Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3.

Serotonin 2A receptors (5-HT2ARs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HT2ARs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HT2ARs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. Here, we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HT2AR levels in the mouse frontal cortex in as little as 6-8 h (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (-/-) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HT2AR, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HT2AR levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.

Education without walls: Using a street medicine program to provide real-world interprofessional learning.

Interprofessional education (IPE) is a core component of the curricula for many healthcare and social work training programs and has been shown to increase student self-efficacy, communication skills, and attitudes toward other professions. Street medicine programs expand options for teaching interprofessional, team-based care of vulnerable populations, such as those experiencing homelessness. Street Medicine Phoenix is an interprofessional team of health professions students and faculty that provides outreach to Phoenix's homeless population. This study demonstrates the impact of volunteering in our street medicine program on the perceived development of interprofessional skills and behaviors. Volunteer teams, with representatives from medicine, nursing, social work, physical therapy, occupational therapy, public health, and undergraduate studies, completed the Interprofessional Collaborative Competencies Attainment Survey (ICCAS) before and after semester-long, monthly outreach events. Results demonstrate statistically significant improvements in overall ICCAS scores for all volunteers, but there was no relationship between number of shifts completed and ICCAS score improvement. Based on these findings, street medicine programs could be considered as an option for providing interprofessional learning to students in healthcare and social work degree programs. Street medicine outreach can supplement didactic and simulation skill-building activities in the IPE curricula with point of care, real-world experiential learning.

Outcomes after lung transplantation in recipients aged 70 years or older.

BACKGROUND: The proportion of lung transplant (LTx) recipients older than 70 years is increasing, thus we assessed long-term survival after LTx in this cohort relative to younger counterparts. PATIENTS AND METHODS: We retrospectively reviewed charts of patients who underwent LTx between 2012 and 2016 at our center and divided patients by age: group A (<65 years), B (65-69 years), and C (≥70 years). Survival statistics were evaluated using the Kaplan-Meier method and Cox regression. RESULTS: The study included 375 LTx recipients: 221 (58.9%) in group A, 109 (29.1%) in group B, and 45 (12.0%) in group C. Group C was mostly men (37/45 [82.2%]; P = 0.003) and had the highest mean serum creatinine at listing (P = 0.02). Survival at 1, 3, and 5 years after transplant in group A (93.2%, 70.1%, 58.8%) was significantly higher than group B (83.5%, 59.6%, 44.0%; P = 0.005, 0.028, 0.006, log-rank test) and was similar to group C (86.7%, 64.4%, 57.8%), although trended higher at 1 year (P = 0.139, 0.274, 0.489, log-rank test). Groups B and C had comparable survival at all time points. CONCLUSIONS: Although survival decreased after age 65, long-term survival was comparable between LTx recipients aged 65-69 years and recipients ≥70 years.

Effects of an exercise program during pediatric stem cell transplantation: A randomized controlled trial.

BACKGROUND: During pediatric hematopoietic stem cell transplant (HSCT), there is significant reduction in physical activity, leading to loss of strength and function, along with decline in quality of life (QoL). This study evaluates the effects of a supervised exercise program on functional ability, mobility, strength, and QoL during and following pediatric HSCT. METHODS: Patients ages 4-21 years presenting for HSCT were randomized to either an intervention group, who underwent exercise routines three times weekly and once weekly on discharge for 6 weeks supervised by a physical therapist, or the control group, which was treated per standard of care. Forty subjects were recruited for the study, 20 in each arm. Physical therapy and QoL assessments were conducted at three time points: pre-HSCT (baseline), on the day of hospital discharge, and 6 weeks after discharge. RESULTS: Exercise capacity and endurance using Six-Minute Walk test (p = .023) and strength using manual muscle testing (p = .005) were improved in the exercise group, compared to the control group. There was evidence that some QoL outcomes (measured using the Patient Reported Outcomes Measurement Information System) were improved 6 weeks post discharge, with observed decreases in anxiety (p = .0009) and fatigue (p = .037). CONCLUSION: Supervised exercise program during pediatric HSCT has positive effects on endurance, functional mobility, and muscle strength, and may also result in improvements in some aspects of QoL. This trial was registered at www. CLINICALTRIALS: gov as NCT04663503.

Effect of Extrinsic Warming of Low-Osmolality CT Contrast Media (Iohexol 350) on Extravasations and Patient Reaction Rates: A Retrospective Study.

