Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition.

BACKGROUND: In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. METHODS AND RESULTS: Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. CONCLUSIONS: Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.

Clinical and economic outcomes associated with lymph node examination status in early-stage non-small cell lung cancer: a real-world US study using the SEER-Medicare linked database.

Background: Clinical practice guidelines recommend adjuvant therapy for patients with early non-small cell lung cancer (eNSCLC), especially those with lymph node metastasis. This study evaluated the prevalence of lymph node examination and its association with adjuvant treatment rates, overall survival (OS), and healthcare costs among United States (US) Medicare patients with resected eNSCLC. Methods: This retrospective observational cohort study used Surveillance, Epidemiology, and End Results cancer registry data linked with Medicare claims data. Eligible patients were aged ≥65 years with newly diagnosed non-small cell lung cancer (NSCLC) stages IA to IIIB [the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th edition] between January 2010 and December 2017 with surgery ≤1 month prior to or ≤12 months after diagnosis. Patients were grouped by lymph node examination status: no examination (pNX), examination and no metastasis (pN0), or metastasis staging in N1 (pN1) or N2 (pN2). OS and costs were evaluated by examination status and number of lymph node examined. OS was analyzed using extended Cox proportional hazards models for specific time periods and time interaction with examination status, and adjusted for patient characteristics. Adjusted post-surgical healthcare costs per patient per month (PPPM) were analyzed using gamma-log regression models. Results: Among the 14,648 patients included in the study, approximately 11% were pNX, whereas most were pN0 (68%), followed by pN1 (11%) and pN2 (10%). Adjuvant treatment rates were higher for pNX (35%) than pN0 (18%), but lower than pN1 (68%) and pN2 (74%) patients (P<0.001). Unadjusted OS for pNX patients was nearly identical to pN2, and significantly worse compared to pN0 and pN1 (P<0.0001). After adjusting for patient characteristics, pNX patients had higher risk of death relative to pN0 patients (P<0.001). Marginal mean adjusted total costs were comparable across pNX ($15,827 PPPM), pN0 ($12,712 PPPM) and pN1 ($17,089 PPPM), but significantly less for pN0 compared to pN2 ($23,566 PPPM) (P=0.002). Conclusions: Inadequate lymph node examination is associated with underutilization of adjuvant treatment and poor OS in resected NSCLC. In the current era of targeted and immunotherapies, lymph node examination is more important than ever, implicating the need for Quality Improvement practices and multidisciplinary coordination.

Optimal combination of arthroplasty type, fixation method and postoperative rehabilitation protocol for complex proximal humerus fractures in the elderly: A network meta-analysis.

PURPOSE: The purpose of this study was to define the optimal combination of surgical technique and postoperative rehabilitation protocol for elderly patients undergoing either hemiarthroplasty (HA) or reverse total shoulder arthroplasty (rTSA) for acute proximal humerus fracture (PHF) by performing a network meta-analysis of the comparative studies in the literature. METHODS: A systematic review of the literature using PRISMA guidelines of MEDLINE, EMBASE, and Cochrane Library was screened from 2007-2023. Inclusion criteria were level I-IV studies utilizing primary HA and/or rTSA published in a peer-reviewed journal, that specified whether humeral stems were cemented or noncemented, specified postoperative rehabilitation protocol, reported results of HA and/or rTSA performed for PHF. Early range of motion (ROM) was defined as the initiation of active ROM at ≤3 weeks after surgery. Level of evidence was evaluated based on the criteria by the Oxford Centre for Evidence-Based Medicine. Clinical outcomes were compared using a frequentist approach to network meta-analysis with a random-effects model that was performed using the netmeta package version 0.9-6 in R. RESULTS: A total of 28 studies (1,119 patients) were included with an average age of 74±3.7 and mean follow-up of 32±11.1 months. In the early ROM cohort (Early), the mean time to active ROM was 2.4±0.76 weeks compared to 5.9±1.04 weeks in the delayed ROM cohort (Delayed). Overall, rTSA-Pressfit-Early resulted in statistically superior outcomes including postoperative forward elevation (126±27.5), abduction (116±30.6), internal rotation (5.27±0.74, corresponding to L3-L1), ASES score (71.8±17), tuberosity union (89%), and lowest tuberosity nonunion rate (9.6%) in patients ≥65 years old with acute PHF undergoing shoulder arthroplasty (all p≤0.05). In total there were 277 (14.5%) complications across the cohorts, of which 89/277 (34%) were in the HA-Cement-Delayed cohort. HA-Cement-Delayed resulted in 2-times higher odds of experiencing a complication when compared to rTSA-Cement-Delayed (p=0.005). Conversely, rTSA-Cement-Early cohort followed by rTSA-Pressfit-Early resulted in a total complication rate of 4.7% and 5.4% (OR, 0.30; p=0.01 & OR, 0.42; p=0.05), respectively. The total rate of scapular notching was higher in the cemented rTSA subgroups (16.5%) versus (8.91%) in the press fit rTSA subgroups (p=0.02). CONCLUSION: Our study demonstrates that patients ≥65 years of age, who sustain a 3-or 4-part PHF achieve the most benefit in terms of range of motion, postoperative functional outcomes, tuberosity union, and overall complication rate when undergoing rTSA with a noncemented stem and early postoperative range of motion when compared to the mainstream preference-rTSA-Cement-Delayed.

