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A 20-year-old man with metastatic large cell neuroendocrine carcinoma of the lung was treated with the delta-like ligand 3-targeting bispecific T cell engager, tarlatamab. Treatment was complicated by transient cytokine release syndrome but resulted in a partial response. Bispecific T cell engagers may offer a novel treatment approach for large cell neuroendocrine carcinoma of the lung.

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¼ Gunshot injuries to the upper extremity (UE) have high likelihood for causing peripheral nerve injury secondary to the high density of vital structures. Roughly one-fourth of patients sustaining a gunshot wound (GSW) to the UE incur a nerve injury. Of these nerve injuries, just over half are neurapraxic. In cases of surgical exploration of UE nerve injuries, nearly one-third demonstrate a transected or discontinuous nerve.¼ Existing literature regarding surgical management of nerve injuries secondary to GSWs comes from both military and civilian injuries. Outcomes are inconsistently reported, and indications are heterogeneous; however, reasonable results can be obtained with nerve reconstruction.¼ Our proposed management algorithm hinges on 4 treatment questions: if there is a nerve deficit present on examination, if there is a concomitant injury in the extremity (i.e., fracture or vascular insult), whether the injured nerve would be in the operative field of the concomitant injury, and whether there was an identified nerve lesion encountered at the time of surgery by another surgeon?¼ Early exploration rather than continued expectant management may offer improved recovery from GSW nerve injuries in particular situations. When an UE nerve deficit is present, establishing follow-up after the initial GSW encounter and early referral to a peripheral nerve surgeon are pivotal.

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OBJECTIVES: The variation in quality and quantity of collateral status (CS) is in part responsible for a wide variability in extent of neural damage following acute ischemic stroke from large vessel occlusion (AIS-LVO). Single-phase CTA based Clot Burden Score (CBS) is a promising marker in estimating CS. The aim of this study is to assess the relationship of pretreatment CTA based CBS with the reference standard DSA based American Society of Interventional and Therapeutic Neuroradiology (ASITN) CS. METHODS: In this retrospective study, inclusion criteria were as follows: a) Anterior circulation LVO confirmed on CTA from 9/1/2017 to 10/01/2023; b) diagnostic CTA; and c) underwent MT with documented DSA CS. Spearman's rank correlation analysis, multivariate logistic regression and ROC analysis was performed to assess the correlation of CTA CBS with DSA CS. p ≤ 0.05 was considered significant. RESULTS: 292 consecutive patients (median age = 68 years; 56.2% female) met our inclusion criteria. CTA CBS and DSA CS showed significant positive correlation (ρ = 0.51, p < 0.001). On multivariate logistic regression analysis CBS was found to be independently associated with DSA CS (adjusted OR = 1.83, p < 0.001, 95% CI: 1.54-2.19), after adjusting for age, sex, race, hyperlipidemia, hypertension, diabetes, prior stroke or TIA, atrial fibrillation, premorbid mRS, admission NIH stroke scale, and ASPECTS. ROC analysis of CBS in predicting good DSA CS showed AUC of 0.76 (p < 0.001; 95%CI: 0.68-0.82). CBS threshold of > 6 has 84.6% sensitivity and 42.3% specificity in predicting good DSA CS. CONCLUSION: CTA CBS is independently associated with DSA CS and serves as a valuable supplementary tool for collateral status estimation. Further research is necessary to enhance our understanding of the role of CTA CBS in clinical decision-making for patients with AIS-LVO. ADVANCES IN KNOWLEDGE: CBS by indirectly estimating CS has shown to predict outcomes in AIS-LVO patients. No studies report association of CBS with reference standard DSA. In this study we further establish CBS as an independent marker of CS.