BACKGROUND. Extrinsic warming of iodinated CT contrast media to body temperature reduces viscosity and injection pressures. However, studies examining the effect of extrinsic warming on clinical adverse events are limited in number and provide conflicting results. Therefore, consensus practice recommendations have been sparse. OBJECTIVE. The purpose of this study is to compare rates of extravasation, allergic and allergiclike reactions, and physiologic reactions between iohexol 350 mg I/mL warmed to body temperature (37°C) versus this agent maintained at room temperature. METHODS. This retrospective study compared adult patients who received CT examinations using IV iohexol 350 that had either been warmed to body temperature or maintained at room temperature. At our institution, contrast media had historically been warmed to body temperature before a protocol change unrelated to this investigation. Information on the patient and CT examination was extracted from the electronic medical record. Adverse events, including extravasations, allergic and allergiclike reactions, and physiologic reactions, were compared between groups. RESULTS. A total of 3939 patients received contrast media warmed to body temperature before the protocol change; 3933 patients received contrast media at room temperature after the protocol change. The body temperature group experienced 11 (0.28%; 95% CI, 0.14-0.50%) adverse events, all extravasations; the allergic and allergic-like reaction rate was 0.00% (97.5% CI, 0.00-0.09%). The room temperature group experienced 17 (0.43%; 95% CI, 0.25-0.69%) adverse events: 13 (0.33%; 95% CI, 0.17-0.56%) extravasations and four (0.10%; 95% CI, 0.03-0.26%) allergic and allergiclike reactions. No physiologic reaction occurred in either group. The two groups were not different in terms of overall reaction rate (p = .19), extravasation rate (p = .69), allergic and allergiclike reaction rate (p = .06), or physiologic reaction rate (p > .99). Logistic regression adjusting for patient and CT characteristics (age, sex, conventional CT vs CTA, contrast media volume, injection location) showed no significant association of patient group and adverse reaction rate (odds ratio, 2.19; 95% CI, 0.68-7.00). Multivariable regression modeling showed an excess of 0.27 adverse events per 100 patients within the room temperature group, which is below a 0.6% noninferiority margin. CONCLUSION. The data suggest that maintaining iohexol 350 at room temperature is noninferior to warming the agent to body temperature before injection. CLINICAL IMPACT. The resources involved to prewarm iohexol 350 before injection may not be warranted.

Current Trends in the Use of Ultrasound Over Chest X-Ray to Identify Pneumothoraces in ICU, Trauma, and ARDS Patients.

Pneumothoraces are a common and potentially fatal complication for critically ill patients in the trauma and intensive care units. Since its use for pneumothorax detection was first reported in 1987, ultrasound has been increasingly used for the detection of thoracic injuries. As ultrasound imaging has improved and operators have potentially become more proficient, it is important to analyze more recent trends in the sensitivities and specificities of ultrasound for the detection of pneumothorax. This literature review and meta-analysis identifies 17 studies that directly compare the sensitivity and specificity of ultrasound and anterior-posterior chest x-ray in the identification of pneumothorax among 2955 patients who developed 793 pneumothoraces as detected by gold standard CT scanning. For the 17 articles analyzed, the pooled sensitivity of trans-thoracic ultrasound was 75.07% (64.92%-85.22%), and the pooled specificity was 98.36% (97.45%-99.26%). The pooled sensitivity of CXR was 45.65% (36.04%-55.26%), and pooled specificity was 99.62% (99.00%-100%). While this review demonstrates an improved sensitivity in the detection of pneumothorax with ultrasound over AP chest x-rays, it did not find a significant trend or improvement in the sensitivity or specificity of ultrasound for detecting pneumothorax over time.

Assessing the Cushion Effect: A Systematic Review and Meta-Analysis of the Role of Obesity in Motor Vehicle Injuries and Fatalities.

