Prophylactic Carpal Tunnel Release During Volar Plating of Distal Radius Fractures: A Review.

Purpose: Patients who fracture their distal radius are at risk of developing carpal tunnel syndrome (CTS). Carpal tunnel syndrome occurs acutely; other patients may present with signs and symptoms of CTS weeks or months after the distal radius fracture. Because CTS may present in a delayed fashion after a distal radius fracture, some surgeons will perform carpal tunnel release (CTR) in patients who undergo open reduction and internal fixation even in those patients who do not have clinical evidence of CTS-a prophylactic CTR. In the current systematic review, we evaluated the literature regarding prophylactic CTR in the setting of surgical treatment of distal radius fractures. Methods: We conducted our literature review based on the preferred reporting items for systematic reviews and meta-analyses guidelines. The search strategy reflected "prophylactic CTR during treatment of distal radius fractures" and was conducted in February 2024. Included studies are summarized in the Table. Results: Six studies met the inclusion criteria. Publication dates ranged from 2001 to 2018. Five studies investigated clinical symptoms and/or electromyography: three of five studies found worsening or persistent median neuropathy, and two of five studies found improvement or no further development of symptoms in their respective patient cohorts. The sixth study found no difference in patient-reported outcomes between either approach. Conclusions: There were no differences in wrist range of motion, postoperative grip strength, or patient-reported outcomes within each of the study cohorts. Based on the findings from the studies included in this review, we do not believe that there is sufficient evidence supporting prophylactic CTR in the setting of surgical treatment of distal radius fractures. Type of study/level of evidence: Therapeutic 2a.

Pre-operative stereotactic radiosurgery and peri-operative dexamethasone for resectable brain metastases: a two-arm pilot study evaluating clinical outcomes and immunological correlates.

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

Pediatric Resuscitation Skill of Bag-Tube Manual Ventilation: Developing and Using a Mobile Simulation Program to Assess Competency of a Multiprofessional PICU Team.

OBJECTIVES: To assess the skill of bag-tube manual ventilation with the flow-inflating bag in multiprofessional PICU team members using a mobile simulation unit. DESIGN: Prospective observational study from January 2022 to April 2022. SETTING: In situ mobile simulation using the flow-inflating bag in an academic PICU. SUBJECTS: Multiprofessional PICU team members including nurses, respiratory therapists, nurse practitioners, fellows, and attendings. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 129 participants who twice completed 1-minute tasks performing bag-tube manual ventilation with a flow-inflating bag. Sessions were video recorded; four could not be analyzed. Only 30% of participants reported being very to extremely confident, and the majority (62%) reported infrequent skill performance. Task success was defined as achieving target pressure ranges during 80% of the delivered breaths, respiratory rate (RR) of 25-35 breaths/min, and successful pop-off valve engagement. Only five of 129 participants (4%) achieved successful ventilation as defined. Overall, participants were more likely to deliver lower pressures and faster rate. Maintaining target positive end-expiratory pressure (PEEP) was least likely to be achieved (19% success), followed by RR (52%), pop-off valve (64%), then peak inspiratory pressure (71%). Nurses were less likely to achieve target pressures compared with all other professions. CONCLUSIONS: Multiprofessional PICU team members have highly variable self-confidence with bag-tube manual ventilation using a flow-inflating bag. Observed performance demonstrates rare success with achieving targeted ventilation parameters, in particular maintenance of PEEP. Future research should focus on developing mobile simulation units to facilitate profession-specific, real-time coaching to teach high-quality manual ventilation that can be translated to the bedside.

Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial.

BACKGROUND: Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. METHODS AND RESULTS: In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. CONCLUSIONS: Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. REGISTRATION: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Causes of Musculoskeletal Pain in Paget's Disease of Bone.

Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling leading to various complications, such as bone deformity, deafness, secondary osteoarthritis, and pathological fracture. Pain is the most common presenting symptom of PDB, but it is unclear to what extent this is due to increased metabolic activity of the disease, complications, or unrelated causes. We conducted a cross-sectional study of 168 people with PDB attending secondary care referral centres in the UK. We documented the presence of musculoskeletal pain and sought to determine its underlying causes. Musculoskeletal pain was reported by 122/168 (72.6%) individuals. The most common cause was osteoarthritis of joints distant from an affected PDB site in 54 (44.3%), followed by metabolically active PDB in 18 (14.7%); bone deformity in 14 (11.4%); osteoarthritis of a joint neighbouring an affected site in 11 (9.0%), neuropathic pain in 10 (8.2%), and various other causes in the remainder. Pain was more common in women (p<0.019) and in older individuals (p<0.001). Circulating concentrations of macrophage colony-stimulating factor (M-CSF) were significantly higher in those with pain (p = 0.008), but there was no difference between groups of patients with and without pain in concentrations of interleukin-6 (IL-6) or biochemical markers of bone turnover. Pain is a common symptom in PDB but is most often due to osteoarthritis at an unaffected site. The study illustrates the importance of fully evaluating people with PDB to determine the underlying cause of pain so that management can be tailored appropriately.

Cervical Laminoplasty versus Laminectomy and Fusion: A Comprehensive Time-Driven Activity-Based Cost Analysis.

STUDY DESIGN: Retrospective study. OBJECTIVE: To compare the true cost between posterior cervical laminectomy and fusion and cervical laminoplasty using time driven activity-based costing methodology. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty (LP) and posterior cervical laminectomy with fusion (LF) are effective procedures for treating cervical myelopathy. A comprehensive accounting of cost differences between LP versus LF is not available. Using time-driven activity-based costing (TDABC), we sought to compare the total facility costs in patients with cervical myelopathy undergoing LP versus LF. METHODS: We conducted a retrospective analysis of 277 LP and 229 LF performed between 2019 and 2023. Total facility costs, which included personnel and supply costs, were assessed using TDABC. Separate analyses including and excluding implant costs were performed. Multiple regression analysis was utilized to assess the independent effect of LP compared to LF on facility costs, with all costs standardized using cost units (CUs). RESULTS: Patients undergoing LP had lower total supply costs (672.5 vs. 765.0 CUs [0.88x], P<0.001) and lower total personnel costs (330.0 vs. 830.0 CUs [0.40x], P<0.001), resulting in a lower total facility cost both including (1,003.8 vs. 1,600.0 CUs [0.63x], P<0.001) and excluding implant costs (770.0 vs. 875.0 CUs [0.88x], P<0.001) (Table 1). After controlling for demographics and comorbidities, LF was associated with increased total facility costs, including (588.5 CUs, 95% CI 517.1-659.9 CUs, P<0.001) and excluding implant costs (104.3 CUs, 95% CI 57.6-151.0 CUs, P<0.001). CONCLUSION: Using time-driven activity-based costing, we found that total facility costs were lower in patients treated with laminoplasty. These findings suggest that laminoplasty may offer a less costly and more efficient surgical option for treating cervical myelopathy.

Assessing the global prevalence of wild birds in trade.

Trade represents a significant threat to many wild species and is often clandestine and poorly monitored. Information on which species are most prevalent in trade and potentially threatened by it therefore remains fragmentary. We used 7 global data sets on birds in trade to identify species or groups of species at particular risk and assessed the extent to which they were congruent in terms of the species recorded in trade. We used the frequency with which species were recorded in the data sets as the basis for a trade prevalence score that was applied to all bird species globally. Literature searches and questionnaire surveys were used to develop a list of species known to be heavily traded to validate the trade prevalence score. The score was modeled to identify significant predictors of trade. Although the data sets sampled different parts of the broad trade spectrum, congruence among them was statistically strong in all comparisons. Furthermore, the frequency with which species were recorded within data sets was positively correlated with their occurrence across data sets, indicating that the trade prevalence score captured information on trade volume. The trade prevalence score discriminated well between species identified from semi-independent assessments as heavily or unsustainably traded and all other species. Globally, 45.1% of all bird species and 36.7% of globally threatened bird species had trade prevalence scores ≥1. Species listed in Appendices I or II of CITES, species with large geographical distributions, and nonpasserines tended to have high trade prevalence scores. Speciose orders with high mean trade prevalence scores included Falconiformes, Psittaciformes, Accipitriformes, Anseriformes, Bucerotiformes, and Strigiformes. Despite their low mean prevalence score, Passeriformes accounted for the highest overall number of traded species of any order but had low representation in CITES appendices. Geographical hotspots where large numbers of traded species co-occur differed among passerines (Southeast Asia and Eurasia) and nonpasserines (central South America, sub-Saharan Africa, and India). This first attempt to quantify and map the relative prevalence in trade of all bird species globally can be used to identify species and groups of species that may be at particular risk of harm from trade and can inform conservation and policy interventions to reduce its adverse impacts.

