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Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.

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PURPOSE: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with an absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies which are often adapted from SCLC and non-small cell lung cancer (NSCLC) approaches. EXPERIMENTAL DESIGN: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed immunohistochemistry and single-cell (sc)RNAseq of core needle biopsies from LCNEC patients and preclinical models. RESULTS: Here, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK and AXL targeting strategies, including a novel preclinical AXL CAR-T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by expression of SCLC subtype-defining transcription factors - especially ASCL1 and NEUROD1 - and, as expected given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including Delta-like ligand 3 (DLL3) and CD56 targeting, as with novel preclinical DLL3 and CD56 CAR T-cells, and DNA damage repair (DDR) inhibition. CONCLUSION: YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.

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BACKGROUND: Variation in residual volume between peritoneal dialysis dwells creates uncertainty in ultrafiltration determination, dialysis efficiency, and poses a risk of overfill if the residual volume is large. Measuring the dilution of a marker molecule during fluid fill offers a convenient approach, however, estimation accuracy depends on the choice of dilution marker. We here evaluate the feasibility of creatinine and urea as dilution markers compared to albumin-based residual volumes and three-pore model estimations. METHOD: This clinical, retrospective analysis comprises 56 residual volume estimations from 20 individuals, based on the dilution of pre-fill dialysate creatinine, urea and albumin concentrations during the dialysis fluid fill phase. Outcomes were compared individually. Bias induced by ultrafiltration, marker molecule mass-transfer and influence of fluid glucose contents was quantified using the three-pore model. Linear regression established conversion factors enabling conversion between the various marker molecules. RESULTS: Creatinine-based calculations overestimated residual volumes by 115 mL (IQR 89-149) in 1.5% dwells and 252 mL (IQR 179-313) in 4.25% glucose dwells. In hypertonic dwells, ultrafiltration was 52 mL (IQR 38-66), while intraperitoneal creatinine mass increased by 67% during fluid fill, being the leading cause of overestimation. Albumin-based volumes conformed strongly with three-pore model estimates. Correction factors effectively enabled marker molecule interchangeability. CONCLUSIONS: Mass-transfer of low molecular weight marker molecules is associated with residual volume overestimation. However, by applying correction factors, creatinine and urea dilution can still provide reasonable estimates, particularly when the purpose is to exclude the presence of a very large residual volume.

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Timely and sufficient decompression are critical objectives in degenerative cervical myelopathy (DCM) and spinal cord injury (SCI). We previously investigated intraoperative cerebrospinal fluid pressure (CSFP) for determining surgical outcomes. However, confounding factors during the intra- and postoperative setting need consideration. These are related to type of respiration (i.e., artificial vs. natural) and anesthesia, which affect CSFP dynamics through the interaction between the cardiorespiratory system and the CSF compartment. This retrospective cohort study (NCT02170155) aims to systematically investigate these factors to facilitate CSFP interpretation. CSFP was continuously measured through a lumbar catheter, intra- and postoperatively, in 21 patients with DCM undergoing decompression surgery. Mean CSFP and cardiac-driven CSFP peak-to-valley amplitude (CSFPp) were analyzed throughout the perioperative period, including the immediate extubation period in eight patients. Intraoperative mean CSFP had a median value and {interquartile range} of 10.8 {5.5} mmHg and increased 1.6-fold to 16.9 {7.1} mmHg postoperatively (p < 0.001). CSFPp increased 3-fold from 0.6 {0.7} to 1.8 {2.5} mmHg (p = 0.001). Increased CSFP persisted overnight. During extubation, there was a notable increase in CSFP and CSFPp of 14.0 {5.8} and 5.1 {3.1} mmHg, respectively. From case-based analysis, this was attributed to an arterial pCO2 increase. There was no correlation between respirator settings and CSFP metrics. There were distinct and quantifiable changes in CSFP dynamics from the intra- to postoperative setting related to type of respiration, anesthesia, and level of consciousness. When monitoring CSFP dynamics in spine surgery across these settings, cardiorespiratory factors must be controlled for.