PURPOSE: A systematic review and meta-analysis were done to evaluate the effect of obesity in injury and mortality due to motor vehicle accidents. MATERIALS & METHODS: The systematic review consisted of 20 studies meeting the inclusion criteria. The meta-analysis was conducted on these studies to analyze obesity as a risk factor for specific injuries, as well as overall injury and mortality compared to non-obese patients. RESULTS: The data revealed that obesity was associated with increased lower extremity injuries (odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.19-1.69, P ≤ 0.05), neck injuries (OR = 3.38, 95% CI = 1.58-5.19, P ≤ 0.05), and overall mortality (OR = 1.51, 95% CI = 1.40-1.61, P ≤ 0.05). When stratified for obesity class with class I as BMI >30.1-34.9, class II BMI 35-39.9, and class III BMI >40, only class II (OR = 1.20, 95% CI = 1.15-1.24, P ≤ 0.05) and class III (OR = 1.49, 95% CI = 1.30-1.68, P ≤ 0.05) were associated with increased mortality risk. No significant differences were seen with head, upper extremity, thoracic, abdominal, or pelvic injuries. CONCLUSION: Obesity is a risk factor in motor vehicle accidents for fatality and injury, specifically lower extremity and neck injuries.

The Role of Obesity in Motor Vehicle Injuries and Fatalities in the Pediatric Population: A Systematic Review.

PURPOSE: A systematic review done to evaluate obesity as a risk factor for injuries and mortality in motor vehicle accidents (MVAs) in the pediatric population, as there has not been a systematic review done in over 10 years. This study aims to update the literature regarding obesity as a risk factor for injuries in MVAs in the pediatric population. MATERIALS AND METHODS: A systematic review was conducted according to the PRISMA guidelines with strict inclusion and exclusion criteria, resulting in the use of 3 total articles to analyze obesity as a risk factor for overall injury and mortality in the pediatric population. RESULTS: Zaveri et al demonstrated a statistically significant, but weak, decrease in the odds of extremity injury in overweight patients ages 2 to 17 years old (odds ratio [OR] = 0.6, 95% confidence interval [CI] = 0.4-1.0, P ≤ 0.05). On the other hand, Pollack et al and Haricharan et al found an increase in extremity injury in the obese population, in ages 9 to 15 years (OR = 2.54, 95% CI = 1.15-5.59, P ≤ 0.05), and 10 to 17 years (Age 10-13: OR = 6.06, 95% CI = 2.23-16.44, P ≤ 0.05, Age 14-17 OR = 1.44, 95% CI = 1.04-2.00, P ≤ 0.05), respectively. Haricharan et al also found an increase in thoracic injuries in obese children, ages 2 to 13 and increased risk of head/face/neck injury in obese children ages 2 to 5 (OR = 3.67, 95% CI = 1.03-13.08, P ≤ 0.05), but a decreased risk of head injury in obese children ages 14 to 17 (OR = 0.33, 95% CI = 0.18-0.60, P ≤ 0.05). CONCLUSIONS: There are sparse data that are conflicting, regarding the effect of obesity on extremity injuries in the pediatric population. Obesity is not protective against thoracic, head, or abdominal injuries. However, it was found to be a risk factor for trunk injuries in ages 2 to 13, as well as head/face/neck injuries for ages 2 to 5. Since the literature is so sparse, further research is warranted in these areas.

A simulation study to investigate the use of concentric tube robots for epilepsy surgery.

PURPOSE: Patients with pharmacoresistant refractory epilepsy may require epilepsy surgery to prevent future seizure occurrences. Conventional surgery consists of a large craniotomy with straight rigid tools with associated outcomes of morbidity, large tissue resections, and long post-operative recovery times. Concentric tube robots have recently been developed as a promising application to neurosurgery due to their nonlinear form and small diameter. The authors present a concept study to explore the feasibility of performing minimally invasive hemispherotomy with concentric tube robots. METHODS: A model simulation was used to achieve the optimal design and surgical path planning parameters of the concentric tube robot for corpus callosotomy and temporal lobectomy. A single medial burr hole was chosen to access the lateral ventricles for both white matter disconnections. RESULTS: The concentric tube robot was able to accurately reach the designated surgical paths on the corpus callosum and the temporal lobe. CONCLUSION: In a model simulation, the authors demonstrated the feasibility of performing corpus callosotomy and temporal lobectomy using concentric tube robots. Further advancements in the technology may increase the applicability of this technique for epilepsy surgery to better patient outcomes.

Clinical Scores Predict Acute and Chronic Complications in Pediatric Osteomyelitis: An External Validation.

