Outcomes of Biodegradable Temporizing Matrix for Soft Tissue Reconstruction of the Hand and Extremities.

Background: NovoSorb biodegradable temporizing matrix (BTM) is a novel, bilayer, synthetic skin substitute made of biodegradable polyurethane foam covered with a sealing membrane. BTM has demonstrated excellent outcomes in burn literature; however, few studies have been published for hand and extremity soft tissue reconstruction. Methods: All patients who underwent extremity reconstruction with BTM from 2018 to 2023 were reviewed. Demographics, presentations, and clinical outcomes were recorded. Results: A total of 86 cases from 54 patients (53.7% pediatric; age range: 0-81 years) were included. Common indications included trauma (36%), infection (18.6%), and malignancy (11.6%). BTM was placed over exposed tendon (38.4%), bone (19%), joints (12.8%), nerves (8.1%), and/or blood vessels (7%). BTM served as temporary wound coverage in 26 cases. Complications included hematoma (8.1%), infection (4.7%), and spontaneous delamination (4.7%). Wound closure was successfully obtained without flap use in 93.3%. Poor BTM take was associated with peripheral vascular disease, hypertension, immunosuppression, and BTM hematoma and infection (<0.05). Conclusion: This study contributes to the growing body of evidence favoring BTM use in challenging reconstructive cases. Although prospective comparative studies are forthcoming, BTM likely has broad applications in reconstructive surgery.

Metformin beyond type 2 diabetes: Emerging and potential new indications.

Metformin is best known as a foundational therapy for type 2 diabetes but is also used in other contexts in clinical medicine with a number of emerging and potential indications. Many of its beneficial effects may be mediated by modest effects on weight loss and insulin sensitivity, but it has multiple other known mechanisms of action. Current clinical uses beyond type 2 diabetes include: polycystic ovarian syndrome; diabetes in pregnancy/gestational diabetes; prevention of type 2 diabetes in prediabetes; and adjunct therapy in type 1 diabetes. As metformin has been in clinical use for almost 70 years, much of the underpinning evidence for its use in these conditions is, by definition, based on trials conducted before the advent of contemporary evidence-based medicine. As a result, some of the above-established uses are 'off-label' in many regulatory territories and their use varies accordingly in different countries. Going forward, several current 'repurposing' investigational uses of metformin are also being investigated: prevention of cancer (including in Li Fraumeni syndrome), renal protection, Alzheimer's disease, metabolic dysfunction-associated steatotic liver disease and promotion of healthy ageing. Despite the longevity of metformin and its important current roles beyond type 2 diabetes in clinical medicine, it has further potential and much research is ongoing.

Expired blood transfusion and mortality outcomes in combat trauma patients.

BACKGROUND: Expired blood can be transfused if clinically indicated but outcome data do not exist. We hypothesized that modestly outdated blood can effectively support a hemorrhaging patient until surgical control is achieved. This study assessed whether expired blood was associated with mortality in combat trauma patients. STUDY DESIGN AND METHODS: A retrospective analysis of Armed Services Blood Program and Department of Defense Trauma Registry databases evaluated combat casualty records (2001-2023). The intervention of interest was transfusion of at least one unit of whole blood (WB), red blood cells (RBC), or platelets within one week past expiration. The outcome of interest was mortality at discharge. A control cohort that only received in-date blood was matched to the treatment cohort for logistic regression analysis. RESULTS: One hundred patients received expired RBCs (86), WB (11), and platelets (3). Mortality at discharge was 11.6% for expired RBC recipients and 13.4% for the control cohort (p = .97). After adjustment for injury severity, expired RBCs were not associated with mortality (OR = 0.40 [95% CI, 0.14-1.16]; p = .09). Of 10 patients who received the most expired RBCs by volume or storage duration, two were deceased at discharge. All 14 expired WB and platelet recipients were alive at discharge, but sample sizes were underpowered for regression analysis. DISCUSSION: Transfusion of modestly outdated RBCs was not associated with mortality in combat trauma patients. Expired WB and platelet recipients did well, but sample sizes were too small to draw significant conclusions. Expired blood should be further investigated for possible use in extenuating circumstances.