Posterior Shoulder Instability Part II - Glenoid Bone-Grafting, Glenoid Osteotomy, and Rehabilitation/Return to Play - An International Expert Delphi Consensus Statement.

PURPOSE: The purpose of this study was to establish consensus statements on glenoid bone-grafting, glenoid osteotomy, rehabilitation, return to play, and follow-up for posterior shoulder instability. METHODS: A consensus process on the treatment of posterior shoulder instability was conducted, with 71 shoulder/sports surgeons from 12 countries participating based on their level of expertise in the field. Experts were assigned to one of 6 working groups defined by specific subtopics within posterior shoulder instability. Consensus was defined as achieving 80-89% agreement, whereas strong consensus was defined as 90-99% agreement, and unanimous consensus was indicated by 100% agreement with a proposed statement. RESULTS: All of the statements relating to rehabilitation, return to play, and follow-up achieved consensus. There was unanimous consensus that the following criteria should be considered: restoration of strength, range of motion, proprioception, and sport-specific skills, with a lack of symptoms. There is no minimum time point required to return to play. Collision athletes and military athletes may take longer to return because of their higher risk for recurrent instability, and more caution should be exercised in clearing them to return to play, with elite athletes potentially having different considerations in returning to play. The relative indications for revision surgery are symptomatic apprehension, multiple recurrent instability episodes, further intra-articular pathologies, hardware failure, and pain. CONCLUSION: The study group achieved strong or unanimous consensus on 59% of statements. Unanimous consensus was reached regarding the criteria for return to play, collision/elite athletes having different considerations in return to play, indications for revision surgery, and imaging only required as routine for those with glenoid bone-grafting/osteotomies at subsequent follow-ups. There was no consensus on optimal fixation method for a glenoid bone-block, the relative indications for glenoid osteotomy, whether fluoroscopy is required or if the labrum should be concomitantly repaired. LEVEL OF EVIDENCE: Level V Expert Opinion.

Posterior Shoulder Instability Part I - Diagnosis, Non-Operative Management, and Labral Repair for Posterior Shoulder Instability - An International Expert Delphi Consensus Statement.

PURPOSE: The purpose of this study was to establish consensus statements on the diagnosis, non-operative management, and labral repair for posterior shoulder instability. METHODS: A consensus process on the treatment of posterior shoulder instability was conducted, with 71 shoulder/sports surgeons from 12 countries participating based on their level of expertise in the field. Experts were assigned to one of 6 working groups defined by specific subtopics within posterior shoulder instability. Consensus was defined as achieving 80-89% agreement, whereas strong consensus was defined as 90-99% agreement, and unanimous consensus was indicated by 100% agreement with a proposed statement. RESULTS: Unanimous agreement was reached on the indications for non-operative management and labral repair which include whether patients had primary or recurrent instability, with symptoms/functional limitations, and whether there was other underlying pathology, or patient's preference to avoid or delay surgery. Additionally, there was unanimous agreement that recurrence rates can be diminished by attention to detail, appropriate indication and assessment of risk factors, recognition of abnormalities in glenohumeral morphology, careful capsulolabral debridement and reattachment, small anchors with inferior placement and multiple fixation points that create a bumper with the labrum, treatment of concomitant pathologies, and a well-defined rehabilitation protocol with strict postoperative immobilization. CONCLUSION: The study group achieved strong or unanimous consensus on 63% of statements related to the diagnosis, nonoperative treatment, and labrum repair for posterior shoulder instability. The statements that achieved unanimous consensus were the relative indications for non-operative management, and the relative indications for labral repair, as well as the steps to minimize complications for labral repair. There was no consensus on whether an arthrogram is needed when performing advanced imaging, the role of corticosteroids/orthobiologics in non-operative management, whether a poster-inferior portal is required.