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Grading of oral epithelial dysplasia (OED) can be challenging with considerable intra- and inter-observer variability. Abnormal immunohistochemical staining patterns of the tumor suppressor protein, p53, have been recently shown to be potentially associated with progression in OED. We retrospectively identified 214 oral biopsies from 203 patients recruited in a longitudinal study between 2001 and 2008 with diagnosis of reactive, non-dysplastic lesions, low-grade lesions (LGLs; mild OED, moderate OED) and high-grade lesions (HGLs; severe OED /carcinoma in situ). Tissue microarrays (TMA) were constructed from the most representative area of the pathology. Three consecutive sections were sectioned and stained for hematoxylin and eosin, p53 immunohistochemistry, and p16 immunohistochemistry. The staining results were reviewed by two pathologists blinded to clinical outcome. Samples were categorized into p53-abnormal OED (n = 46), p53-conventional OED (n = 118), and p53-HPV (HPV-associated) OED (n = 12) using a previously published pattern-based approach. All cases of p53-HPV (HPV-associated) OED were identified in HGLs. In contrast, cases of p53-abnormal OED were observed in mild OED (9.5%), moderate OED (23%), and severe OED /carcinoma in situ (51%). None of the 27 reactive or non-dysplastic lesions showed abnormal p53 staining patterns. Among the 135 LGLs, 23 cases (17.0%; 2 mild OED and 21 moderate OED) progressed to HGL or squamous cell carcinoma, with 11 cases showing progression within the first 3 years. Remarkably, 82% (9/11) of these faster-progressors showed abnormal p53 patterns. Survival analysis revealed that p53-abnormal OED had significantly poorer progression-free probability (p<0.0001) with hazard ratio of 11.24 (95%CI, 4.26-29.66), compared to p53-conventional OED. Furthermore, p53-abnormal OED had poorer local-recurrence-free survival compared to p53 wild-type OED (p = 0.03). The study supports that OED with p53-abnormal pattern is at high-risk for progression and recurrence, independent of the dysplasia grade.

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Objectives: COVID-19 severity prediction scores need further validation due to evolving COVID-19 illness. We evaluated existing COVID-19 risk prediction scores in Aotearoa New Zealand, including for Maori and Pacific peoples who have been inequitably affected by COVID-19. Methods: We conducted a multicenter retrospective cohort study in adults hospitalized with COVID-19 from January to May 2022, including all Maori and Pacific patients, and every second non-Maori, non-Pacific (NMNP) patient to achieve equal analytic power by ethnic grouping. We assessed the accuracy of existing severity scores (4C Mortality, CURB-65, PRIEST, and VACO) to predict death in the hospital or within 28 days. Results: Of 2319 patients, 582 (25.1%) identified as Maori, 914 (39.4%) as Pacific, and 862 (37.2%) as NMNP. There were 146 (6.3%, 95% confidence interval 5.4-7.4%) deaths, with a predicted probability of death higher than observed mortality for VACO (10.4%), modified PRIEST (15.1%) and 4C mortality (15.5%) scores, but lower for CURB-65 (4.5%). C-statistics (95% CI) of severity scores were: 4C mortality: Maori 0.82 (0.75, 0.88), Pacific 0.87 (0.83, 0.90), NMNP 0.90 (0.86, 0.93); CURB-65: Maori 0.83 (0.69, 0.92), Pacific 0.87 (0.82, 0.91), NMNP 0.86 (0.80, 0.91); modified PRIEST: Maori 0.85 (0.79, 0.90), Pacific 0.81 (0.76, 0.86), NMNP 0.83 (0.78, 0.87); and VACO: Maori 0.79 (0.75, 0.83), Pacific 0.71 (0.58, 0.82), NMNP 0.78 (0.73, 0.83). Conclusions: Following re-calibration, existing risk prediction scores accurately predicted mortality.

