Combining targeted DNA repair inhibition and immune-oncology approaches for enhanced tumor control.

Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased engagement of the anti-tumor immune response. Additionally, we discuss mechanistic and clinical rationale for pairing targeted DDRis with immunotherapy for enhanced tumor control. We also review biomarkers for patient selection and promising new immunotherapy approaches poised to form the foundation of next-generation DDRi and immunotherapy combinations.

Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions.

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.

Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development-Current State-of-the-Art and Future Perspectives.

The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology, and genetics. Unreliable target identification and poor translatability of preclinical models have been identified as major causes of failure. To improve predictions of clinical efficacy and safety, interest has shifted to three-dimensional culture methods in which human cells can retain many physiologically and functionally relevant phenotypes for extended periods of time. Here, we review the state of the art of available organotypic culture techniques and critically review emerging models of human tissues with key importance for pharmacokinetics, pharmacodynamics, and toxicity. In addition, developments in bioprinting and microfluidic multiorgan cultures to emulate systemic drug disposition are summarized. We close by highlighting important trends regarding the fabrication of organotypic culture platforms and the choice of platform material to limit drug absorption and polymer leaching while supporting the phenotypic maintenance of cultured cells and allowing for scalable device fabrication. We conclude that organotypic and microphysiological human tissue models constitute promising systems to promote drug discovery and development by facilitating drug target identification and improving the preclinical evaluation of drug toxicity and pharmacokinetics. There is, however, a critical need for further validation, benchmarking, and consolidation efforts ideally conducted in intersectoral multicenter settings to accelerate acceptance of these novel models as reliable tools for translational pharmacology and toxicology. SIGNIFICANCE STATEMENT: Organotypic and microphysiological culture of human cells has emerged as a promising tool for preclinical drug discovery and development that might be able to narrow the translation gap. This review discusses recent technological and methodological advancements and the use of these systems for hit discovery and the evaluation of toxicity, clearance, and absorption of lead compounds.

Just a phase? Causal probing reveals spurious phasic dependence of sustained attention.

For over a decade, electrophysiological studies have reported correlations between attention / perception and the phase of spontaneous brain oscillations. To date, these findings have been interpreted as evidence that the brain uses neural oscillations to sample and predict upcoming stimuli. Yet, evidence from simulations have shown that analysis artefacts could also lead to spurious pre-stimulus oscillations that appear to predict future brain responses. To address this discrepancy, we conducted an experiment in which visual stimuli were presented in time to specific phases of spontaneous alpha and theta oscillations. This allowed us to causally probe the role of ongoing neural activity in visual processing independent of the stimulus-evoked dynamics. Our findings did not support a causal link between spontaneous alpha / theta rhythms and behaviour. However, spurious correlations between theta phase and behaviour emerged offline using gold-standard time-frequency analyses. These findings are a reminder that care should be taken when inferring causal relationships between neural activity and behaviour using acausal analysis methods.

Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study.

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03043872.

Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC. METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment. FINDINGS: From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity. INTERPRETATION: Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required. FUNDING: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center.

Dissecting the impact of complement component 4A in bipolar disorder.

The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N = 1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI.

Lower complement C1q levels in first-episode psychosis and in schizophrenia.

Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10-05), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications.

Neurodevelopmental disorders-high-resolution rethinking of disease modeling.

Neurodevelopmental disorders arise due to various risk factors that can perturb different stages of brain development, and a combinatorial impact of these risk factors programs the phenotype in adulthood. While modeling the complete phenotype of a neurodevelopmental disorder is challenging, individual developmental perturbations can be successfully modeled in vivo in animals and in vitro in human cellular models. Nevertheless, our limited knowledge of human brain development restricts modeling strategies and has raised questions of how well a model corresponds to human in vivo brain development. Recent progress in high-resolution analysis of human tissue with single-cell and spatial omics techniques has enhanced our understanding of the complex events that govern the development of the human brain in health and disease. This new knowledge can be utilized to improve modeling of neurodevelopmental disorders and pave the way to more accurately portraying the relevant developmental perturbations in disease models.

Potential sensitive period effects of maltreatment on amygdala, hippocampal and cortical response to threat.