Optimizing Muscle-Tendon Lengths in Reverse Total Shoulder Arthroplasty: Evaluation of Surgical and Implant-Design-Related Parameters.

BACKGROUND: Optimizing the function of muscles that cross the glenohumeral articulation in reverse total shoulder arthroplasty (RTSA) is controversial. The current study used a geometric model of the shoulder to systematically examine surgical placement and implant-design parameters to determine which RTSA configuration most closely reproduces native muscle-tendon lengths of the deltoid and rotator cuff. METHODS: A geometric model of the glenohumeral joint was developed and adjusted to represent small, medium, and large shoulders. Muscle-tendon lengths were assessed for the anterior deltoid, middle deltoid, posterior deltoid, and supraspinatus from 0 to 90° of scaption; for the subscapularis from 0° to 60° of internal rotation (IR) and 0° to 60° of scaption; for the infraspinatus from 0° to 60° of external rotation (ER) and 0° to 60° of scaption; and for the teres minor from 0° to 60° of ER at 90° of scaption. RTSA designs were virtually implanted using the following parameters: (1) surgical placement with a centered or inferior glenosphere position and a humeral offset of 0, 5, or 10 mm relative to the anatomic neck plane, (2) implant design involving a glenosphere size of 30, 36, or 42 mm, glenosphere lateralization of 0, 5, or 10 mm, and humeral neck-shaft angle of 135°, 145°, or 155°. Thus, 486 RTSA-shoulder size combinations were analyzed. Linear regression assessed the strength of association between parameters and the change in each muscle-tendon length from the native length. RESULTS: The configuration that most closely restored anatomic muscle-tendon lengths in a small shoulder was a 30-mm glenosphere with a centered position, 5 mm of glenoid lateralization, 0 mm of humeral offset, and a 135° neck-shaft angle. For a medium shoulder, the corresponding combination was 36 mm, centered, 5 mm, 0 mm, and 135°. For a large shoulder, it was 30 mm, centered, 10 mm, 0 mm, and 135°. The most important implant-design parameter associated with restoration of native muscle-tendon lengths was the neck-shaft angle, with a 135° neck-shaft angle being favored (ß = 0.568 to 0.657, p < 0.001). The most important surgical parameter associated with restoration of native muscle-tendon lengths was humeral offset, with a humeral socket placed at the anatomic neck plane being favored (ß = 0.441 to 0.535, p < 0.001). CONCLUSIONS: A combination of a smaller, lateralized glenosphere, a humeral socket placed at the anatomic neck plane, and an anatomic 135° neck-shaft angle best restored native deltoid and rotator cuff muscle-tendon lengths in RTSA. CLINICAL RELEVANCE: This study of surgical and implant factors in RTSA highlighted optimal configurations for restoration of native muscle-tendon lengths of the deltoid and rotator cuff, which has direct implications for surgical technique and implant selection. Additionally, it demonstrated the most influential surgical and implant factors with respect to muscle-tendon lengths, which can be used to aid intraoperative decision-making.

The origin of betaine in mouse oocytes and preimplantation embryos†.

Betaine has important roles in preimplantation mouse embryos, including as an organic osmolyte that functions in cell volume regulation in the early preimplantation stages and as a donor to the methyl pool in blastocysts. The origin of betaine in oocytes and embryos was largely unknown. Here, we found that betaine was present from the earliest stage of growing oocytes. Neither growing oocytes nor early preantral follicles could take up betaine, but antral follicles were able to transport betaine and supply the enclosed oocyte. Betaine is synthesized by choline dehydrogenase, and female mice lacking Chdh did not have detectable betaine in their oocytes or early embryos. Supplementing betaine in their drinking water restored betaine in the oocyte only when supplied during the final stages of antral follicle development but not earlier in folliculogenesis. Together with the transport results, this implies that betaine can only be exogenously supplied during the final stages of oocyte growth. Previous work showed that the amount of betaine in the oocyte increases sharply during meiotic maturation due to upregulated activity of choline dehydrogenase within the oocyte. This betaine present in mature eggs was retained after fertilization until the morula stage. There was no apparent role for betaine uptake via the SIT1 (SLC6A20) betaine transporter that is active at the 1- and 2-cell stages. Instead, betaine was apparently retained because its major route of efflux, the volume-sensitive organic osmolyte - anion channel, remained inactive, even though it is expressed and capable of being activated by a cell volume increase.