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STUDY DESIGN: Randomised controlled trial. OBJECTIVES: The objective is to describe an electroencephalography (EEG) neurofeedback intervention that will be provided in a randomised controlled trial for people with neuropathic pain following spinal cord injury (SCI): the StoPain Trial. In this trial, participants in the treatment group will implement an EEG neurofeedback system as an analgesic intervention at home, while participants in the control group will continue with the treatments available to them in the community. SETTING: University-based study in Sydney, Australia. METHODS/RESULTS: This manuscript describes the rationale and components of the EEG neurofeedback intervention designed for individuals with SCI neuropathic pain and intended for home-based implementation. Our report is based on the criteria of the Template for Intervention Description and Replication (TIDieR) checklist, and includes why the efficacy of EEG neurofeedback will be investigated, what will be provided, who will administer it, and how, where, when, and how much the EEG neurofeedback intervention will be administered. CONCLUSIONS: This manuscript provides a detailed description of a complex intervention used in a randomised controlled trial. This description will facilitate the subsequent interpretation of the trial results and allow for the replication of the intervention in clinical practice and future trials. SPONSORSHIP: Australian Government Medical Research Future Fund (2020 Rare Cancers Rare Diseases and Unmet Needs Scheme: 2006020).

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Therapeutic recombinant protein production relies on industrial scale culture of mammalian cells to produce active proteins in quantities sufficient for clinical use. The combination of stresses from industrial cell culture environment and recombinant protein production can overwhelm the protein synthesis machinery in the endoplasmic reticulum (ER). This leads to a buildup of improperly folded proteins which induces ER stress. Cells respond to ER stress by activating the Unfolded Protein Response (UPR). To restore proteostasis, ER sensor proteins reduce global protein synthesis and increase chaperone protein synthesis, and if that is insufficient the proteins are degraded. If proteostasis is still not restored, apoptosis is initiated. Increasing evidence suggests crosstalk between ER proteostasis and DNA damage repair (DDR) pathways. External factors (e.g., metabolites) from the cellular environment as well as internal factors (e.g., transgene copy number) can impact genome stability. Failure to maintain genome integrity reduces cell viability and in turn protein production. This review focuses on the association between ER stress and processes that affect protein production and secretion. The processes mediated by ER stress, including inhibition of global protein translation, chaperone protein production, degradation of misfolded proteins, DNA repair, and protein secretion, impact recombinant protein production. Recombinant protein production can be reduced by ER stress through increased autophagy and protein degradation, reduced protein secretion, and reduced DDR response.

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Purpose: Unplanned excisions are defined as excisions of malignant tumors performed without preoperative cross-sectional imaging or diagnostic biopsy, frequently resulting in residual disease and re-excision secondary to positive surgical margins. The purpose of this study was to compare the relative morbidity of planned versus unplanned upper-extremity sarcoma excisions. Methods: A single tertiary referral hospital pathology database was queried from January 2015 through 2022 for primary upper-extremity sarcomas (forearm, wrist, hand, and finger). Demographics, tumor features, survival characteristics, and outcomes were retrospectively reviewed. Results: Forty-two upper-extremity sarcoma patients were identified, two-thirds of whom had unplanned excisions. Those with unplanned excisions were more likely to be female (relative risk [RR]: 1.9; P = .002), undergo initial excision at a nonsarcoma center (RR: 14.0; P < .001), have masses distal to the forearm (RR: 1.6; P = .02), and have smaller masses (4.8 vs 7.4 cm, P = .03). 71.4% of tumors were high grade, and 60.7% less than 5 cm in size.Unplanned excisions had positive margins in 96.4% of cases and were more likely to undergo re-excision (odds ratio [OR]: 20.0; P = .001), more total resections (2.7 vs 1.4, P = .009), sacrifice of neurovascular structures (OR: 6.1; P = .04), adjuvant radiation therapy (OR: 4.5; P = .05), adjuvant systemic therapy (OR: 10.9; P = .03), or experience a complication (OR: 17.6; P = .002) at an average of 38.0 months of follow-up.Nearly half of all unplanned excision patients developed a local recurrence or metastatic disease. Six patients required an amputation versus one in the planned cohort (P = .17), and 26.5% of patients died at an average of 32.5 months from presentation. Conclusions: Distal upper-extremity sarcoma excisions are frequently unplanned, with high rates of morbidity compared with planned excisions. Surgeons should have a low threshold for cross-sectional imaging and core needle biopsy of atypical lesions, irrespective of size, with referral to a sarcoma center. Type of study/level of evidence: Prognostic IV.