Childhood maltreatment is a leading risk factor for psychopathology, though it is unclear why some develop risk averse disorders, such as anxiety and depression, and others risk-taking disorders including substance abuse. A critical question is whether the consequences of maltreatment depend on the number of different types of maltreatment experienced at any time during childhood or whether there are sensitive periods when exposure to particular types of maltreatment at specific ages exert maximal effects. Retrospective information on severity of exposure to ten types of maltreatment during each year of childhood was collected using the Maltreatment and Abuse Chronology of Exposure scale. Artificial Intelligence predictive analytics were used to delineate the most important type/time risk factors. BOLD activation fMRI response to threatening versus neutral facial images was assessed in key components of the threat detection system (i.e., amygdala, hippocampus, anterior cingulate, inferior frontal gyrus and ventromedial and dorsomedial prefrontal cortices) in 202 healthy, unmedicated, participants (84 M/118 F, 23.2 ± 1.7 years old). Emotional maltreatment during teenage years was associated with hyperactive response to threat whereas early childhood exposure, primarily to witnessing violence and peer physical bullying, was associated with an opposite pattern of greater activation to neutral than fearful faces in all regions. These findings strongly suggest that corticolimbic regions have two different sensitive period windows of enhanced plasticity when maltreatment can exert opposite effects on function. Maltreatment needs to be viewed from a developmental perspective in order to fully comprehend its enduring neurobiological and clinical consequences.

A study of size-selective renal elimination using a novel human model.

The recently discovered selective glomerular hypofiltration syndromes have increased interest in the actual elimination of molecules in the human kidney. In the present study, a novel human model was introduced to directly measure the single-pass renal elimination of molecules of increasing size. Plasma concentrations of urea, creatinine, C-peptide, insulin, pro-BNP, ß2-microglobulin, cystatin C, troponin-T, orosomucoid, albumin, and IgG were analysed in arterial and renal venous blood from 45 patients undergoing Transcatheter Aortic Valve Implantation (TAVI). The renal elimination ratio (RER) was calculated as the arteriovenous concentration difference divided by the arterial concentration. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI equations for both creatinine and cystatin C. Creatinine (0.11 kDa) showed the highest RER (21.0 ± 6.3%). With increasing molecular size, the RER gradually decreased, where the RER of cystatin C (13 kDa) was 14.4 ± 5.3% and troponin-T (36 kDa) was 11.3 ± 4.6%. The renal elimination threshold was found between 36 and 44 kDa as the RER of orosomucoid (44 kDa) was -0.2 ± 4.7%. The RER of creatinine and cystatin C showed a significant and moderate positive linear relationship with eGFR (r = 0.48 and 0.40). In conclusion, a novel human model was employed to demonstrate a decline in renal elimination with increasing molecular size. Moreover, RERs of creatinine and cystatin C were found to correlate with eGFR, suggesting the potential of this model to study selective glomerular hypofiltration syndromes.

Evaluating Male Patients' Understanding of Osteoporosis Evaluation and Treatment Following a Distal Radius Fracture.

PURPOSE: Current estimates suggest that 1-2 million men in the United States have osteoporosis, yet the majority of osteoporosis literature focuses on postmenopausal women. Our aim was to understand men's awareness and knowledge of osteoporosis and its treatment. METHODS: Semistructured interviews were conducted with 20 male patients >50 years old who sustained a low-energy distal radius fracture. The goal was to ascertain patients' knowledge of osteoporosis, its management, and experience discussing osteoporosis with their primary care physicians (PCP). RESULTS: Participants had little knowledge of osteoporosis or its treatment. Many participants regarded osteoporosis as a women's disease. Most participants expressed concern regarding receiving a diagnosis of osteoporosis. Several patients stated that they believe osteoporosis may have contributed to their fracture. Families, friends, or mass media served as the primary information source for participants, but few had good self-reported understanding of the disease itself. The majority of participants reported never having discussed osteoporosis with their PCPs although almost half had received a dual x-ray absorptiometry scan. Participants expressed general interest in being tested/screened and generally were willing to undergo treatment despite the perception that medication has serious side effects. One patient expressed concern that treatment side effects could be worse than having osteoporosis. CONCLUSION: Critical knowledge gaps exist regarding osteoporosis diagnosis and treatment in at-risk male patients. Specifically, most patients were unaware they could be osteoporotic because of the perception of osteoporosis as a women's disease. Most patients had never discussed osteoporosis with their PCP. CLINICAL RELEVANCE: Male patients remain relatively unaware of osteoporosis as a disease entity. Opportunity exists for prevention of future fragility fractures by improving communication between patients and physicians regarding osteoporosis screening in men following low-energy distal radius fractures.