Validation of the Subaxial Cervical Spine Injury Classification score in children: a single-institution experience at a level 1 pediatric trauma center.

OBJECTIVE: The Subaxial Cervical Spine Injury Classification (SLIC) score has not been previously validated for a pediatric population. The authors compared the SLIC treatment recommendations for pediatric subaxial cervical spine trauma with real-world pediatric spine surgery practice. METHODS: A retrospective cohort study at a pediatric level 1 trauma center was conducted in patients < 18 years of age evaluated for trauma from 2012 to 2021. An SLIC score was calculated for each patient, and the subsequent recommendations were compared with actual treatment delivered. Percentage misclassification, sensitivity, specificity, positive (PPV) and negative predictive value (NPV), and area under the receiver operating characteristic (ROC) curve (AUC) were calculated. RESULTS: Two hundred forty-three pediatric patients with trauma were included. Twenty-five patients (10.3%) underwent surgery and 218 were managed conservatively. The median SLIC score was 2 (interquartile range = 2). Sixteen patients (6.6%) had an SLIC score of 4, for which either conservative or surgical treatment is recommended; 27 children had an SLIC score ≥ 5, indicating a recommendation for surgical treatment; and 200 children had an SLIC score ≤ 3, indicating a recommendation for conservative treatment. Of the 243 patients, 227 received treatment consistent with SLIC score recommendations (p < 0.001). SLIC sensitivity in determining surgically treated patients was 79.2% and the specificity for accurately determining who underwent conservative treatment was 96.1%. The PPV was 70.3% and the NPV was 97.5%. There was a 5.7% misclassification rate (n = 13) using SLIC. Among patients for whom surgical treatment would be recommended by the SLIC, 29.6% (n = 8) did not undergo surgery; similarly, 2.5% (n = 5) of patients for whom conservative management would be recommended by the SLIC had surgery. The ROC curve for determining treatment received demonstrated excellent discriminative ability, with an AUC of 0.96 (OR 3.12, p < 0.001). Sensitivity decreased when the cohort was split by age (< 10 and ≥ 10 years old) to 0.5 and 0.82, respectively; specificity remained high at 0.98 and 0.94. CONCLUSIONS: The SLIC scoring system recommended similar treatment when compared with the actual treatment delivered for traumatic subaxial cervical spine injuries in children, with a low misclassification rate and a specificity of 96%. These findings demonstrate that the SLIC can be useful in guiding treatment for pediatric patients with subaxial cervical spine injuries. Further investigation into the score in young children (< 10 years) using a multicenter cohort is warranted.

Sustained delivery of celecoxib from nanoparticles embedded in hydrogel injected into the biopsy cavity to prevent biopsy-induced breast cancer metastasis.

PURPOSE: We have previously reported that protracted Cyclooxygenase-2 (COX-2) activity in bone marrow-derived cells (BMDCs) infiltrating into biopsy wounds adjacent to the biopsy cavity of breast tumors in mice promotes M2-shift of macrophages and pro-metastatic changes in cancer cells, effects which were suppressed by oral administration of COX-2 inhibitors. Thus, local control of COX-2 activity in the biopsy wound may mitigate biopsy-induced pro-metastatic changes. METHODS: A combinatorial delivery system-thermosensitive biodegradable poly(lactic acid) hydrogel (PLA-gel) incorporating celecoxib-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Cx-NP/PLA-gel)-was injected into the biopsy cavity of Py230 murine breast tumors to achieve local control of COX-2 activity in the wound stroma. RESULTS: A single intra-biopsy cavity injection of PLA-gel loaded with rhodamine-encapsulated nanoparticles (NPs) showed sustained local delivery of rhodamine preferentially to infiltrating BMDCs with minimal to no rhodamine uptake by the reticuloendothelial organs in mice. Moreover, significant reductions in M2-like macrophage density, cancer cell epithelial-to-mesenchymal transition, and blood vessel density were observed in response to a single intra-biopsy cavity injection of Cx-NP/PLA-gel compared to PLA-gel loaded with NPs containing no payload. Accordingly, intra-biopsy cavity injection of Cx-NP/PLA-gel led to significantly fewer metastatic cells in the lungs than control-treated mice. CONCLUSION: This study provides evidence for the feasibility of sustained, local delivery of payload preferential to BMDCs in the wound stroma adjacent to the biopsy cavity using a combinatorial delivery system to reduce localized inflammation and effectively mitigate breast cancer cell dissemination.

