A Genome-wide Association Study Reveals a Novel Susceptibility Locus for Pancreas Divisum at 3q29.

INTRODUCTION: Pancreas divisum (PD) is a common congenital anomaly of the pancreas, but its genetic basis remains unknown. The purpose of this genome-wide association study was to identify genetic loci associated with PD. METHODS: Using the Mass General Brigham Biobank, patients diagnosed with PD were identified. Quality control and imputation were performed using standard approaches. Single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 5% were tested for association with PD using mixed linear model-based association analysis. The significance threshold was set at 5 × 10-8. RESULTS: A total of 13,940 subjects were included, of which 251 (1.8%) were diagnosed with PD. A genetic locus in chromosome 3q29 was found to be associated with PD (lead SNP rs3850646, MAFPD = 34.6% vs. MAFcontrols = 26.4%, beta = 0.0106, P = 1.47 × 10-8). The identified locus is located in the phosphatidylinositol glycan anchor biosynthesis class Xand p21 activated kinase 2genes. The heritability of PD was estimated at 27.5%. (Expression quantitative trait loci) and chromatin interaction analysis found 12 genes whose expression may be regulated by SNPs in this genomic locus. CONCLUSIONS: The results of this study suggest that a genetic locus at 3q29 is associated with PD. This locus is in the phosphatidylinositol glycan anchor biosynthesis class X and p21 activated kinase 2 genes. Twelve candidate genes were identified whose expression may be regulated by this locus. These findings may help us understand both normal and aberrant pancreatic development and may aid in clinical evaluation and genetic counseling of patients with PD and associated diseases, such as acute pancreatitis.

Lower Mortality with Cryoprecipitate During Massive Transfusion in Penetrating but Not Blunt Trauma.

BACKGROUND: Balanced blood product transfusion improves the outcomes of trauma patients with exsanguinating hemorrhage, but it remains unclear whether administering cryoprecipitate improves mortality. We aimed to examine the impact of early cryoprecipitate transfusion on the outcomes of the trauma patients needing massive transfusion (MT). METHODS: All MT patients 18 years or older in the 2017 Trauma Quality Improvement Program (TQIP) were retrospectively reviewed. MT was defined as the transfusion of ≥10 units of blood within 24 hours. Propensity score analysis (PSA) was used to 1:1 match then compare patients who received and those who did not receive cryoprecipitate in the first 4 hours after injury. Outcomes included in-hospital mortality, 1-day mortality, in-hospital complications and transfusion needs at 24 hours. RESULTS: Of 1,004,440 trauma patients, 1,454 MT patients received cryoprecipitate and 2,920 did not. After PSA, 877 patients receiving cryoprecipitate were matched to 877 patients who did not. In-hospital mortality was lower among patients who received cryoprecipitate (49.4% v. 54.9%, P = 0.022), as was 1-day mortality. Sub-analyses showed that mortality was lower with cryoprecipitate in patients with penetrating (37.5% versus. 48%, adjusted P = 0.008), but not blunt trauma (58.5% versus. 59.8%, adjusted P = 1.000). In penetrating trauma, the cryoprecipitate group also had lower 1-day mortality (21.8% versus. 38.6%, P <0.001) and a higher rate of hemorrhage control surgeries performed within 24 hours (71.4% versus. 63.3%, P = 0.018). CONCLUSIONS: Cryoprecipitate in MT is associated with improved survival in penetrating, but not blunt, trauma. Randomized trials are needed to better define the role of cryoprecipitate in MT.

Low-Molecular Weight Heparin is Superior to Unfractionated Heparin for Elderly Trauma Patients.