Race/Ethnicity Analysis of Vascular Alterations in Optical Coherence Tomography Angiography in Diabetic Patients.

PURPOSE: Racial and ethnic minorities have a higher prevalence of diabetic retinopathy (DR) and present at advanced stages of disease. In an urban hospital population, we investigated microvascular differences in optical coherence tomography angiography (OCTA) between racial/ethnic groups while adjusting for socioeconomic status (SES). METHODS: 3 × 3 mm2 macular OCTA scans were obtained for analysis of foveal avascular zone (FAZ) area, FAZ perimeter as well as superficial (SCP) and deep capillary plexus (DCP) vessel density (VD), vessel length density (VLD), and adjusted flow index (AFI). SES was measured using the Area Deprivation Index. Multivariable regression models were used to adjust estimates for relevant confounders. RESULTS: 217 non-diabetic and 1,809 diabetic patients were included in the study, consisting of 42.2% Hispanic, 24.9% non-Hispanic (NH) Asian, 6.8% NH Black, 9.7% NH White and 16.3% Other patients. NH White was used as the reference group. Hispanic, NH Asian, and NH Black patients had significantly greater FAZ areas and FAZ perimeters, and lower DCP VD and VLD, among both non-diabetic and diabetic patients (Benjamini-Hochberg adjusted P-values <0.05). The addition of SES scores in the models did not modify any regressions significantly. CONCLUSIONS: In patients with and without diabetes, racial and ethnic minorities have significant retinal microvasculature differences when compared to NH White patients, regardless of SES. These differences are pronounced in DCP and may predispose racial/ethnic minorities to worse outcomes in DR, thus widening disparities in ophthalmic care.

A brief mindfulness-based intervention for stress, pain, emotion and attention regulation in military service members with mild traumatic brain injury.

AIM: The primary aim of this study was to conduct an open pilot clinical trial of a brief mindfulness-based intervention for persistent postconcussion symptoms that occur after mild traumatic brain injury in military service members. For many service members, operational tempo and other time constraints may prevent them from completing a standard mindfulness-based stress reduction course. Thus, this study sought to examine the effectiveness of a five-session intervention called mindfulness-based stress, pain, emotion, and attention regulation (MSPEAR). METHODS: Participants were active duty service members with a history of mild traumatic brain injury (TBI) and persisting postconcussion symptoms, all of whom were recruited from an outpatient TBI rehabilitation program at a military treatment facility. Of the 38 service members that were initially enrolled, 25 completed the 5-session MSPEAR intervention, and 20 returned for a 5-week follow-up evaluation. Questionnaires assessing perceived stress, positive affect, pain interference and catastrophizing, sleep disturbances, perceived behavioral and attention regulation, self-efficacy and satisfaction with life were administered at preintervention, postintervention, and at 5-week follow-up intervals. Neuropsychological testing at preintervention and 5-week follow-up included performance validity measures, attention, working memory, and executive function measures. T-tests were run to compare for questionnaire measures at preintervention (Time 1) to postintervention (Time 2). Repeated analysis of variances were conducted to compare questionnaire and neuropsychological measures at Time 1, Time 2, and at Time 3 which is the 5-week follow-up. RESULTS: Improvements in perceived stress, positive affect, behavioral regulation, metacognition, sleep disturbance, self-efficacy, and satisfaction with life were found immediately after the MSPEAR intervention and were maintained at the 5-week follow-up. Magnification and helplessness aspects of pain catastrophizing improved when comparing preintervention to the 5-week follow-up. Pain interference was not significantly different across study assessment times. Neuropsychological testing revealed improvements in sustained attention, working memory, cognitive flexibility, and inhibitory control when comparing preintervention to the 5-week follow-up assessment. CONCLUSIONS: The MSPEAR intervention appears to show promise as a brief and effective therapy for specific postconcussion symptoms after mild traumatic brain injury in military service members. Each of the components of MSPEAR including stress, pain catastrophizing, emotion and attention regulation showed improvements in this study, and bears further investigation in a larger scale, preferably randomized controlled trial in those active duty military service members who experience persisting symptoms after a mild traumatic brain injury.