Non-Inferiority Trials: A Systematic Review on Methodological Quality and Reporting Standards.

BACKGROUND: Non-inferiority (NI) trials require unique trial design and methods, which pose challenges in their interpretation and applicability, risking introduction of inferior therapies in clinical practice. With the abundance of novel therapies, NI trials are increasing in publication. Prior studies found inadequate quality of reporting of NI studies, but were limited to certain specialties/journals, lacked NI margin evaluation, and did not examine temporal changes in quality. We conducted a systematic review without restriction to journal type, journal impact factor, disease state or intervention to evaluate the quality of NI trials, including a comprehensive risk of bias assessment and comparison of quality over time. METHODOLOGY: We searched PubMed and Cochrane Library databases for NI trials published in English in 2014 and 2019. They were assessed for: study design and NI margin characteristics, primary results, and risk of bias for blinding, concealment, analysis method and missing outcome data. RESULTS: We included 823 studies. Between 2014 and 2019, a shift from publication in specialty to general journals (15% vs 28%, p < 0.001) and from pharmacological to non-pharmacological interventions (25% vs 38%, p = 0.025) was observed. The NI margin was specified in most trials for both years (94% vs 95%). Rationale for the NI margin increased (36% vs 57%, p < 0.001), but remained low, with clinical judgement the most common rationale (30% vs 23%), but more 2019 articles incorporating patient values (0.3% vs 21%, p < 0.001). Over 50% of studies were open-label for both years. Gold standard method of analyses (both per protocol + (modified) intention to treat) declined over time (43% vs 36%, p < 0.001). DISCUSSION: The methodological quality and reporting of NI trials remains inadequate although improving in some areas. Improved methods for NI margin justification, blinding, and analysis method are warranted to facilitate clinical decision-making.

Intravenous lipid emulsion interference in coagulation testing: an ex vivo analysis.

INTRODUCTION: Intravenous lipid emulsion is used in the rescue treatment of certain poisonings. A complication is interference with laboratory analyses. The aim of this study was to determine the impact of intravenous lipid emulsion on routine laboratory analysis of coagulation parameters ex vivo and determine if any of the analytical techniques remain reliable. METHODS: Samples were obtained from 19 healthy volunteers and divided in triplicate. One sample served as a control, and the other two were diluted to simulate the treatment of an average adult with Intralipid® 20 per cent Fresenius Kabi 100 mL (dilution-1) or 500 mL (dilution-2). Coagulation tests performed were prothrombin time, activated prothrombin time, D-dimer concentration and fibrinogen. Coagulation testing was performed by three techniques. Test-1 was performed on a Sysmex CN6000 analyzer. Test-2 was performed with a manual mechanical endpoint method using the semi-automated Stago KC4 Delta. Test-3 involved high-speed centrifugation before repeat testing on the Sysmex CN6000 analyzer. RESULTS: For test-1, only nine (47 per cent) samples in dilution-1 could be analyzed for coagulation tests, and no coagulation tests could be analyzed for dilution-2 because of lipaemia. For test-2 and test-3, all samples could be analyzed, and all results of both testing methods fell within the limits of the laboratory reference range. DISCUSSION: Difficulties in laboratory analysis of patients having received intravenous lipid emulsion are due to multiple factors. Most automated coagulation analyzers use optical measurements, which can be unreliable in the presence of a high intravenous lipid concentration. By altering the lipaemia in the testing solution using high-speed centrifugation or by using manual mechanical endpoint detection, we were able to obtain reliable results. These findings are limited by the use of an ex vivo method and healthy volunteers. CONCLUSIONS: This ex vivo model confirms that Intralipid® interferes with routine coagulation studies. It is important that clinicians are aware and inform their laboratories of its administration.