BACKGROUND: Several studies have demonstrated that low-molecular weight heparin (LMWH) is superior to unfractionated heparin (UFH) in trauma patients. The superiority of either one has not been established for the elderly. In this study, we compared LMWH to UFH in elderly trauma patients. METHODS: A retrospective analysis of the American College of Surgeons' Trauma Quality Improvement Program database was performed for patients aged ≥65 y. Propensity score matching was performed to minimize confounders between the two groups. Outcomes included venous thromboembolic (VTE) and bleeding events. RESULTS: Overall, 93,987 patients were identified (mean age 77.1 ± 7.3 y, females 55,035 [58.6%]), of which 67,738 (72.1%) patients received LMWH and 26,249 (27.9%) received UFH. After Propensity score matching, LMWH was associated with a lower incidence of deep venous thrombosis (1.7% versus 2.1%, P = 0.007) and pulmonary embolisms (0.6% versus 1%, P< 0.001). LMWH was also associated with fewer bleeding complications (transfusions: 2.8% versus 3.5%, P< 0.001, procedures: 0.7% versus 0.9%, P = 0.007). Sub-analyses showed that differences in VTE rates were identified in patients with mild injuries (Injury Severity Score [ISS] <16, 0.6% versus 1.9%, P< 0.001). Differences in bleeding complications were identified in patients with injuries of mild (ISS <16, transfusions: 3% versus 3.8%, P< 0.001, surgeries: 0.3% versus 0.4%, P= 0.015) and moderate severity (ISS 16-24, transfusions: 1.9% versus 2.7%, P= 0.038, surgeries: 1% versus 1.7%, P= 0.013). CONCLUSION: LMWH prophylaxis is superior to UFH for VTE prevention among elderly trauma patients. LMWH prophylaxis is associated with fewer bleeding complications compared to UFH in patients with injuries of mild or moderate severity.

Rhabdomyolysis in Severe COVID-19: Male Sex, High Body Mass Index, and Prone Positioning Confer High Risk.

BACKGROUND: Bedside experience and studies of critically ill patients with coronavirus disease 2019 (COVID-19) indicate COVID-19 to be a devastating multisystem disease. We aim to describe the incidence, associated variables, and outcomes of rhabdomyolysis in critically ill COVID-19 patients. MATERIALS AND METHODS: Data for all critically ill adult patients (≥18 years old) admitted to the ICU at a large academic medical center with confirmed COVID-19 between March 13, 2020 and April 18, 2020 were prospectively collected. Patients with serum creatine kinase (CK) concentrations greater than 1000 U/L were diagnosed with rhabdomyolysis. Patients were further stratified as having moderate (serum CK concentration 1000-4999 U/L) or severe (serum CK concentration ≥5000 U/L) rhabdomyolysis. Univariate and multivariate analyses were performed to identify outcomes and variables associated with the development of rhabdomyolysis. RESULTS: Of 235 critically ill COVID-19 patients, 114 (48.5%) met diagnostic criteria for rhabdomyolysis. Patients with rhabdomyolysis more often required mechanical ventilation (P < 0.001), prone positioning (P < 0.001), pharmacological paralysis (P < 0.001), renal replacement therapy (P = 0.010), and extracorporeal membrane oxygenation (ECMO) (P = 0.025). They also had longer median ICU length of stay (LOS) (P < 0.001) and hospital LOS (P < 0.001). No difference in mortality was observed. Male sex, patients with morbid obesity, SOFA score, and prone positioning were independently associated with rhabdomyolysis. CONCLUSIONS: Nearly half of critically ill COVID-19 patients in our cohort met diagnostic criteria for rhabdomyolysis. Male sex, morbid obesity, SOFA score, and prone position were independently associated with rhabdomyolysis.

Supplemental oxygen therapy in trauma patients: An exploratory registry-based study.