BACKGROUND: Pediatric acute hematogenous osteomyelitis (AHO) outcomes are highly dependent on the disease severity. Recently, the A-SCORE and C-SCORE, were proposed as predictors of an acute complicated course and chronic morbidity, respectively. The purpose of this study was to externally validate the A-SCORE and C-SCORE at a single institution. METHODS: This IRB-approved retrospective chart review included AHO patients admitted at a tertiary referral hospital between October 1, 2015 and December 31, 2019. The inclusion criteria were ages 0 to 18 and clinical response to treatment. The exclusion criteria were immunocompromised status or penetrating inoculation. RESULTS: The A-SCORE demonstrated an area under the receiver operator curve (ROC area) of >86% with regards to all acute complications. It also demonstrated sensitivities >85% and specificities >92% at the cut-off of 4 (Youden index) for all acute complications. The C-SCORE demonstrated an ROC area of 100% with regards to chronic osteomyelitis. It also demonstrated sensitivities >70% and specificities >93% for the chronic morbidity variables seen in our population at the cut-off of 3 (Youden index.). CONCLUSIONS: These novel composite clinical scores, in combination with clinical judgment, could help guide early care decisions. The A-SCORE and C-SCORE are useful risk stratification tools in the management of pediatric AHO and in predicting acute complicated courses or chronic sequelae of AHO, respectively. These scoring systems, if integrated into standardized pediatric AHO guidelines, can allow clinicians to stratify the AHO population and guide clinical decision making. LEVEL OF EVIDENCE: Level III (prognostic study, retrospective chart review).

IMPPACT (Intravenous Monotherapy for Postoperative Perforated Appendicitis in Children Trial): Randomized Clinical Trial of Monotherapy Versus Multi-drug Antibiotic Therapy.

BACKGROUND: Perforated appendicitis is the most common cause of intraabdominal abscess (IAA) in children. The optimal postoperative antibiotic regimen to reduce IAA has evolved in the last decade from triple-drug to 2-drug therapy (CM). Recent retrospective studies show decreased infectious complications with monotherapy PT. To date prospective comparative data are lacking. Therefore, a prospective randomized trial comparing PT versus CM was conducted. METHODS: A multi-institutional prospective randomized trial was performed in children with perforated appendicitis comparing postoperative antibiotic regimens PT or CM. The primary outcome was 30-day postoperative IAA formation. Perforation was strictly defined as a hole in the appendix or fecalith in the abdomen, documented with intraoperative photographs. RESULTS: One hundred sixty-two patients were enrolled during the study period. No differences in age, weight, or duration of presenting symptoms were identified. In addition, length of stay, duration of intravenous antibiotic treatment, discharge oral antibiotic treatment, and antibiotic-related complications did not differ between groups. Compared to the CM group, the PT group had significantly lower IAA rate [6.1% vs 23.8%, odd ratio (OR) 4.80, P = 0.002], lower postoperative computed tomography imaging rate (13.9% vs 29.3%, OR 2.57, P = 0.030), and fewer emergency room visits (8.8% vs 26.4%, OR 3.73, P = 0.022). Multivariate logistic regression analysis found the use of CM versus PT (OR 9.21, P = 0.021) to be the most significant predictor for developing IAA. CONCLUSIONS: In children with perforated appendicitis, postoperative monotherapy with PT is superior to standard 2-drug therapy with CM and does not increase antibiotic-related complications or antibiotic exposure duration.

Altered pulmonary blood volume distribution as a biomarker for predicting outcomes in COVID-19 disease.

INTRODUCTION: Evidence suggests that vascular inflammation and thrombosis may be important drivers of poor clinical outcomes in patients with COVID-19. We hypothesised that a significant decrease in the percentage of blood volume in vessels with a cross-sectional area between 1.25 and 5 mm2 relative to the total pulmonary blood volume (BV5%) on chest computed tomography (CT) in COVID-19 patients is predictive of adverse clinical outcomes. METHODS: We performed a retrospective analysis of chest CT scans from 10 hospitals across two US states in 313 COVID-19-positive and 195 COVID-19-negative patients seeking acute medical care. RESULTS: BV5% was predictive of outcomes in COVID-19 patients in a multivariate model, with a BV5% threshold below 25% associated with OR 5.58 for mortality, OR 3.20 for intubation and OR 2.54 for the composite of mortality or intubation. A model using age and BV5% had an area under the receiver operating characteristic curve of 0.85 to predict the composite of mortality or intubation in COVID-19 patients. BV5% was not predictive of clinical outcomes in patients without COVID-19. CONCLUSIONS: The data suggest BV5% as a novel biomarker for predicting adverse outcomes in patients with COVID-19 seeking acute medical care.