Análisis de la prevalencia mundial de aves silvestres en el mercado Resumen El mercado representa una amenaza importante para muchas especies silvestres y a menudo es clandestino y mal vigilado. Por ello, la información sobre las especies más presentes en el mercado y bajo amenaza potencial todavía está fragmentada. Utilizamos siete conjuntos de datos mundiales sobre aves comercializadas para identificar especies o grupos de especies bajo riesgo especial y evaluamos hasta qué punto eran congruentes en cuanto a las especies registradas en el comercio. Utilizamos la frecuencia con la que las especies se registraban en los conjuntos de datos como base para una puntuación de prevalencia del comercio que se aplicó a todas las especies de aves a nivel mundial. Para validar la puntuación de prevalencia del comercio, realizamos búsquedas bibliográficas y cuestionarios para elaborar una lista de especies que se sabe son objeto de comercio intenso. Modelamos la puntuación para identificar los predictores significativos del mercado. Aunque los conjuntos de datos muestrearon partes distintas del amplio espectro del mercado, la congruencia entre ellos fue estadísticamente robusta en todas las comparaciones. Además, la frecuencia con la que se registraron las especies dentro de los conjuntos de datos se correlacionó positivamente con su presencia en todos los conjuntos de datos, lo que indica que la puntuación de prevalencia del mercado captó información sobre el volumen de este. La puntuación de prevalencia del mercado distinguió entre las especies identificadas a partir de evaluaciones semiindependientes como objeto de comercio intenso o insostenible y todas las demás especies. A nivel mundial, el 45.1% de todas las especies de aves y el 36.7% de las especies de aves amenazadas mundialmente tenían puntuaciones de prevalencia del mercado ≥1. Las especies incluidas en los Apéndices I o II de CITES, las especies con una amplia distribución geográfica y los no paseriformes tendieron a tener puntuaciones elevadas de prevalencia del mercado. Los órdenes de especies con puntuaciones medias de prevalencia del mercado elevadas fueron Falconiformes, Psittaciformes, Accipitriformes, Anseriformes, Bucerotiformes y Strigiformes. A pesar de su baja puntuación media de prevalencia, los Passeriformes representaron el mayor número total de especies comercializadas de todos los órdenes, pero tuvieron una baja representación en los apéndices de CITES. Los puntos calientes geográficos en los que coexisten un gran número de especies comercializadas difieren entre los paseriformes (Sudeste Asiático y Eurasia) y los no paseriformes (centro de Sudamérica, África subsahariana e India). Este primer intento de cuantificar y cartografiar la prevalencia relativa en el comercio de todas las especies de aves a escala mundial puede utilizarse para identificar especies y grupos de especies que pueden correr un riesgo especial de sufrir daños a causa del comercio y puede servir de base para intervenciones políticas y de conservación destinadas a reducir sus efectos adversos.

Brief report: incidence and outcomes of pediatric tracheal intubation-associated cardiac arrests in the ICU-RESUS clinical trial.