Hand Surgery Fellowship Case Minimums: History and Design.

In the 1960s, the American Society for Surgery of the Hand embarked on an endeavor to improve and standardize the educational experience in hand surgery. By the 1980s, numerous programs existed across the country with the Accreditation Council for Graduate Medical Education formally recognizing orthopedic surgery-based fellowships in 1985 and plastic surgery-based fellowships in 1986. In order to sit for what was then termed the Certificate of Additional Qualification examination, applicants had to demonstrate performance of a specific number of procedures while in practice. Borrowing from this theme, the Accreditation Council for Graduate Medical Education began to analyze programs according to the relative proportion of cases done by fellows at individual institutions compared to national trends. Beginning in 2019 and working collaboratively with the Accreditation Council for Graduate Medical Education, the Hand Fellowship Director's Association has since modified the methods by which programs are evaluated, pivoting away from comparative percentages to the establishment of case minimums. The development of this process has been iterative with the resultant outcome being an evaluation system that focuses on educational quality and technical proficiency over sheer numerical volume.

Shoulder Arthroplasty in the Upper Extremity Weight-bearing Patient: A Systematic Review of Clinical Outcomes and Complications.

BACKGROUND: Patients who rely on their upper extremities for ambulation, or upper extremity ambulators (UEAs), place considerable stress on their shoulders through the use of assistive devices like walkers, crutches, canes, and wheelchairs. It has been postulated that UEAs may be at increased risk for complications following shoulder arthroplasty. This study aimed to systematically review the literature related to (1) patient-reported outcomes measures (PROMs), (2) functional outcomes, and (3) complications in UEAs who undergo shoulder arthroplasty. METHODS: A systematic review of the PubMed/MEDLINE, Embase, and Cochrane databases was performed to identify studies reporting clinical outcomes of shoulder arthroplasty in UEAs. Patient demographics, clinical characteristics, PROMs, radiographic outcomes, and postoperative range of motion were collected and compared to control patients (i.e. bipedal ambulators) from the constituent studies. RESULTS: A total of eight studies evaluating 248 UEA cases and 206 control cases were included for review. Ambulatory assistive devices utilized by UEAs included walkers (39%), wheelchairs (38%), canes (22%), and a crutch (<1%). Among UEA cases, 197 (79%) reverse total shoulder arthroplasty, 37 (15%) anatomic total shoulder arthroplasty, and 14 (6%) hemiarthroplasty were performed. Overall, patients exhibited significant improvements in mean American Shoulder and Elbow Surgeons (ASES) scores, Constant-Murley scores, Simple Shoulder Test (SST) scores, and Visual Analog Scale (VAS) scores postoperatively. Among 3 studies that included comparison with control groups of bipedal ambulators, no significant differences in outcomes were identified. The overall clinical complication rate was 17% for UEAs compared to 9.1% for controls. The rate of revision surgery was 7.7% for UEAs and 4.9% for bipedal ambulators. CONCLUSIONS: UEAs experience satisfactory pain relief, functional improvements, and good subjective outcomes following shoulder arthroplasty. However, complication and revision rates are higher compared to those for bipedal ambulators, and the majority of UEAs undergo reverse shoulder arthroplasty (RSA) compared to anatomic total shoulder arthroplasty (aTSA).

Anatomic TSA for B2 glenoids treated with asymmetric reaming has equivalent survivorship and patient outcomes compared to type A glenoids at mean 9 years follow-up.