Clinical Outcomes in Prospective versus Retrospective Studies on Arthroscopic Bankart Repair: A Systematic Review.

BACKGROUND: The majority of the current literature on arthroscopic Bankart repair is retrospective and discrepancies exist regarding clinical outcomes including recurrent instability and return to play amongst studies of different levels of evidence. PURPOSE: The purpose of this study is to perform a systematic review of the literature to compare the outcomes of prospective and retrospective studies on arthroscopic Bankart repair. METHODS: A search was performed using the PubMed/Medline database for all studies that reported clinical outcomes on Bankart repair for anterior shoulder instability. The search term "Bankart repair" with all results being analyzed via strict inclusion and exclusion criteria. Three independent investigators extracted data and scored each included study based on the 10 criteria of the Modified Coleman Methodology Score (CMS) out of 100. A chi-square test was performed to assess if recurrent instability, revision, return to play, and complications are independent of prospective and retrospective studies. RESULTS: One hundred ninety-three studies were included in the analysis with 53 prospective studies and 140 retrospective in design. Encompassing a total of 13,979 patients and 14,019 surgical procedures for Bankart repair for shoulder instability. The rate of re-dislocation in the prospective studies was 8.0% vs. 5.9% in retrospective (p < 0.001). The rate of recurrent subluxation in the prospective studies was 3.4% vs. 2.4% in retrospective (p = 0.004). The rate of revision was higher in retrospective studies at 4.9% vs. 3.9% in prospective studies (p = 0.013) There was no significant difference in terms of overall rate to return to play in prospective and retrospective studies was 90% and 91%, respectively (p=0.548). The overall rate of complications in the prospective cohort was 0.27% and 0.78% in the retrospective studies (p = 0.002). CONCLUSION: The overall rates of recurrent dislocations, subluxations are higher in prospective studies compared to retrospective studies. However, rates of revision were reportedly higher in retrospective studies. Complications after arthroscopic Bankart repair are rare in both prospective and retrospective studies, and there was no difference in rates of return to play.

Outcomes and Complications of Revision Reverse Shoulder Arthroplasty Following Failed Primary Anatomical Shoulder Arthroplasty or Hemiarthroplasty: A Systematic Review.

BACKGROUND: The purpose of this study is to systematically review the evidence in the literature to ascertain the functional outcomes, range of motion (ROM) and complication and reoperation rates following revision reverse shoulder arthroplasty (RSA) for a failed primary total shoulder arthroplasty (TSA) or hemiarthroplasty (HA). METHODS: Two independent reviewers performed the literature search based on PRISMA guidelines, utilizing the EMBASE, MEDLINE, and The Cochrane Library Databases. Studies were included if they reported clinical outcomes for revision RSA for a failed primary TSA or HA. RESULTS: Our review found 23 studies including 1,041 shoulders (627 TSA, 414 HA) meeting our inclusion criteria. The majority of patients were female (66.1%), with an average age of 69.0 years (range 39-93) with a mean follow-up of 46.3 months. ASES and VAS pain scores improved from 32.6 to 61.9 and 6.7 to 2.7, respectively. ROM results including forward flexion, abduction and external rotation that improved from 59.4° to 107.7°, 50.7° to 104.4°, and 19.8° to 26.3° respectively. Only one out of the ten studies reporting internal rotation found a statistically significant difference with mean internal rotation improving from S1-S3 preoperatively to L4-L5 postoperatively for patients undergoing HA. The overall complication rate and reoperation rate were 23.4% and 12.5% respectively. The most common complications were glenoid component loosening (6.0%), fracture (periprosthetic, intraoperative, or other scapula fractures) (n=4.7%), and infection (n=3.3%). CONCLUSION: Revision RSA for a failed primary TSA and HA has been shown to result in excellent functional outcomes and improved ROM suggesting patients who have failed TSA or HA may benefit from a revision RSA.

The Polyanalgesic Consensus Conference (PACC)®: Intrathecal Drug Delivery Guidance on Safety and Therapy Optimization When Treating Chronic Noncancer Pain.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians and scientists based on expertise with international representation to establish evidence-based guidance on intrathecal drug delivery in treating chronic pain. This Polyanalgesic Consensus Conference (PACC)® project, created more than two decades ago, intends to provide evidence-based guidance for important safety and efficacy issues surrounding intrathecal drug delivery and its impact on the practice of neuromodulation. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when PACC® last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence is scant. RESULTS: The PACC® examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The PACC® recommends best practices regarding intrathecal drug delivery to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate.