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Presión del Líquido Cefalorraquídeo , Descompresión Quirúrgica , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Presión del Líquido Cefalorraquídeo/fisiología , Anciano , Descompresión Quirúrgica/métodos , Periodo Posoperatorio , Vértebras Cervicales/cirugía , Adulto , Estudios de Cohortes

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BACKGROUND: Degenerative cervical myelopathy (DCM) is a progressive chronic spinal cord injury estimated to affect 1 in 50 adults. Without standardised guidance, clinical research studies have selected outcomes at their discretion, often underrepresenting the disease and limiting comparability between studies. Utilising a standard minimum data set formed via multi-stakeholder consensus can address these issues. This combines processes to define a core outcome set (COS)-a list of key outcomes-and core data elements (CDEs), a list of key sampling characteristics required to interpret the outcomes. Further "how" these outcomes should be measured and/or reported is then defined in a core measurement set (CMS). This can include a recommendation of a standardised time point at which outcome data should be reported. This study defines a COS, CDE, and CMS for DCM research. METHODS AND FINDINGS: A minimum data set was developed using a series of modified Delphi processes. Phase 1 involved the setup of an international DCM stakeholder group. Phase 2 involved the development of a longlist of outcomes, data elements, and formation into domains. Phase 3 prioritised the outcomes and CDEs using a two-stage Delphi process. Phase 4 determined the final DCM minimal data set using a consensus meeting. Using the COS, Phase 5 finalised definitions of the measurement construct for each outcome. In Phase 6, a systematic review of the literature was performed, to scope and define the psychometric properties of measurement tools. Phase 7 used a modified Delphi process to inform the short-listing of candidate measurement tools. The final measurement set was then formed through a consensus meeting (Phase 8). To support implementation, the data set was then integrated into template clinical research forms (CRFs) for use in future clinical trials (Phase 9). In total, 28 outcomes and 6 domains (Pain, Neurological Function, Life Impact, Radiology, Economic Impact, and Adverse Events) were entered into the final COS. Thirty two outcomes and 4 domains (Individual, Disease, Investigation, and Intervention) were entered into the final CDE. Finally, 4 outcome instruments (mJOA, NDI, SF-36v2, and SAVES2) were identified for the CMS, with a recommendation for trials evaluating outcomes after surgery, to include baseline measurement and at 6 months from surgery. CONCLUSIONS: The AO Spine RECODE-DCM has produced a minimum data set for use in DCM clinical trials today. These are available at https://myelopathy.org/minimum-dataset/. While it is anticipated the CDE and COS have strong and durable relevance, it is acknowledged that new measurement tools, alongside an increasing transition to study patients not undergoing surgery, may necessitate updates and adaptation, particularly with respect to the CMS.

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Vértebras Cervicales , Consenso , Técnica Delphi , Enfermedades de la Médula Espinal , Humanos , Vértebras Cervicales/cirugía , Enfermedades de la Médula Espinal/cirugía , Evaluación de Resultado en la Atención de Salud/métodos , Resultado del Tratamiento , Proyectos de Investigación

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Introduction: A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes. Methods: To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro , and in vivo model systems. We then investigated how DDR regulation is associated with SCLC biology, chemotherapy response, and tumor evolution following therapy. Results: Using multi-omic profiling, we demonstrate that SCLC tumors cluster into three DDR phenotypes with unique molecular features. Hallmarks of these DDR clusters include differential expression of DNA repair genes, increased replication stress, and heightened G2/M cell cycle arrest. SCLCs with elevated DDR phenotypes exhibit increased neuroendocrine features and decreased "inflamed" biomarkers, both within and across SCLC subtypes. Treatment naive DDR status identified SCLC patients with different responses to frontline chemotherapy. Tumors with initial DDR Intermediate and DDR High phenotypes demonstrated greater tendency for subtype switching and emergence of heterogeneous phenotypes following treatment. Conclusions: We establish that SCLC can be classified into one of three distinct, clinically relevant DDR clusters. Our data demonstrates that DDR status plays a key role in shaping SCLC phenotypes, chemotherapy response, and patterns of tumor evolution. Future work targeting DDR specific phenotypes will be instrumental in improving patient outcomes.