BACKGROUND: Walch B2 glenoids can present a challenge to shoulder arthroplasty surgeons. Short-term studies have demonstrated that corrective reaming to 10° of retroversion in anatomic total shoulder arthroplasty (aTSA) can result in good outcomes, however there is little data reporting the long-term outcomes in this cohort. B2 glenoids treated with high-side reaming present a theoretical risk of early glenoid component failure as one may ream into the subchondral bone. This study aimed to demonstrate that 1) B2 glenoids treated with corrective reaming have durable results and 2) offer similar results to Walch A1/2 in long-term follow-up. METHODS: Patients who underwent aTSA by a single surgeon (E.L.F.) were identified from a shoulder arthroplasty registry. Inclusion criteria included Walch A1, A2 or B2 glenoid, a diagnosis of primary shoulder osteoarthritis, and a minimum radiographic and clinical follow-up of 5 years. 43 patients with B2 glenoids were compared to a cohort of 42 patients with A1 or A2 glenoids. Preoperative computed tomography (CT) and radiographs were utilized to assess deformity, glenoid version, and posterior subluxation of the humeral head. Postoperatively, patients were assessed with radiographs and patient-reported outcome measures including American Shoulder and Elbow Surgeons (ASES) score, Simple Shoulder Test (SST) score, and Visual Analog Scale (VAS). RESULTS: 85 shoulders (82 patients, 42 B2 and 43 A1/A2 glenoids) with an average follow-up of 9.4 years were included. In the B2 cohort, the average retroversion was 21.1° and posterior subluxation was 69.4% compared with 10.6°(p<0.001) and 57.5% (p<0.001) in the A1 or A2 cohort. The cohort demographics were similar except for male sex (B2 69.8% vs A1 or A2 37.2%, p=0.008). There was no difference between the cohorts in their improvement in ASES (p=0.807), SST (p=0.586), or VAS (p=0.930) scores. There was no difference in lateral humeral offset (p=0.889) or acromial humeral interval (p=0.468) between initial postoperative and final follow-up visits. Survivorship for B2 glenoids was 97.6%, 94.1% and 73.3% at 5, 10 and 15 years, respectively compared to 97.6%, 91.9% and 83.5% in type A glenoids. The revision rate was similar between the two groups (p=0.432). Lazarus score (p=0.682) and rates of humeral radiolucency (p=0.366) and humeral osteolysis (p=0.194) were similar between the two cohorts at final follow-up. CONCLUSION: Asymmetric reaming of patients with B2 glenoids is a reliable method of glenoid preparation with excellent mid- to long-term clinical results, patient reported outcomes, and low revision rates similar to their A1 and A2 counterparts.

Cemented vs. press-fit humeral stems: a matched cohort analysis at a mean follow-up of 10 years.

BACKGROUND: Although cementation of humeral stems has long been considered the gold standard for anatomic shoulder arthroplasty (aTSA), cementless, or press-fit, fixation offers a relatively cheaper and less demanding alternative, particularly in the setting of a revision procedure. However, this approach has been accompanied by concerns of implant loosening and high rates of radiolucency. In the present study, we performed a propensity-matched comparison of clinical and patient-reported outcomes between cemented and cementless fixation techniques for aTSA. We hypothesized that cemented fixation of the humeral component would have significantly better implant survival while providing comparable functional outcomes at final follow-up. METHODS: This study was a retrospective comparison of 50 shoulders undergoing aTSA: 25 using cemented humeral fixation vs. 25 using press-fit humeral fixation. Patients in the 2 groups were propensity matched according to age, sex, and preoperative American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score. Primary outcome measures included range of motion (ROM) (forward elevation, external rotation, internal rotation), patient-reported outcomes (ASES, Simple Shoulder Test [SST], visual analog scale [VAS]), and implant survival. RESULTS: At baseline, the 2 fixation groups were similar in regard to age, sex, body mass index, preoperative ASES score, and surgical indication. Mean follow-up was 11.7 ± 4.95 years in the cemented cohort and 9.13 ± 3.77 years in the press-fit cohort (P = .045). Both groups demonstrated significant improvements postoperatively in all included ROM and patient-reported outcomes. However, press-fit patients reported significantly better VAS, ASES, and SST scores. Mean VAS pain score was 1.1 ± 1.8 in press-fit patients and 3.2 ± 3.0 in cemented patients (P = .005). The mean ASES score was 87.7 ± 12.4 in press-fit patients and 69.5 ± 22.7 in cemented patients (P = .002). Lastly, the mean SST score was 9.8 ± 3.1 in press-fit patients and 7.7 ± 3.7 in cemented patients (P = .040). Both fixation techniques provided lasting implant survivorship with only a single revision operation in each of the cohorts. CONCLUSION: Herein, we provide a propensity-matched, long-term comparison of patients receiving anatomic shoulder arthroplasty stratified according to humeral stem fixation technique. The results of this analysis illustrate that both types of humeral fixation techniques yield durable and significant improvements in shoulder function with similar rates of survival at 10 years of follow-up.

A Rapid Review on the Effectiveness and Use of Wearable Biofeedback Motion Capture Systems in Ergonomics to Mitigate Adverse Postures and Movements of the Upper Body.