BACKGROUND: Supplemental oxygen (SO) is one of the most commonly administered drugs in trauma patients and is recommended by guidelines. However, evidence supporting uniform administration is sparse, and excess oxygen use has been shown to be harmful in other patient populations. We hypothesized that SO may be harmful in patients with oxygen saturation > 97%. METHODS: Patients with available information on SO-therapy in the American Trauma Quality Improvement Program 2017 database were included. Patients were categorized into 3 groups according to Emergency Department (ED) oxygen saturation: (1) saturation < 94%; (2) saturation 94%-97%; (3) saturation 98%-100%. Primary outcome was in-hospital mortality with comparisons made between patients who received SO or not. Secondary outcome was acute respiratory distress syndrome (ARDS). Patients were compared after propensity score matching. RESULTS: Overall, 864 340 patients were identified. Mean age was 47.4 ± 24.4 years, and median injury severity score was 9. SO was associated with an increased risk of in-hospital mortality: (all patients: adjusted odds ratio [aOR] with 95% confidence interval [CI] 3.07 [2.92-3.22], ED saturation <94%: 2.63 [2.38-2.91], ED saturation 94%-97%: 2.71 [2.47-2.97], ED saturation >97%: 3.38 [3.16-3.61]. Same pattern was seen for in-hospital ARDS: (aOR 1.79, 95% CI [1.59-2.02], ED saturation <94%: aOR 1.75, 95% CI [1.37-2.24], ED saturation 94%-97%: aOR 1.81, 95% CI [1.43-2.29, ED saturation >97%: aOR 2.31, 95% CI [1.92-2.79]). CONCLUSION: Based on propensity matched, registry data for trauma patients, the administration of SO was associated with a higher incidence of in-hospital mortality and ARDS. The highest risk was found in patients with an ED saturation >97%.

Genetic risk factors for postoperative atrial fibrillation-a nationwide genome-wide association study (GWAS).

Background: Atrial fibrillation (AF) is a major cause of morbidity with a high prevalence among the elderly and has an established genetic disposition. Surgery is a well-known risk factor for AF; however, it is currently not recognized how much common genetic variants influence the postoperative risk. The purpose of this study was to identify Single Nucleotide Polymorphisms associated with postoperative AF. Methods: The UK Biobank was utilized to conduct a Genome-Wide Association Study (GWAS) to identify variants associated with AF after surgery. An initial discovery GWAS was performed in patients that had undergone surgery with subsequent replication in a unique non-surgical cohort. In the surgical cohort, cases were defined as newly diagnosed AF within 30 days after surgery. The threshold for significance was set at 5 × 10-8. Results: After quality control, 144,196 surgical patients with 254,068 SNPs were left for analysis. Two variants (rs17042171 (p = 4.86 × 10-15) and rs17042081 (p = 7.12 × 10-15)) near the PITX2-gene reached statistical significance. These variants were replicated in the non-surgical cohort (1.39 × 10-101 and 1.27 × 10-93, respectively). Several other loci were significantly associated with AF in the non-surgical cohort. Conclusion: In this GWAS-analysis of a large national biobank, we identified 2 variants that were significantly associated with postoperative AF. These variants were subsequently replicated in a unique non-surgical cohort. These findings bring new insight in the genetics of postoperative AF and may help identify at-risk patients and guide management.

Peri-operative blood transfusion and risk of infectious complications following intestinal-cutaneous fistula surgical repair: A retrospective nationwide analysis.

BACKGROUND: Peri-operative blood transfusion (BT) may lead to transfusion-induced immunomodulation. We aimed to investigate the association between peri-operative BT and infectious complications in patients undergoing intestinal-cutaneous fistulas (ICF) repair. METHODS: We queried the ACS-NSQIP 2006-2017 database to include patients who underwent ICF repair. The main outcome was 30-day infectious complications. Univariate and multivariable logistic regression analyses were performed to assess the predictors of post-operative infections. RESULTS: Of 4,197 patients included, 846 (20.2%) received peri-operative BT. Transfused patients were generally older, sicker and had higher ASA (III-V). After adjusting for relevant covariates, patients who received intra and/or post-operative (and not pre-operative) BT had higher odds of infectious complications compared (OR = 1.22, 95% CI 1.01-1.48). Specifically, they had higher odds of organ-space surgical site infection (OR = 1.61, 95% CI 1.21-2.13), but not other infectious complications. CONCLUSIONS: Intra and/or post-operative (and not pre-operative) BT is an independent predictor of infectious complications in ICF repair.