BACKGROUND: Tracheal intubation (TI)-associated cardiac arrest (TI-CA) occurs in 1.7% of pediatric ICU TIs. Our objective was to evaluate resuscitation characteristics and outcomes between cardiac arrest patients with and without TI-CA. METHODS: Secondary analysis of cardiac arrest patients in both ICU-RESUS trial and ancillary CPR-NOVA study. The primary exposure was TI-CA, defined as cardiac arrest occurred during TI procedure or within 20 min after endotracheal tube placement. The primary outcome was survival to hospital discharge with favorable neurological outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged). RESULTS: Among 315 children with cardiac arrests, 48 (15.2%) met criteria for TI-CA. Pre-existing medical conditions were similar between groups. Pre-arrest non-invasive mechanical ventilation was more common among TI-CA patients (18/48, 37.5%) compared to non-TI-CA patients (35/267, 13.1%). In 48% (23/48), the TI-CA occurred within 20 min after intubation (i.e., not during intubation). Duration of CPR was longer in TI-CA patients (median 11.0 min, interquartile range [IQR]: 2.5, 35.5) than non-TI-CA patients (median 5.0 min, IQR 2.0, 21.0), p = 0.03. Return of spontaneous circulation occurred in 32/48 (66.7%) TI-CA versus 186/267 (69.7%) non-TI-CA, p = 0.73. Survival to hospital discharge with favorable neurological outcome occurred in 29/48 (60.4%) TI-CA versus 146/267 (54.7%) non-TI-CA, p = 0.53. CONCLUSIONS: Fifteen percent of these pediatric ICU cardiac arrests were associated with TI. Half of TI-CA occurred after endotracheal tube placement. While duration of CPR was longer in TI-CA patients, there were no differences in unadjusted outcomes following TI-CA versus non-TI-CA. TRIAL REGISTRATION: The ICU-RESUS (ClinicalTrials.gov Identifier: NCT02837497).

Disparities in Surgical Intervention and Health-Related Quality of Life Among Racial/Ethnic Groups With Degenerative Lumbar Spondylolisthesis.

BACKGROUND AND OBJECTIVES: Racial and socioeconomic disparities in spine surgery for degenerative lumbar spondylolisthesis persist in the United States, potentially contributing to unequal health-related quality of life (HRQoL) outcomes. This is important as lumbar spondylolisthesis is one of the most common causes of surgical low back pain, and low back pain is the largest disabler of individuals worldwide. Our objective was to assess the relationship between race, socioeconomic factors, treatment utilization, and outcomes in patients with lumbar spondylolisthesis. METHODS: This cohort study analyzed prospectively collected data from 9941 patients diagnosed with lumbar spondylolisthesis between 2015 and 2020 at 5 academic hospitals. Exposures were race, socioeconomic status, health coverage, and HRQoL measures. Main outcomes and measures included treatment utilization rates between racial groups and the association between race and treatment outcomes using logistic regression, adjusting for patient characteristics, socioeconomic status, health coverage, and HRQoL measures. RESULTS: Of the 9941 patients included (mean [SD] age, 67.37 [12.40] years; 63% female; 1101 [11.1%] Black, Indigenous, and People of Color [BIPOC]), BIPOC patients were significantly less likely to use surgery than White patients (odds ratio [OR] = 0.68; 95% CI, 0.62-0.75). Furthermore, BIPOC race was associated with significantly lower odds of reaching the minimum clinically important difference for physical function (OR = 0.74; 95% CI, 0.60; 0.91) and pain interference (OR = 0.77; 95% CI, 0.62-0.97). Medicaid beneficiaries were significantly less likely (OR = 0.65; 95% CI, 0.46-0.92) to reach a clinically important improvement in HRQoL when accounting for race. CONCLUSION: This study found that BIPOC patients were less likely to use spine surgery for degenerative lumbar spondylolisthesis despite reporting higher pain interference, suggesting an association between race and surgical utilization. These disparities may contribute to unequal HRQoL outcomes for patients with lumbar spondylolisthesis and warrant further investigation to address and reduce treatment disparities.

Apomorphine titration with and without anti-emetic pretreatment in patients with Parkinson's disease experiencing OFF episodes: A modified Delphi panel.