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

Determinants of intended prevention behaviour against mosquitoes and mosquito-borne viruses in the Netherlands and Spain using the MosquitoWise survey: cross-sectional study.

BACKGROUND: Recently, Europe has seen an emergence of mosquito-borne viruses (MBVs). Understanding citizens' perceptions of and behaviours towards mosquitoes and MBVs is crucial to reduce disease risk. We investigated and compared perceptions, knowledge, and determinants of citizens' behavioural intentions related to mosquitoes and MBVs in the Netherlands and Spain, to help improve public health interventions. METHODS: Using the validated MosquitoWise survey, data was collected through participant panels in Spain (N = 475) and the Netherlands (N = 438). Health Belief Model scores measuring behavioural intent, knowledge, and information scores were calculated. Confidence Interval-Based Estimation of Relevance was used, together with potential for change indexes, to identify promising determinants for improving prevention measure use. RESULTS: Spanish participants' responses showed slightly higher intent to use prevention measures compared to those of Dutch participants (29.1 and 28.2, respectively, p 0.03). Most participants in Spain (92.2%) and the Netherlands (91.8%) indicated they used at least one prevention measure, but differences were observed in which types they used. More Spanish participants indicated to have received information on mosquitoes and MBVs compared to Dutch participants. Spanish participants preferred health professional information sources, while Dutch participants favoured government websites. Determinants for intent to use prevention measures included "Knowledge", "Reminders to Use Prevention Measures", and "Information" in the Netherlands and Spain. Determinants for repellent use included "Perceived Benefits" and "Cues to Action", with "Perceived Benefits" having a high potential for behavioural change in both countries. "Self-Efficacy" and "Knowledge" were determinants in both countries for breeding site removal. CONCLUSION: This study found differences in knowledge between the Netherlands and Spain but similarities in determinants for intent to use prevention measures, intent to use repellents and intent to remove mosquito breeding sites. Identified determinants can be the focus for future public health interventions to reduce MBV risks.

The Influence of the Extracorporeal Membrane Oxygenation Circuit and Components on Anticoagulation Management: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the influence of extracorporeal membrane oxygenation (ECMO) circuit components on anticoagulation practices for pediatric ECMO for the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Management of ECMO anticoagulation in the setting of different ECMO circuit components. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Twenty-nine references were used for data extraction and informed recommendations, evidence-based consensus statements, and good practice statements. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for the influence of ECMO circuit and components on anticoagulation management. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One good practice statement, 2 weak recommendations, and 2 consensus statements are presented. CONCLUSIONS: The incorporation of new component technologies into clinical practice has outpaced clinical investigations of anticoagulation strategies for pediatric ECMO. Future investigations should leverage academic and industrial collaborations, translational platforms, and modern biostatistical methods to improve patient outcomes.

Treatment effects in epilepsy: a mathematical framework for understanding response over time.

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting over 65 million people worldwide. Treatment typically commences with the use of anti-seizure medications, including both mono- and poly-therapy. Should these fail, more invasive therapies such as surgery, electrical stimulation and focal drug delivery are often considered in an attempt to render the person seizure free. Although a significant portion ultimately benefit from these treatment options, treatment responses often fluctuate over time. The physiological mechanisms underlying these temporal variations are poorly understood, making prognosis a significant challenge when treating epilepsy. Here we use a dynamic network model of seizure transition to understand how seizure propensity may vary over time as a consequence of changes in excitability. Through computer simulations, we explore the relationship between the impact of treatment on dynamic network properties and their vulnerability over time that permit a return to states of high seizure propensity. For small networks we show vulnerability can be fully characterised by the size of the first transitive component (FTC). For larger networks, we find measures of network efficiency, incoherence and heterogeneity (degree variance) correlate with robustness of networks to increasing excitability. These results provide a set of potential prognostic markers for therapeutic interventions in epilepsy. Such markers could be used to support the development of personalized treatment strategies, ultimately contributing to understanding of long-term seizure freedom.