Estimating Community Disruption from Nighttime Gunshots in 6 U.S. Cities, 2015 to 2021.

BACKGROUND: Gunshots affect those directly involved in an incident and those in the surrounding community. The community-level impact of nighttime gunshots, which may be particularly disruptive to the sleep of nearby community members, is unknown. OBJECTIVE: Our aim is to estimate the number of people potentially affected by nighttime gunshots and the relationship between nighttime gunshots and median household income in the USA. DESIGN: We collected publicly available data on the timing and location of gunshots in six U.S. cities (Baltimore, MD; Boston, MA; Washington, D.C.; New York, NY; Philadelphia, PA; and Portland, OR) from 2015 to 2021. We then analyzed the data by computing rate ratios (RRs) to compare the frequency of gunshots during nighttime hours (6:00 pm to 5:59 am) versus daytime hours (6:00 am to 5:59 pm). Additionally, we used geospatial mapping to create choropleth maps to visualize the variation in nighttime gunshot density across cities. We estimated, using city-wide population, person-nights potentially impacted by the sound of gunshots within areas of 0.2- (low) and 0.5-mile (high) radius. Finally, for five of six cities where data on median household income were available by census tract, we built nonlinear regression models to estimate the relationship between the number of nighttime gunshots and median household income. KEY RESULTS: We analyzed 72,236 gunshots. Gunshots were more common during the nighttime than daytime (overall RR = 2.5). Analyses demonstrated that the low estimates for the mean annual number of person-nights impacted by nighttime gunshots were 0.4 million in Baltimore and Portland, 1.3 million in Philadelphia, 1.6 million in Boston, 2.9 million in New York City, and 5.9 million in Washington. The number of nighttime gunshots was inversely related to median household income. CONCLUSIONS: Nighttime gunshots are prevalent, particularly in low-income neighborhoods, and may have under-recognized effects on the surrounding community.

SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has caused nearly 7 million deaths worldwide. Severe cases are marked by an aggressive inflammatory response known as hypercytokinemia, contributing to endothelial damage. Although vaccination has reduced hospitalizations, hypercytokinemia persists in breakthrough infections, emphasizing the need for disease models mimicking this response. Using a 3D microphysiological system (MPS), we explored the vascular role in SARS-CoV-2-induced hypercytokinemia. Methods: The vascularized micro-organ (VMO) MPS, consisting of human-derived primary endothelial cells (ECs) and stromal cells within an extracellular matrix, was used to model SARS-CoV-2 infection. A non-replicative pseudotyped virus fused to GFP was employed, allowing visualization of viral entry into human ECs under physiologic flow conditions. Expression of ACE2, TMPRSS2, and AGTR1 was analyzed, and the impact of viral infection on ACE2 expression, vascular inflammation, and vascular morphology was assessed. Results: The VMO platform facilitated the study of COVID-19 vasculature infection, revealing that ACE2 expression increased significantly in direct response to shear stress, thereby enhancing susceptibility to infection by pseudotyped SARS-CoV-2. Infected ECs secreted pro-inflammatory cytokines, including IL-6 along with coagulation factors. Cytokines released by infected cells were able to activate downstream, non-infected EC, providing an amplification mechanism for inflammation and coagulopathy. Discussion: Our findings highlight the crucial role of vasculature in COVID-19 pathogenesis, emphasizing the significance of flow-induced ACE2 expression and subsequent inflammatory responses. The VMO provides a valuable tool for studying SARS-CoV-2 infection dynamics and evaluating potential therapeutics.

Glenohumeral morphological predictors of recurrent shoulder instability following arthroscopic Bankart repair.