Synergistic roles for human U1 snRNA stem-loops in pre-mRNA splicing.

During spliceosome assembly, interactions that bring the 5' and 3' ends of an intron in proximity are critical for the production of mature mRNA. Here, we report synergistic roles for the stem-loops 3 (SL3) and 4 (SL4) of the human U1 small nuclear RNA (snRNA) in maintaining the optimal U1 snRNP function, and formation of cross-intron contact with the U2 snRNP. We find that SL3 and SL4 bind distinct spliceosomal proteins and combining a U1 snRNA activity assay with siRNA-mediated knockdown, we demonstrate that SL3 and SL4 act through the RNA helicase UAP56 and the U2 protein SF3A1, respectively. In vitro analysis using UV crosslinking and splicing assays indicated that SL3 likely promotes the SL4-SF3A1 interaction leading to enhancement of A complex formation and pre-mRNA splicing. Overall, these results highlight the vital role of the distinct contacts of SL3 and SL4 in bridging the pre-mRNA bound U1 and U2 snRNPs during the early steps of human spliceosome assembly.

Primary Bacterial Pyomyositis in Children: A Systematic Review.

BACKGROUND: Tropical pyomyositis has had a recent increase in the United States, Europe, and other nontropical areas. The purpose of this study was to provide an accurate description of the demographics, presenting features, sites of involvement, microbiology, imaging modalities, medical and surgical management, complications, and predictors of clinical course. METHODS: We searched PubMed, Cochrane, Web of Science Collection, Scopus, and Embase databases yielding 156 studies. Of these, 23 articles were selected for statistical analysis. RESULTS: The average age at presentation was 8.4±1.9 years with males more commonly affected. Fever, painful limp, and localized pain were the most common presenting symptoms. Pelvis, lower extremity, trunk and spine, in descending order, were the most commonly affected locations. Iliopsoas, obturator musculature, and gluteus musculature were the most commonly affected muscle groups. The mean time to diagnosis was 6.6±3.05 days. Staphylococcus aureus was the most common offending organism. The mean length of hospital stay was 12.0±4.6 days. Medical management alone was successful in 40% of cases (143/361) with an average duration of 9.5±4.0 and 22.7±7.2 days of intravenous and oral antibiotics, respectively. Surgical management consisted of open drainage in 91.3% (199/218) or percutaneous drainage in 8.7% (19/218) of cases. Painful limp, fever, and larger values of white cell count and erythrocyte sedimentation rate were associated with an increased need for surgery. Obturator and calf muscle involvement were strongly associated with multifocal involvement. There were 42 complications in 41 patients (11.3%). Methicillin-resistant S. aureus was associated with an increased risk of complications. The most common complications were osteomyelitis, septicemia, and septic arthritis. CONCLUSIONS: Primary pyomyositis should be considered in cases suggesting pediatric infection. Magnetic resonance imaging is the most commonly used imaging modality; however, ultrasound is useful given its accessibility and low cost. Medical management alone can be successful, but surgical treatment is often needed. The prognosis is favorable. Early diagnosis, appropriate medical management, and potential surgical drainage are required for effective treatment. LEVEL OF EVIDENCE: Level IV-systematic review.

Outcomes of paediatric cardiac patients after 30 minutes of cardiopulmonary resuscitation prior to extracorporeal support.

OBJECTIVES: To characterise the mortality and neurological outcomes of paediatric cardiac patients requiring cardiopulmonary resuscitation for more than 30 minutes prior to extracorporeal membrane oxygenation cannulation and to identify risk factors associated with adverse outcomes in this population. MATERIALS AND METHODS: Observational retrospective cohort study in paediatric cardiac patients undergoing cardiopulmonary resuscitation for greater than 30 minutes prior to cannulation in a tertiary children's hospital, from July 2000 to July 2013. RESULTS: Seventy-three paediatric cardiac patients requiring cardiopulmonary resuscitation for more than 30 minutes prior to cannulation were included in the study. Survival to hospital discharge was 43.8%, with 75% of survivors having either normal neurologic function or only mild disability. Multivariable logistic regression analysis demonstrated that increased use of calcium during resuscitation (odds ratio 14.5, p 0.01), cardiopulmonary resuscitation duration >50 minutes (odds ratio 4.12, p 0.03), >6 interruptions of chest compressions during cannulation (odds ratio 6.40, p 0.03), the need for continuous renal replacement therapy (odds ratio 11.1, p 0.001), and abnormal pupillary response during extracorporeal membrane oxygenation (odds ratio 33.9, p 0.006) were independent predictors for hospital mortality. CONCLUSION: Survival after cardiopulmonary resuscitation for more than 30 minutes prior to extracorporeal membrane oxygenation cannulation in our paediatric cardiac cohort was 43.8%. Factors associated with mortality included calcium use during resuscitation, longer cardiopulmonary resuscitation, increased chest compression pauses during cannulation, the use of continuous renal replacement therapy, and abnormal pupils during extracorporeal membrane oxygenation support. A prospective assessment of these factors in paediatric cardiac patients may be beneficial in improving outcomes.