Percutaneous Aspiration and Sclerotherapy as Primary Management for a Symptomatic Benign Adrenal Cyst.

Adrenal cysts are a rare benign adrenal pathology. Although the majority of adrenal cysts are asymptomatic, large cysts may present with debilitating symptoms of mass effect. Surgical adrenalectomy or cyst fenestration has been the primary mode of management for such symptomatic cysts, but these interventions can be associated with excessive morbidity, particularly when considered in the context of benign disease. Here, we present a case of a 34-year-old female with a longstanding, growing, benign left adrenal cyst associated with nonspecific abdominal symptoms. After multidisciplinary discussion, the patient was managed with primary ultrasound/fluoroscopic guided percutaneous sclerotherapy of her adrenal cyst. This technique achieved complete cyst resolution that was durable on 7-month follow-up and was associated with significant improvement of the patient's symptoms. This case illustrates the potential for primary percutaneous sclerotherapy for primary management of benign adrenal cysts.

Wildfires and Human Health.

This JAMA Insights explores the adverse effects of wildfires on human health and health care systems and offers suggestions on how clinicians can help mitigate the health threats posed by wildfires.

Differential Components of Bradykinesia in Parkinson Disease Revealed by Deep Brain Stimulation.

Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson's disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue.

Resolving chaperone-assisted protein folding on the ribosome at the peptide level.

Protein folding in vivo begins during synthesis on the ribosome and is modulated by molecular chaperones that engage the nascent polypeptide. How these features of protein biogenesis influence the maturation pathway of nascent proteins is incompletely understood. Here, we use hydrogen-deuterium exchange mass spectrometry to define, at peptide resolution, the cotranslational chaperone-assisted folding pathway of Escherichia coli dihydrofolate reductase. The nascent polypeptide folds along an unanticipated pathway through structured intermediates not populated during refolding from denaturant. Association with the ribosome allows these intermediates to form, as otherwise destabilizing carboxy-terminal sequences remain confined in the ribosome exit tunnel. Trigger factor binds partially folded states without disrupting their structure, and the nascent chain is poised to complete folding immediately upon emergence of the C terminus from the exit tunnel. By mapping interactions between the nascent chain and ribosomal proteins, we trace the path of the emerging polypeptide during synthesis. Our work reveals new mechanisms by which cellular factors shape the conformational search for the native state.

A Multicenter Training and Interrater Reliability Study of the BASED Score for Infantile Epileptic Spasms Syndrome.

PURPOSE: The best possible outcomes in infantile epileptic spasms syndrome require electroclinical remission; however, determining electrographic remission is not straightforward. Although the determination of hypsarrhythmia has inadequate interrater reliability (IRR), the Burden of AmplitudeS and Epileptiform Discharges (BASED) score has shown promise for the reliable interictal assessment of infantile epileptic spasms syndrome. Our aim was to develop a BASED training program and assess the IRR among learners. We hypothesized moderate or better IRR for the final BASED score and the presence or absence of epileptic encephalopathy (+/-EE). METHODS: Using a web-based application, 31 learners assessed 12 unmarked EEGs (length 1-6 hours) from children with infantile epileptic spasms syndrome. RESULTS: For all readers, the IRR was good for the final BASED score (intraclass correlation coefficient 0.86) and +/-EE (Marginal Multirater Kappa 0.63). For all readers, the IRR was fair to good for all individual BASED score elements. CONCLUSIONS: These findings support the use of our training program to quickly learn the BASED scoring method. The BASED score may be a valuable clinical and research tool. Given that the IRR for the determination of epileptic encephalopathy is not perfect, clinical acumen remains paramount. Additional experience with the BASED scoring technique among learners and advances in collaborative EEG evaluation platforms may improve IRR.