Introduction: In the United States (US), prophylactic treatment with the antiemetic trimethobenzamide has been used before initiating apomorphine therapy. However, US trimethobenzamide stores have been depleted, leaving uncertainty regarding whether antiemetic pretreatment is needed. Methods: This modified Delphi panel aimed to inform circumstances when apomorphine is initiated without antiemetic pretreatment. During Round 1, a panel of 9 US movement disorder specialists rated the appropriateness of prescribing apomorphine therapy with and without antiemetic pretreatment across 192 patient scenarios and were able to review their scores in relation to other scores. During the Round 2, consensus was defined for each scenario as either strong (>75 % agreement) or moderate (66 % agreement). Results: There was strong consensus on 118 of 192 scenario's (97 as appropriate and 21 as inappropriate), moderate consensus on 29 scenarios, some agreement on 32 scenarios, and lack of agreement on 13 scenarios. In the absence of an antiemetic, there was strong consensus that titration schedules should be flexible and based on dose response. However, the group only reached moderate consensus on the speed of titration, highlighting the need for more systematic information on this area. In the presence of an antiemetic, panelists considered usual initial dosing and flexible titration to be appropriate in most scenarios except for when the patient is already experiencing dopaminergic adverse events. Conclusions: Experts generally reached consensus that apomorphine can usually be prescribed without antiemetic pretreatment. Recommendations described here reflect the areas of greatest agreement among a panel of experts based on current available evidence.

Early depletion of gut microbiota shape oligodendrocyte response after traumatic brain injury.

White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the regulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression, and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI.

Transcriptional Repressor BCL11A in Erythroid Cells.

BCL11A, a zinc finger repressor, is a stage-specific transcription factor that controls the switch from fetal (HbF, α2γ2) to adult (HbA, α2ß2) hemoglobin in erythroid cells. While BCL11A was known as a factor critical for B-lymphoid cell development, its relationship to erythroid cells and HbF arose through genome-wide association studies (GWAS). Subsequent work validated its role as a silencer of γ-globin gene expression in cultured cells and mice. Erythroid-specific loss of BCL11A rescues the phenotype of engineered sickle cell disease (SCD) mice, thereby suggesting that downregulation of BCL11A expression might be beneficial in patients with SCD and ß-thalassemia. Common genetic variation in GWAS resides in an erythroid-specific enhancer within the BCL11A gene that is required for its own expression. CRISPR/Cas9 gene editing of the enhancer revealed a GATA-binding site that confers a large portion of its regulatory function. Disruption of the GATA site leads to robust HbF reactivation. Advancement of a guide RNA targeting the GATA-binding site in clinical trials has recently led to approval of first-in-man use of ex vivo CRISPR editing of hematopoietic stem/progenitor cells (HSPCs) as therapy of SCD and ß-thalassemia. Future challenges include expanding access and infrastructure for delivery of genetic therapy to eligible patients, reducing potential toxicity and costs, exploring prospects for in vivo targeting of hematopoietic stem cells (HSCs), and developing small molecule drugs that impair function of BCL11A protein as an alternative option.

Corrigendum to "Recommendations for a paradigm shift in approach to increase the recognition and treatment of sialorrhea in Parkinson's disease" [Clin. Parkinsonism Related Dis. 9 (2023) 100223].

[This corrects the article DOI: 10.1016/j.prdoa.2023.100223.].

Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU-resuscitation study.

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

Orthopaedic Surgery and Indusry: What our Potential Patients Believe.

PURPOSE: Physician and surgeon involvement in industry has received considerable attention in recent decades. In this study, we outline the perspective of the general US population regarding (1) disclosure, (2) ownership, and (3) compensation between physicians/surgeons and industry. We hypothesize that the general population would be largely supportive of the physician/surgeon-industry relationship. METHODS: An online, survey-based, descriptive study was conducted through a crowdsourcing platform, Amazon Mechanical Turk. Survey respondents were presented with a seven-item questionnaire inquiring about the physician/surgeon and industry relationship. An "attention check" question was included; those who failed this question were excluded. Descriptive statistics were used to assess the data and a McNemar chi-squared test for paired, dichotomous data. RESULTS: A total of 993 respondents were included. Survey responses are summarized in Table 1. 70.6% of respondents stated that it was "important" or "extremely important" to disclose that the patient be informed whether implants used in surgery had been developed by the operating surgeon. 71.1% of respondents reported that it was "important" or "extremely important" to disclose partial ownership within industry. Seventy-one percent of respondents stated it was "important" or "extremely important" to disclose royalty payments pertaining to surgical implants. 95.6% of respondents suggested that it was acceptable for surgeons to accept free airfare and lodging, and 95.2% of respondents stated that it was acceptable for the surgeon to be compensated for time away from practice to learn about new equipment. DISCUSSION: In our survey of 993 respondents, we found that relationships with industry are considered acceptable if appropriate disclosure is given to patients. We also found that although respondents suggested that physicians and surgeons may be influenced by a free meal, compensation for trips to try new equipment and time spent away from practice is considered appropriate. LEVEL OF EVIDENCE: 2c, Ecological studies.