Music and Medicine Come Together Over Pain in the Air Medical Transport Environment.

OBJECTIVE: This study aimed to determine if noise-canceling headphones (NCHs) with music supersedes pain reduction of other hearing protection for patients transported by Guardian Air Transport via rotor or fixed wing aircraft from 2017 to 2019. METHODS: We designed a randomized pilot study in which patients who received NCHs with or without music were compared with controls who received non-NCH hearing protection alone. Four hundred fifty-four adults 19 to 64 years of age and 36 pediatric patients 4 to 18 years old who received ≥ 1 dose of opioids were included. RESULTS: In the aggregate population, opioid use was reduced by 31% from 14.3 to 10.0 morphine milligram equivalent/h transport (P = .131) with music compared with controls. The mean total pain reduction in the aggregate population from -2.5 (standard deviation [SD] = 3.2) to -4.0 (SD = 2.9) was 1.6-fold more than controls compared with NCH and music (P = .008). This effect was most profound in the pediatric population where the mean total pain reduction with NCHs and music (-5.4, SD = 3.1) was 3.4-fold more than controls (-1.6, SD = 2.7, P = .021). CONCLUSIONS: Music may provide greater subjective pain relief when combined with NCHs in the air transport environment; further research is required.

Myeloid Disease Mutations of Splicing Factor SRSF2 Cause G2-M Arrest and Skewed Differentiation of Human Hematopoietic Stem and Progenitor Cells.

Myeloid malignancies, including myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia, are characterized by abnormal proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). Reports on analysis of bone marrow samples from patients have revealed a high incidence of mutations in splicing factors in early stem and progenitor cell clones, but the mechanisms underlying transformation of HSPCs harboring these mutations remain unknown. Using ex vivo cultures of primary human CD34+ cells as a model, we find that mutations in splicing factors SRSF2 and U2AF1 exert distinct effects on proliferation and differentiation of HSPCs. SRSF2 mutations cause a dramatic inhibition of proliferation via a G2-M phase arrest and induction of apoptosis. U2AF1 mutations, conversely, do not significantly affect proliferation. Mutations in both SRSF2 and U2AF1 cause abnormal differentiation by skewing granulo-monocytic differentiation toward monocytes but elicit diverse effects on megakaryo-erythroid differentiation. The SRSF2 mutations skew differentiation toward megakaryocytes whereas U2AF1 mutations cause an increase in the erythroid cell populations. These distinct functional consequences indicate that SRSF2 and U2AF1 mutations have cell context-specific effects and that the generation of myeloid disease phenotype by mutations in the genes coding these two proteins likely involves different intracellular mechanisms. Stem Cells 2018;36:1663-1675.

Factors associated with skin cancer in lung transplant recipients: A single-center experience.

BACKGROUND: Skin cancer is common after solid organ transplantation, but few have investigated it after lung transplant (LTx). OBJECTIVE: We assessed incidence and predictors of non-melanoma skin cancer (NMSC) post-LTx. METHODS: We studied patients who underwent LTx at our center from 2012 to 2015. RESULTS: Of 287 patients, mean age was 59.6 ± 11 years, 170 (59.2%) were men, and 231 (80.5%) were white. Seventy-six (26.5%) developed NMSC over a median follow-up of 32 months (IQR, 23-45). Of those with NMSC, 37% developed subsequent skin cancer of the same type. Independent predictors of decreased odds of NMSC and squamous cell carcinoma (SCC) were non-white race (P = .002; P = .003) and body mass index >30 kg/m2 compared with underweight patients (P = .001, P = .009). Patients with skin cancer pre-LTx had higher risk of post-LTx skin cancer (P = .02). Voriconazole use ≥100 days was associated with increased risk of SCC (P = .03), but not increased risk of basal cell carcinoma. Out of 76, 4 (5.3%) died from skin cancer. LIMITATIONS: Retrospective, single-center study. CONCLUSION: Squamous cell carcinoma risk post-LTx may increase with prolonged voriconazole use in white patients with pre-LTx history of skin cancer, whereas excess body weight may be protective from NMSC. Regular pre- and post-LTx skin cancer screenings and guidelines are warranted.