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Research in the field of traumatic brain injury has until now heavily relied on the use of animal models to identify potential therapeutic approaches. However, a long series of failed clinical trials has brought many scientists to question the translational reliability of pre-clinical results obtained in animals. The search for an alternative to conventional models that better replicate human pathology in traumatic brain injury is thus of the utmost importance for the field. Recently, orthotopic xenotransplantation of human brain organoids into living animal models has been achieved. This review summarizes the existing literature on this new method, focusing on its potential applications in preclinical research, both in the context of cell replacement therapy and disease modelling. Given the obvious advantages of this approach to study human pathologies in an in vivo context, we here critically review its current limitations while considering its possible applications in traumatic brain injury research.

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Lesiones Traumáticas del Encéfalo , Organoides , Humanos , Animales , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/terapia , Quimera , Modelos Animales de Enfermedad

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INTRODUCTION: In the AEGEAN trial, neoadjuvant durvalumab plus platinum-based chemotherapy (D+CT) followed by adjuvant durvalumab, versus neoadjuvant chemotherapy alone, significantly improved pathological complete response (pCR) rate and event-free survival (EFS) in patients with resectable NSCLC. In the PACIFIC trial, consolidation durvalumab significantly improved progression-free (PFS) and overall survival (OS) for patients with unresectable stage III NSCLC after chemoradiotherapy. Strong pathological and clinical outcomes with chemoimmunotherapy have generated interest in its use to enable patients with borderline-resectable NSCLC to undergo surgery. Additionally, for patients initially deemed resectable but who later become unresectable/inoperable during neoadjuvant treatment, consolidation immunotherapy after chemoradiotherapy should be explored. PATIENTS AND METHODS: MDT-BRIDGE (NCT05925530) is a multicenter, phase II, non-randomized study in ∼140 patients with EGFR/ALK wild-type, stage IIB-IIIB (N2) NSCLC. Following baseline multidisciplinary team (MDT) assessment to determine resectable/borderline-resectable status, all patients receive 2 cycles of neoadjuvant D+CT every 3 weeks, followed by MDT reassessment of resectability. Patients deemed resectable receive 1-2 additional cycles of D+CT followed by surgery (Cohort 1). Patients deemed unresectable receive standard-of-care chemoradiotherapy (Cohort 2). Cohort 1 patients who become ineligible for surgery can enter Cohort 2. Following surgery or chemoradiotherapy, patients receive adjuvant or consolidation durvalumab for 1 year. The primary endpoint is resection rate in all patients. Additional endpoints include resection rates by baseline resectable/borderline-resectable status, resection outcomes, EFS/PFS, OS, pCR rate, circulating tumor DNA dynamics pre- and post-surgery (including correlation with clinical outcomes), and safety. CONCLUSION: Enrollment began in February 2024; primary completion is anticipated in April 2026.

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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Quimioradioterapia , Neoplasias Pulmonares , Terapia Neoadyuvante , Estadificación de Neoplasias , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Terapia Neoadyuvante/métodos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Quimioradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Femenino , Masculino , Quimioterapia Adyuvante/métodos , Quimioterapia de Consolidación/métodos , Persona de Mediana Edad , Adulto , Anciano