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BACKGROUND: In 2019, New York City (NYC) launched NYC Care (NYCC), a healthcare access program through NYC Health + Hospitals (H + H) for individuals who are ineligible for federally funded health insurance programs or cannot purchase insurance through the State Marketplace, predominantly undocumented individuals. OBJECTIVE: To examine the sociodemographic characteristics, healthcare use patterns, and chronic disease quality measures for diabetes mellitus (DM) and hypertension among NYCC patients compared with Medicaid patients seen at NYC H + H. DESIGN: Observational study. PARTICIPANTS: Adults aged 18 years and older enrolled in NYCC (N = 83,003) or Medicaid (N = 512,012) as of January 1, 2022. Patients were included if they had at least one visit between January 1, 2021, and December 31, 2021. MAIN MEASURES: Sociodemographic characteristics, healthcare use patterns, and quality measures for DM and hypertension. KEY RESULTS: NYCC patients (n = 83,003) were, on average, older, more likely to be Hispanic with Spanish as their preferred language, had more comorbidities, and had more primary care (adjusted incidence rate ratio 2.75 [95% confidence interval 2.71, 2.80]) and specialty care (2.22 [2.17, 2.26]) visits compared to Medicaid patients (n = 512,012). Rates of emergency department visits were similar between the two groups (1.02 [1.00, 1.04]), but NYCC patients had relatively fewer hospitalizations (0.64 [0.62, 0.67]). NYCC patients with DM or hypertension had higher rates of having a documented hemoglobin A1c or blood pressure in 2022, respectively, and clinically similar rates of chronic disease control (mean difference in hemoglobin A1c - 0.05 [- 0.09, - 0.01] in patients with DM and mean difference in blood pressure - 0.38 [- 0.67, - 0.10]/ - 0.64 [- 0.82, - 0.46]) compared with Medicaid patients. CONCLUSIONS: NYCC effectively enrolled a large number of uninsured participants and provided them with healthcare access similar to that of Medicaid patients. Future studies should evaluate the impact of NYCC enrollment on healthcare utilization and disease outcomes.

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BACKGROUND: Crohn's disease (CD) is a chronic inflammatory condition affecting the gastrointestinal tract, characterized by complications such as strictures, fistulas, and neoplasia. Despite medical advancements, a significant number of patients with Crohn's disease require surgery, and many experience post-operative complications and recurrence. Previous studies have analyzed gene expression to study recurrence and post-operative complications independently. This study aims to identify overlapping differentially expressed genes and pathways for recurrence and post-operative complications. METHODS: A dataset including 45 patients with Crohn's disease, including gene expression from ileum and colon tissue, endoscopic recurrence, and intra-abdominal septic complications was analyzed. Gene set enrichment analysis was used to identify gene pathways associated with the outcomes. Finally, a multi-variable logistic regression model was created to assess whether gene pathways were independently associated with both outcomes. RESULTS: In ileum tissue, several inflammatory pathways, including interferon alpha and gamma response were upregulated in patients with endoscopic recurrence and intra-abdominal septic complications. In addition, there was upregulation of the epithelial mesenchymal transition pathway. In colon tissue, metabolic processes, such as myogenesis and oxidative phosphorylation were downregulated in both outcomes. In a multivariate model, downregulation of myogenesis in colon tissue was significantly associated with both endoscopic recurrence and intra-abdominal septic complications. CONCLUSION: These findings shed light on the underlying biology of these outcomes and suggest potential biomarkers or therapeutic targets to reduce their occurrence. Further validation and multi-institutional studies are warranted to confirm these results and improve post-operative outcomes for patients with Crohn's disease.