Work-related diseases and disorders remain a significant global health concern, necessitating multifaceted measures for mitigation. One potential measure is work technique training utilizing augmented feedback through wearable motion capture systems. However, there exists a research gap regarding its current effectiveness in both real work environments and controlled settings, as well as its ability to reduce postural exposure and retention effects over short, medium, and long durations. A rapid review was conducted, utilizing two databases and three previous literature reviews to identify relevant studies published within the last twenty years, including recent literature up to the end of 2023. Sixteen studies met the inclusion criteria, of which 14 were of high or moderate quality. These studies were summarized descriptively, and the strength of evidence was assessed. Among the included studies, six were rated as high quality, while eight were considered moderate quality. Notably, the reporting of participation rates, blinding of assessors, and a-priori power calculations were infrequently performed. Four studies were conducted in real work environments, while ten were conducted in controlled settings. Vibration feedback was the most common feedback type utilized (n = 9), followed by auditory (n = 7) and visual feedback (n = 1). All studies employed corrective feedback initiated by the system. In controlled environments, evidence regarding the effectiveness of augmented feedback from wearable motion capture systems to reduce postural exposure ranged from strong evidence to no evidence, depending on the time elapsed after feedback administration. Conversely, for studies conducted in real work environments, the evidence ranged from very limited evidence to no evidence. Future reach needs are identified and discussed.

Emerging issues in fisheries science by fisheries scientists.

The current epoch in fisheries science has been driven by continual advances in laboratory techniques and  increasingly sophisticated approaches to analysing datasets. We now have the scientific knowledge and tools to proactively identify obstacles to the sustainable management of marine resources. However, in addition to technological advances, there are predicted global environmental changes, each with inherent implications for fisheries. The 2023 symposium of the Fisheries Society of the British Isles called for "open and constructive knowledge exchange between scientists, stakeholders, managers and policymakers" (https://fsbi.org.uk/symposium-2023/), a nexus of collaborative groups best placed to identify issues and solutions. Arguably, the Centre of Environment, Aquaculture and Fisheries Science (Cefas) and their Scientific Advice for Fisheries Management (SAFM) Team sit at the centre of such a network. SAFM regularly engages with managers and stakeholders, undertakes scientific research, provides fisheries advice to the UK government, and are leading experts within the International Council for the Exploration of the Sea (ICES). As such, this paper is an opinion piece, linked to individual authors specialisms, that aims to highlight emerging issues affecting fisheries and suggest where research efforts could be focused that contribute to sustainable fisheries.

Mid-term outcomes following reverse total shoulder arthroplasty.

PURPOSE: The utilization of reverse total shoulder arthroplasty now exceeds the incidence of anatomic shoulder arthroplasty. Previous mid-to-long-term studies on rTSA have reported a decrease in shoulder function as follow-up increased. The purpose of this study was to provide data on mid-term outcomes and implant survival in a series focusing on reverse total shoulder arthroplasty. MATERIALS AND METHODS: Demographic information such as age at surgery, revision surgery status, BMI, and smoking status were recorded. The clinical endpoints measured in this study were range of motion scores (forward elevation, external rotation, internal rotation) and patient reported outcomes (VAS, ASES, SST). Radiographic variables captured included preoperative glenoid morphology, humeral lucency, and glenoid loosening. RESULTS: Fifty-six shoulders were included in this study. The overall mean age at surgery was 72.5 ± 7.2 years with an average follow-up time of 6.8 ± 3.5 years. The mean BMI was 28.1 ± 5.5. All measurements of range of motion saw significant and sustained improvements. Overall, forward elevation improved from 82° preoperatively to 133° postoperatively (p < 0.01). External rotation improved from 23° preoperatively to 36° (p < 0.01), while internal rotation improved from L3 to L1 (p = 0.05). ASES scores improved from 31 preoperatively to 70 postoperatively (p < 0.01). SST scores improved from 2 preoperatively to 7 (p < 0.01). VAS pain index scores improved from 6 to 2 following surgery (p < 0.01). Postoperative scapular notching was seen in 18 patients at final follow-up. Glenoid loosening was seen in 3 shoulders. Humeral loosening was seen in 18 shoulders. Tuberosity resorption was seen in 8 shoulders. The 5 year survival estimate was 98%, and the 10 year survival estimate was 83%. CONCLUSION: In this series, we found that rTSA provides mid-term improvements in range of motion in patients while reducing pain levels. When considered together, this demonstrates that most patients undergoing rTSA can have excellent use of their shoulder from age at surgery to end-of-life.