Dead space fractions in neonates following first-stage palliation for hypoplastic left heart syndrome.

PURPOSE: (1) To characterise changes in dead space fraction during the first 120 post-operative hours in neonates undergoing stage 1 palliation for hypoplastic left heart syndrome, including hybrid procedure; (2) to document whether dead space fraction varied by shunt type (Blalock-Taussig shunt and Sano) and hybrid procedure; and (3) to determine the association between dead space fraction and outcomes. METHODS: Retrospective chart review in neonates undergoing stage 1 palliation for hypoplastic left heart syndrome in a cardiac intensive care unit over a consecutive 30-month period. A linear mixed model was used to determine the differences in dead space over time. Multivariable linear regression and a multivariable linear mixed model were used to assess the association between dead space and outcomes at different time points and over time, respectively. RESULTS: Thirty-four neonates received either a Blalock-Taussig shunt (20.5%), Sano shunt (59%), or hybrid procedure (20.5%). Hospital mortality was 8.8%. Dead space fractions in patients undergoing the hybrid procedure were significantly lower on day 1 (p = 0.01) and day 2 (p = 0.02) and increased over time. A dead space fraction >0.6 on post-operative days 3-5 was significantly associated with decreased duration of mechanical ventilation in all surgical groups (p 0.6 on post-operative days 3-5 was associated with lower duration of mechanical ventilation in all surgical groups. A more comprehensive, prospective assessment of dead space in this delicate patient population would likely be beneficial in improving outcomes.

Primary paraesophageal hernia repair with Gore® Bio-A® tissue reinforcement: long-term outcomes and association of BMI and recurrence.

BACKGROUND: Laparoscopic repair remains the gold-standard treatment for paraesophageal hernia (PEH). We analyzed long-term symptomatic outcomes and surgical reintervention rates after primary PEH repair with onlay synthetic bioabsorbable mesh (W. L. Gore & Associates, Inc., Flagstaff, AZ) and examined body mass index (BMI) as a possible risk factor for poor outcomes and for recurrence. METHODS: We queried a prospectively maintained database to identify patients who underwent laparoscopic primary PEH repair with onlay patch of a bioprosthetic absorbable mesh (Bio-A® Gore®) between 05/28/2009 and 12/31/2013. Electronic health records were accessed to record demographic and operative data and were reviewed up to the present to identify any repeat procedures. Patients were grouped according to preoperative BMI (A: BMI < 25; B: BMI = 25-29.9; C: BMI = 30-34.9; D: BMI ≥ 35). Patients completed standardized satisfaction and symptom surveys. RESULTS: In total, 399 patients were included. Most patients (n = 261; 65.4%) were women. Mean age was 59.6 ± 13.4 years; mean BMI was 29.9 ± 5.0 kg/m2. The patients were grouped as follows: A, 53 patients (13.3%); B, 166 (41.6%); C, 115 (28.8%); D: 65 (16.3%). Four procedures (1.0%) were converted from laparoscopy to open procedures. All patients underwent an antireflux procedure (225 Nissen, 170 Toupet, 4 Dor). A mean follow-up of 44.7 ± 22.8 months was available for 305 patients (76.4%). 24/305 patients (7.9%) underwent reoperation, and the number of reoperations did not differ among groups (P = 0.64). Long-term symptomatic outcomes were available for 217/305 patients (71.1%) at a mean follow-up of 54.0 ± 13.1  months; no significant difference was observed among groups. 194/217 patients (89.4%) reported good to excellent satisfaction, with no significant differences among the groups. CONCLUSIONS: Laparoscopic primary PEH repair with onlay Bio-A® mesh is a safe and feasible procedure with excellent long-term patient-centered outcomes and acceptable symptomatic recurrence rate. BMI does not appear to be related to the need for surgical reintervention.