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Objectives: This multicenter cohort study describes Aotearoa New Zealand children hospitalized during the country's first wave of sustained SARS-CoV-2 transmission, Omicron variant. Methods: Children younger than 16 years, hospitalized for >6 hours with COVID-19 across New Zealand from January to May 2022 were included. Admissions for all Maori and Pacific and every second non-Maori non-Pacific children were selected to support equal explanatory power for ethnic grouping. Attribution of hospital admission, demography, clinical presentation, comorbidity, treatment, and outcome data were collected. Results: Of 444 hospitalizations of children positive for COVID-19, 292 (65.5%) from 290 children were considered admissions attributable to COVID-19. Of these admissions, 126 (43.4%) were aged under 1; 118 (40.7%), 99 (34.1%), and 87 (30.0%) were children of Maori, Pacific, and non-Maori non-Pacific ethnicity, respectively. Underlying respiratory disease was the most common comorbidity, present in 22 children (7.6%); 16 children (5.5%) were immunosuppressed. Median length of stay was 1 day (interquartile range 0.0-2.0). Four children received antiviral, 69 (24%) antibacterial, and 24 (8%) supplemental oxygen. Although eight children required intensive care, there were no deaths. Conclusions: Children hospitalized during the first significant wave of SARS-CoV-2 infection in New Zealand presented with a multi-system viral illness and rarely with severe disease.

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Embryonic and early postnatal promotor-driven deletion of the phosphatase and tensin homolog (PTEN) gene results in neuronal hypertrophy, hyperexcitable circuitry and development of spontaneous seizures in adulthood. We previously documented that focal, vector-mediated PTEN deletion in mature granule cells of adult dentate gyrus triggers dramatic growth of cell bodies, dendrites, and axons, similar to that seen with early postnatal PTEN deletion. Here, we assess the functional consequences of focal, adult PTEN deletion, focusing on its pro-epileptogenic potential. PTEN deletion was accomplished by injecting AAV-Cre either bilaterally or unilaterally into the dentate gyrus of double transgenic PTEN-floxed, ROSA-reporter mice. Hippocampal recording electrodes were implanted for continuous digital EEG with concurrent video recordings in the home cage. Electrographic seizures and epileptiform spikes were assessed manually by two investigators, and corelated with concurrent videos. Spontaneous electrographic and behavioral seizures appeared after focal PTEN deletion in adult dentate granule cells, commencing around 2 months post-AAV-Cre injection. Seizures occurred in the majority of mice with unilateral or bilateral PTEN deletion and led to death in several cases. PTEN-deletion provoked epilepsy was not associated with apparent hippocampal neuron death; supra-granular mossy fiber sprouting was observed in a few mice. In summary, focal, unilateral deletion of PTEN in the adult dentate gyrus suffices to provoke time-dependent emergence of a hyperexcitable circuit generating hippocampus-origin, generalizing spontaneous seizures, providing a novel model for studies of adult-onset epileptogenesis.

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BACKGROUND: Collateral status (CS) plays a crucial role in infarct growth rate, risk of postthrombectomy hemorrhage, and overall clinical outcomes in patients with acute ischemic stroke (AIS) secondary to anterior circulation large-vessel occlusions (LVOs). Hypoperfusion intensity ratio has been previously validated as an indirect noninvasive pretreatment imaging biomarker of CS. In addition to imaging, derangements in admission laboratory findings can also influence outcomes in patients with AIS-LVO. Therefore, our study aims to assess the relationship between admission laboratory findings, baseline characteristics, and CS, as assessed by hypoperfusion intensity ratio in patients with AIS-LVO. METHODS AND RESULTS: In this retrospective study, consecutive patients presenting with AIS secondary to anterior circulation LVO who underwent pretreatment computed tomography perfusion were included. The computed tomography perfusion data processed by RAPID (Ischema View, Menlo Park, CA) generated the hypoperfusion intensity ratio. Binary logistic regression models were used to assess the relationship between patients' baseline characteristics, admission laboratory findings, and poor CS. A total of 221 consecutive patients with AIS-LVO between January 2017 and September 2022 were included in our study (mean±SD age, 67.0±15.8 years; 119 men [53.8%]). Multivariable logistic regression showed that patients with AIS caused by cardioembolic and cryptogenic causes (adjusted odds ratio [OR], 2.67; 95% CI, 1.20-5.97; P=0.016), those who presented with admission National Institutes of Health Stroke Scale score ≥12 (adjusted OR, 3.12; 95% CI, 1.61-6.04; P=0.001), and male patients (adjusted OR, 2.06; 95% CI, 1.13-3.77; P=0.018) were associated with poor CS. CONCLUSIONS: Stroke caused by cardioembolic or cryptogenic causes, admission National Institutes of Health Stroke Scale score of ≥12, and male sex were associated with poor CS, as defined by hypoperfusion intensity ratio in the patients with AIS-LVO.