PURPOSE: The purpose of this study was to evaluate glenohumeral morphological features on a magnetic resonance arthrogram (MRA) to determine risk factors for recurrence of anterior shoulder instability following arthroscopic Bankart repair (ABR). METHODS: A retrospective review of patients who underwent ABR between 2012 and 2017 was performed to identify patients who had recurrence of instability following stabilisation (Group 1). These were pair-matched in a 2:1 ratio for age, gender and sport with a control (Group 2) who underwent ABR without recurrence. Preoperative MRAs were evaluated for risk factors for recurrence, with glenoid bone loss and Hill-Sachs lesions also measured. Multilinear and multilogistic regression models were used to evaluate factors affecting recurrence. RESULTS: Overall, 72 patients were included in this study, including 48 patients without recurrence and 24 patients with recurrent instability. There was a significant difference between the two groups in mean glenoid bone loss (Group 1: 7.3% vs. Group 2: 5.7%, p < 0.0001) and the rate of off-track Hill-Sachs lesions (Group 1: 20.8% vs. Group 2: 0%, p = 0.0003). Of the variables analysed in logistic regression, increased glenoid anteversion (p = 0.02), acromioclavicular (AC) degeneration (p = 0.03) and increased Hill-Sachs width were associated with increased risk of failure. Increased chondral version (p = 0.01) and humeral head diameter in the anteriorposterior view were found to be protective and associated with a greater likelihood of success. CONCLUSION: Glenoid anteversion was a risk factor for recurrent instability, whereas increased chondral version and humeral head diameter were associated with higher rates of success following ABR. Glenoid bone loss, presence of an off-track Hill-Sachs lesion, increased Hill-Sachs width and AC degeneration were also associated with failure. These findings should be used by surgeons to stratify risk for recurrence following ABR. LEVEL OF EVIDENCE: Level III.

Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.

OBJECTIVE: Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve ß-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy. RESEARCH DESIGN AND METHODS: We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial. RESULTS: Among trials meeting their primary end point, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (P = 0.030 and P < 0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. The use of C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R2 for 12-month C-peptide AUC adjusted for age and baseline value was 0.80, P < 0.001), and this finding supported the concept of smaller trial sizes down to 54 participants. CONCLUSIONS: Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early-phase clinical trials.

Considering the cellular landscape in marrow stimulation techniques for cartilage repair.

BACKGROUND: Marrow stimulation is a common reparative approach to treat injuries to cartilage and other soft tissues (e.g., rotator cuff). It involves the recruitment of bone marrow elements and mesenchymal stem cells (MSCs) into the defect, theoretically initiating a regenerative process. However, the resulting repair tissue is often weak and susceptible to deterioration with time. The populations of cells at the marrow stimulation site (beyond MSCs), and their contribution to inflammation, vascularity, and fibrosis, may play a role in quality of the repair tissue. SUMMARY: In this review, we accomplish three goals: 1) systematically review clinical trials on the augmentation of marrow stimulation and evaluate their assumptions on the biological elements recruited; 2) detail the cellular populations in bone marrow and their impact on healing; and 3) highlight emerging technologies and approaches that could better guide these specific cell populations towards enhanced cartilage or soft tissue formation. KEY MESSAGES: We found that most clinical trials do not account for cell heterogeneity, nor do they specify the regenerative element recruited, and those that do typically utilize descriptions such as "clots", "elements", and "blood". Furthermore, our review of bone marrow cell populations demonstrates a dramatically heterogenous cell population, including hematopoietic cells, immune cells, fibroblasts, macrophages, and only a small population of MSCs. Finally, the field has developed numerous innovative techniques to enhance the chondrogenic potential (and reduce the anti-regenerative impacts) of these various cell types. We hope this review will guide approaches that account for cellular heterogeneity and improve marrow stimulation techniques to treat chondral defects.

High-threshold and low-overhead fault-tolerant quantum memory.

The accumulation of physical errors1-3 prevents the execution of large-scale algorithms in current quantum computers. Quantum error correction4 promises a solution by encoding k logical qubits onto a larger number n of physical qubits, such that the physical errors are suppressed enough to allow running a desired computation with tolerable fidelity. Quantum error correction becomes practically realizable once the physical error rate is below a threshold value that depends on the choice of quantum code, syndrome measurement circuit and decoding algorithm5. We present an end-to-end quantum error correction protocol that implements fault-tolerant memory on the basis of a family of low-density parity-check codes6. Our approach achieves an error threshold of 0.7% for the standard circuit-based noise model, on par with the surface code7-10 that for 20 years was the leading code in terms of error threshold. The syndrome measurement cycle for a length-n code in our family requires n ancillary qubits and a depth-8 circuit with CNOT gates, qubit initializations and measurements. The required qubit connectivity is a degree-6 graph composed of two edge-disjoint planar subgraphs. In particular, we show that 12 logical qubits can be preserved for nearly 1 million syndrome cycles using 288 physical qubits in total, assuming the physical error rate of 0.1%, whereas the surface code would require nearly 3,000 physical qubits to achieve said performance. Our findings bring demonstrations of a low-overhead fault-tolerant quantum memory within the reach of near-term quantum processors.