Association Between NEDD4L Variation and the Genetic Risk of Acute Appendicitis: A Multi-institutional Genome-Wide Association Study.

Importance: The familial aspect of acute appendicitis (AA) has been proposed, but its hereditary basis remains undetermined. Objective: To identify genomic variants associated with AA. Design, Setting, and Participants: This genome-wide association study, conducted from June 21, 2019, to February 4, 2020, used a multi-institutional biobank to retrospectively identify patients with AA across 8 single-nucleotide variation (SNV) genotyping batches. The study also examined differential gene expression in appendiceal tissue samples between patients with AA and controls using the GSE9579 data set in the National Institutes of Health's Gene Expression Omnibus repository. Statistical analysis was conducted from October 1, 2019, to February 4, 2020. Main Outcomes and Measures: Single-nucleotide variations with a minor allele frequency of 5% or higher were tested for association with AA using a linear mixed model. The significance threshold was set at P = 5 × 10-8. Results: A total of 29 706 patients (15 088 women [50.8%]; mean [SD] age at enrollment, 60.1 [17.0] years) were included, 1743 of whom had a history of AA. The genomic inflation factor for the cohort was 1.003. A previously unknown SNV at chromosome 18q was found to be associated with AA (rs9953918: odds ratio, 0.99; 95% CI, 0.98-1.00; P = 4.48 × 10-8). This SNV is located in an intron of the NEDD4L gene. The heritability of appendicitis was estimated at 30.1%. Gene expression data from appendiceal tissue donors identified NEDD4L to be among the most differentially expressed genes (14 of 22 216 genes; ß [SE] = -2.71 [0.44]; log fold change = -1.69; adjusted P = .04). Conclusions and Relevance: This study identified SNVs within the NEDD4L gene as being associated with AA. Nedd4l is involved in the ubiquitination of intestinal ion channels and decreased Nedd4l activity may be implicated in the pathogenesis of AA. These findings can improve the understanding of the genetic predisposition to and pathogenesis of AA.

Thirty-day outcomes in the operative management of intestinal-cutaneous fistulas: A NSQIP analysis.

INTRODUCTION: Intestinal-cutaneous fistulas (ICFs) constitute a major surgical challenge. Definitive surgical treatment of ICFs continues to be associated with significant morbidity. The purpose of this study was to utilize a nationwide database to define the morbidity associated with current treatment strategies in the surgical management of ICFs. METHODS: The 2006-2017 American College of Surgeon National Surgical Quality Improvement datasets (ACS-NSQIP) were used to assess 30-day morbidity and mortality after surgical repair of ICFs. Outcomes for emergent repair were compared to elective repair of ICFs. RESULTS: Overall, 4197 patients undergoing ICF-repair were identified. Mean age was 55.9 (SD 15.3). Patients were generally comorbid (62.9% were in ASA class III). The observed in-hospital mortality was 2.3%. However, the observed morbidity rate was 47.3%. Of the observed morbidity, 35.6% was due to post-operative infectious complications (superficial surgical site infections (SSI), deep SSI, organ/space SSI, wound disruption, pneumonia, urinary tract infection (UTI) sepsis or septic shock). The most common infectious complication was sepsis (13.1%). 30-day readmission rate was 15.3% and the 30-day reoperation rate was 11.0%. Emergent repair was associated with a sevenfold increase in mortality (11.9% vs 1.8%, P < 0.001) CONCLUSION: The management of patients with ICFs is complex and is associated with significant morbidity. Half of patients undergoing surgical management of ICFs developed in-hospital complications.

Modified Frailty Index-5 Score and Post-Operative Infectious Complications in Patients Undergoing Surgery for Intestinal-Cutaneous Fistula: A Nationwide Retrospective Cohort Analysis.