Association of EEG characteristics with outcomes following pediatric ICU cardiac arrest: A secondary analysis of the ICU-RESUScitation trial.

BACKGROUND AND OBJECTIVES: There are limited tools available following cardiac arrest to prognosticate neurologic outcomes. Prior retrospective and single center studies have demonstrated early EEG features are associated with neurologic outcome. This study aimed to evaluate the prognostic value of EEG for pediatric in-hospital cardiac arrest (IHCA) in a prospective, multicenter study. METHODS: This cohort study is a secondary analysis of the ICU-Resuscitation trial, a multicenter randomized interventional trial conducted at 18 pediatric and pediatric cardiac ICUs in the United States. Patients who achieved return of circulation (ROC) and had post-ROC EEG monitoring were eligible for inclusion. Patients < 90 days old and those with pre-arrest Pediatric Cerebral Performance Category (PCPC) scores > 3 were excluded. EEG features of interest included EEG Background Category, and presence of focal abnormalities, sleep spindles, variability, reactivity, periodic and rhythmic patterns, and seizures. The primary outcome was survival to hospital discharge with favorable neurologic outcome. Associations between EEG features and outcomes were assessed with multivariable logistic regression. Prediction models with and without EEG Background Category were developed and receiver operator characteristic curves compared. RESULTS: Of the 1129 patients with an index cardiac arrest who achieved ROC in the parent study, 261 had EEG within 24 h of ROC, of which 151 were evaluable. The cohort included 57% males with a median age of 1.1 years (IQR 0.4, 6.8). EEG features including EEG Background Category, sleep spindles, variability, and reactivity were associated with survival with favorable outcome and survival, (all p < 0.001). The addition of EEG Background Category to clinical models including age category, illness category, PRISM score, duration of CPR, first documented rhythm, highest early post-arrest arterial lactate improved the prediction accuracy achieving an AUROC of 0.84 (CI 0.77-0.92), compared to AUROC of 0.76 (CI 0.67-0.85) (p = 0.005) without EEG Background Category. CONCLUSION: This multicenter study demonstrates the value of EEG, in the first 24 h following ROC, for predicting survival with favorable outcome after a pediatric IHCA.

Mechanistic and kinetic insights into transcription factor biology via acute protein depletion.

Genetic downregulation of the BCL11A transcription factor (TF) reverses the switch from fetal to adult hemoglobin and is effective in treating ß-hemoglobinopathies. Genetic ablation results in a gradual reduction in protein abundance and does not lend itself to the analysis of the immediate consequences of protein loss or the determination of the direct interactors/targets of the protein of interest. We achieved acute degradation of the largely disordered and 'undruggable' BCL11A protein by fusing it with a conditional degradation (degron) tag, FKBP12F36V, called degradable tags (dTAG). Small molecules then depleted the BCL11A-dTAG through endogenous proteolytic pathways. By integrating acute depletion with nascent transcriptomics and cell cycle separation techniques, we demonstrate the necessity of BCL11A occupancy at the target chromatin for sustained transcriptional repression in erythroid cells. We advocate for expanding the exploration of TF function to include acute depletion, which holds the potential to unveil unprecedented kinetic insights into TF mechanisms of action.

Integrated Safety and Efficacy Analyses of Phase 3 Trials of a Microbiome Therapeutic for Recurrent CDI.

INTRODUCTION: Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. OBJECTIVE, DESIGN, AND PATIENTS: To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. METHODS: VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24. RESULTS: TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6-13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6-19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression. CONCLUSIONS: VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.