In concert with the emerging biological approach to the brain, " brain medicine " is proposed as a new name to denote this practice in the simplest terms: a focus on all aspects of the brain., Competing Interests: Dr. George has served as a consultant for Boston Scientific, BrainsWay, Cyberonics, GlaxoSmithKline, Jazz, LivaNova, Magnus Medical, MicroTransponder, Neostim, NeoSync, Neurolief, Neuronetics, NeuroPace, and Sooma; and he uses transcranial magnetic stimulation devices from BrainsWay, Magstim, MagVenture, Neuronetics, Neurosoft, and Nexstim. The other authors report no financial relationships with commercial interests.

Introduction: Flexor tendons are traditionally repaired under either general anaesthesia (GA) or regional anaesthesia (RA), allowing for the use of an arm tourniquet to minimise blood loss and establish a bloodless surgical field. However, the use of tourniquets exposes the patient to certain risks, including skin, muscle and nerve injuries. A recent advancement in anaesthesia delivery involves the use of a wide-awake approach where no sedation nor tourniquets are used (wide-awake local anaesthesia no tourniquet (WALANT)). WALANT uses local anaesthetic with epinephrine to provide pain relief and vasoconstriction, reducing operative bleeding. Several studies revealed potential benefits for WALANT compared with GA or RA. However, there remains a paucity of high-quality evidence to support the use of WALANT. As a result of this uncertainty, the clinical practice varies considerably. We aim to evaluate the feasibility of WALANT as an alternative to GA and RA in patients undergoing surgical repair of flexor tendon injuries. This involves addressing factors such as clinician and patient support for a trial, clinical equipoise, trial recruitment and dropout and the most relevant outcomes measures for a future definitive trial., Methods and Analysis: WAFER is a multicentre, single-blinded, parallel group, randomised controlled trial (RCT) to assess the feasibility of WALANT versus RA and GA. The target population is patients with acute traumatic flexor tendon injuries, across 3 major hand surgery units in England involving a total of 60 participants. Outcome assessors will be blinded. The primary outcome will be the ability to recruit patients into the trial, while secondary outcomes include difference in functional outcome, patient-reported outcome measures, health-related quality of life, cost-effectiveness and complication rates., Ethics and Dissemination: Ethical approval was obtained from the London-City and East Research Ethics Committee (22/PR/1197). Findings will be disseminated through peer-reviewed publication, conferences, patient information websites and social media networks., Trial Registration Number: ISRCTN identifier: 15052559., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)