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Introduction: New diagnostic techniques are a substantial research focus in degenerative cervical myelopathy (DCM). This cross-sectional study determined the significance of cardiac-related spinal cord motion and the extent of spinal stenosis as indicators of mechanical strain on the cord. Methods: Eighty-four DCM patients underwent MRI/clinical assessments and were classified as MRI+ [T2-weighted (T2w) hyperintense lesion in MRI] or MRI- (no T2w-hyperintense lesion). Cord motion (displacement assessed by phase-contrast MRI) and spinal stenosis [adapted spinal canal occupation ratio (aSCOR)] were related to neurological (sensory/motor) and neurophysiological readouts [contact heat evoked potentials (CHEPs)] by receiver operating characteristic (ROC) analysis. Results: MRI+ patients (N = 31; 36.9%) were more impaired compared to MRI- patients (N = 53; 63.1%) based on the modified Japanese Orthopedic Association (mJOA) subscores for upper {MRI+ [median (Interquartile range)]: 4 (4-5); MRI-: 5 (5-5); p < 0.01} and lower extremity [MRI+: 6 (6-7); MRI-: 7 (6-7); p = 0.03] motor dysfunction and the monofilament score [MRI+: 21 (18-23); MRI-: 24 (22-24); p < 0.01]. Both patient groups showed similar extent of cord motion and stenosis. Only in the MRI- group displacement identified patients with pathologic assessments [trunk/lower extremity pin prick score (T/LEPP): AUC = 0.67, p = 0.03; CHEPs: AUC = 0.73, p = 0.01]. Cord motion thresholds: T/LEPP: 1.67 mm (sensitivity 84.6%, specificity 52.5%); CHEPs: 1.96 mm (sensitivity 83.3%, specificity 65.6%). The aSCOR failed to show any relation to the clinical assessments. Discussion: These findings affirm cord motion measurements as a promising additional biomarker to improve the clinical workup and to enable timely surgical treatment particularly in MRI- DCM patients. Clinical trial registration: www.clinicaltrials.gov, NCT02170155.

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Holo-omics is the use of omics data to study a host and its inherent microbiomes - a biological system known as a "holobiont". A microbiome that exists in such a space often encounters habitat stability and in return provides metabolic capacities that can benefit their host. Here we present an overview of beneficial host-microbiome systems and propose and discuss several methodological frameworks that can be used to investigate the intricacies of the many as yet undefined host-microbiome interactions that influence holobiont homeostasis. While this is an emerging field, we anticipate that ongoing methodological advancements will enhance the biological resolution that is necessary to improve our understanding of host-microbiome interplay to make meaningful interpretations and biotechnological applications.

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Microbiota , Humanos , Interacciones Microbiota-Huesped/genética , Animales , Simbiosis , Proteómica/métodos , Metabolómica/métodos , Genómica/métodos

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Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis.

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Encéfalo , Cromosomas Humanos Par 1 , Metilación de ADN , Proteínas de Unión al ADN , Epigénesis Genética , Pez Cebra , Humanos , Pez Cebra/genética , Animales , Metilación de ADN/genética , Cromosomas Humanos Par 1/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , ADN Helicasas/genética , ADN Helicasas/metabolismo , Neuronas/metabolismo , Esclerosis Múltiple Crónica Progresiva/genética , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Adulto

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The purpose of this review is to delineate aspects of energy metabolism at rest and during exercise that may be subject to sex differences and the potential underlying mechanisms involved. It focuses on distinct aspects of female physiology with an oriented discussion following the reproductive life stages of healthy, eumenorrheic females, including premenopausal time frames, pregnancy, perimenopause, and menopause. Finally, this review aims to address methodological challenges surrounding sexual dimorphism in energy metabolism investigations and confounding factors in this field. During resting conditions, females tend to have higher rates of non-oxidative free fatty acid clearance, which could contribute to lower respiratory exchange ratio measures. At the same time, carbohydrate energy metabolism findings are mixed. In general, females favor lipid energy metabolism during moderate-intensity exercise, while men favor carbohydrate energy metabolism. Factors such as age, dietary intake, genetics, and methodological decisions confound study findings, including properly identifying and reporting the menstrual cycle phase when female subjects are eumenorrheic. Pregnancy presents a unique shift in physiological systems, including energy metabolism, which can be observed at rest and during exercise. Changes in body composition and hormonal levels during the post-menopausal period directly impact energy metabolism, specifically lipid metabolism. This change in physiological state factors into the evidence showing a reduction in our understanding of sex differences in lipid metabolism during exercise in older adults. This review reveals a need for a focused understanding of female energy metabolism that could help exercise and nutrition professionals optimize female health and performance across the lifespan.