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Rapid advances in biological knowledge and technological innovation have greatly advanced the fields of stem cell and gene therapies to combat a broad spectrum of neurologic disorders. Researchers are currently exploring a variety of stem cell types (e.g., embryonic, progenitor, induced pluripotent) and various transplantation strategies, each with its own advantages and drawbacks. Similarly, various gene modification techniques (zinc finger, TALENs, CRISPR-Cas9) are employed with various delivery vectors to modify underlying genetic contributors to neurologic disorders. While these two individual fields continue to blaze new trails, it is the combination of these technologies which enables genetically engineered stem cells and vastly increases investigational and therapeutic opportunities. The capability to culture and expand stem cells outside the body, along with their potential to correct genetic abnormalities in patient-derived cells or enhance cells with extra gene products, unleashes the full biological potential for innovative, multifaceted approaches to treat complex neurological disorders. In this review, we provide an overview of stem cell and gene therapies in the context of neurologic disorders, highlighting recent advances and current shortcomings, and discuss prospects for future therapies in clinical settings.

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

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Background: Schedule design may contribute to successful completion of synchronous telehealth visits by video (versus audio-only). Clustering telehealth visits on schedules may minimize workflow inefficiencies. Methods: We analyzed data from 21 primary care sites in an urban public health care system from March 1 to September 30, 2022. We used linear regression to test for associations between the number of consecutive telehealth visits scheduled per clinicians' half-day sessions (1 to 9+) and the proportion of telehealth visits scheduled and, separately, completed as video (versus audio-only). Results: For each additional consecutive telehealth visit scheduled, there was a 6.85% [95% confidence interval 4.80 - 8.90%] increase in the absolute percentage of visits scheduled as video visits. For each additional consecutive telehealth visit scheduled, there was a 2.88% [0.59 - 5.18%] increase in the absolute percentage of visits completed as video visits. Conclusions: Clustered telehealth visits are positively associated with scheduling and completion of telehealth visits by video.

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BACKGROUND: Various classification systems for tear trough deformity (TTD) have been published; however, their complexity can pose challenges in clinical use, especially for less experienced surgeons. It is believed that artificial intelligence (AI) technology can address some of these challenges by reducing inadvertent errors and improving the accuracy of medical practice. In this study, we aimed to establish a reliable and precise digital image grading model for TTD using smartphone-based photography enhanced using AI deep learning technology. This model is designed to aid and guide surgeons, particularly those who are less experienced or from younger generations, during clinical examinations and in making decisions regarding further surgical interventions. MATERIALS AND METHODS: A total of 504 patients and 983 photos were included in the study. We adopted the Barton's grading system for TTD. All photos were taken using the same smartphone and processed and analyzed using the medical AI assistant (MAIA™) software. The photos were then randomly divided into two groups to establish training and testing models. RESULTS: The confusion matrix for the training model demonstrated a sensitivity of 56%, specificity of 87.3%, F1 score of 0.57, and an area under the curve (AUROC) of 0.85. For the testing group, the sensitivity was 49.3%, specificity was 85%, F1 score was 0.49, and AUROC was 0.83. Representative heatmaps were also generated. CONCLUSION: Our study is the first to demonstrate that tear trough deformities can be easily categorized using a built-in smartphone camera in conjunction with an AI deep learning program. This approach can reduce errors during clinical patient evaluations, particularly for less experienced practitioners.

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