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Metabolismo Energético , Ejercicio Físico , Metabolismo de los Lípidos , Humanos , Femenino , Ejercicio Físico/fisiología , Embarazo , Factores Sexuales , Composición Corporal , Menopausia/fisiología , Caracteres Sexuales , Metabolismo de los Hidratos de Carbono , Masculino , Descanso/fisiología , Ciclo Menstrual/fisiología , Premenopausia/fisiología , Premenopausia/metabolismo

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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.

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Ergonomía , Movimiento , Postura , Dispositivos Electrónicos Vestibles , Humanos , Postura/fisiología , Ergonomía/métodos , Movimiento/fisiología , Biorretroalimentación Psicológica/métodos , Biorretroalimentación Psicológica/instrumentación , Captura de Movimiento

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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, patient-reported outcomes measures, radiographic outcomes, and postoperative range of motion were collected and compared to control patients (ie 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 (TSA), 37 (15%) anatomic TSA, and 14 (6%) hemiarthroplasty were performed. Overall, patients exhibited significant improvements in mean American Shoulder and Elbow Surgeons scores, Constant-Murley scores, Simple Shoulder Test scores, and Visual Analog Scale 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 compared to anatomic TSA.

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The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I2 = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.

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Neoplasias , Farmacogenética , Adulto , Humanos , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Mutación de Línea Germinal , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pruebas de Farmacogenómica , Variantes Farmacogenómicas , Carga Sintomática

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Men who have sex with men (MSM) are significantly more likely to report poor health compared to the general population in Japan and internationally. Social capital has been observed as an important component of positive health and well-being outcomes among MSM. However, there is limited research investigating how alter sexuality (possessors of actual resources embedded in social capital networks) mitigates health outcomes. In an online survey of 1564 MSM in Japan, we investigated social correlates of poor self-rated health among MSM, including MSM and heterosexual social networks. Multiple logistic regression revealed that poor health was associated with older age, lower education, and part-time and unemployment. Poor health was inversely correlated with bisexual behavior and high MSM or heterosexual social capital. In order to decrease health disparities among MSM in Japan, interventions focusing on increasing social capital among deprived groups, such as those with lower socio-economic status, older MSM, and those whose sex partners are exclusively male, may be effective.

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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.

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Biomarcadores de Tumor , Inmunoterapia , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/terapia , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Femenino , Masculino , Inmunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales/uso terapéutico , Resultado del Tratamiento , Estadificación de Neoplasias , Anticuerpos Monoclonales Humanizados/uso terapéutico , Pronóstico , Adulto

RESUMEN

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. Forty-three patients with B2 glenoids were compared to a cohort of 42 patients with A1 or A2 glenoids. Preoperative computed tomography (CT) and radiographs were used 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 Standardized Shoulder Assessment Form (ASES) score, Simple Shoulder Test (SST) score, and visual analog scale (VAS). RESULTS: Eighty-five 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 < .001) and 57.5% (P < .001), respectively, 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 = .008). There was no difference between the cohorts in their improvement in ASES (P = .807), SST (P = .586), and VAS (P = .930) scores. There was no difference in lateral humeral offset (P = .889) or acromial humeral interval (P = .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 with 97.6%, 91.9%, and 83.5% in type A glenoids. The revision rate was similar between the 2 groups (P = .432). Lazarus score (P = .682) and rates of humeral radiolucency (P = .366) and humeral osteolysis (P = .194) were similar between the 2 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.

RESUMEN

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.

Asunto(s)

Educación de Postgrado en Medicina , Becas , Mano , Ortopedia , Humanos , Acreditación , Competencia Clínica , Educación de Postgrado en Medicina/historia , Mano/cirugía , Historia del Siglo XX , Historia del Siglo XXI , Ortopedia/educación , Cirugía Plástica/educación , Estados Unidos

RESUMEN

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.

Asunto(s)

Conservación de los Recursos Naturales , Explotaciones Pesqueras , Animales , Acuicultura , Reino Unido