Background: Post-operative infectious complications after repair of intestinal-cutaneous fistulas (ICF) represent a substantial burden and these outcomes vary widely in the literature. We aimed to evaluate the use of the modified frailty index-5 (mFI-5) to account for physiologic reserve to predict infectious complications in patients with ICF undergoing operative repair. Methods: We used the American College of Surgeon National Surgical Quality Improvement Program (ACS-NSQIP) 2006-2017 dataset to include patients who underwent ICF repair. The main outcome measure was 30-day infectious complications (surgical site infection [SSI], sepsis, pneumonia, and urinary tract infection [UTI]). The risk of 30-day post-operative infectious complications was assessed based on mFI-5 score. We performed multivariable logistic regression analyses to evaluate the association between infectious complications and mFI-5. Results: We identified 4,197 patients who underwent an ICF repair. The median age (interquartile range [IQR]) was 57 (46, 67) years, and the majority of patients were female (2,260; 53.9%); white (3,348; 79.8%); and 1,586 (38.3%) were obese. After adjustment for relevant confounders such as baseline patient characteristics, and operative details, mFI-5 was independently associated with infectious complications (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.25-3.21), particularly SSI (OR, 2.16; 95% CI, 1.28-3.63) and pneumonia (OR, 5.31; 95% CI, 2.29-12.35), but not UTI or sepsis. Conclusions: We showed that the mFI-5 is a strong predictor of infectious complications after ICF repair. It can be utilized to account for physiologic reserve, therefore reducing the variability of outcomes reported for ICF repair.

Preoperative frailty predicts postoperative outcomes in intestinal-cutaneous fistula repair.

BACKGROUND: The outcomes of operative repair of intestinal-cutaneous fistulas vary widely throughout the literature. We aimed to investigate whether the modified frailty index-5 is a reliable tool to account for physiologic reserve and whether it serves as a predictor of Clavien-Dindo grade IV complications in those with intestinal-cutaneous fistulas undergoing operative repair. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program 2006 to 2017 database to include patients who underwent intestinal-cutaneous fistulas repair. The outcome of interest was 30-day Clavien-Dindo grade IV complications. The incidence of 30-day post-operative Clavien-Dindo grade IV complications were evaluated based on calculated modified frailty index-5 score. Multivariable logistic regression analyses were performed to assess the association of Clavien-Dindo grade IV complications and modified frailty index-5. RESULTS: A total of 3,995 patients were identified who underwent an intestinal-cutaneous fistulas repair. The median age (interquartile range) was 57 years (46, 67), and most patients were female (2,143 [53.7%]), White (3,206 [80.3%]), and 1,512 (38.2%) were obese. After adjusting for relevant covariates such as demographics, comorbidities, and operative details, modified frailty index-5 was independently associated with Clavien-Dindo grade IV complications (odds ratio = 2.81, 95% confidence interval 1.64-4.82; P < .001). CONCLUSION: Modified frailty index-5 is an independent predictor of Clavien-Dindo grade IV complications following intestinal-cutaneous fistulas repair. It can be used to account for physiologic reserve, thus reducing the variability of outcomes reported for intestinal-cutaneous fistulas repair.

Multisystem outcomes and predictors of mortality in critically ill patients with COVID-19: Demographics and disease acuity matter more than comorbidities or treatment modalities.

BACKGROUND: We sought to describe characteristics, multisystem outcomes, and predictors of mortality of the critically ill COVID-19 patients in the largest hospital in Massachusetts. METHODS: This is a prospective cohort study. All patients admitted to the intensive care unit (ICU) with reverse-transcriptase-polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection between March 14, 2020, and April 28, 2020, were included; hospital and multisystem outcomes were evaluated. Data were collected from electronic records. Acute respiratory distress syndrome (ARDS) was defined as PaO2/FiO2 ratio of ≤300 during admission and bilateral radiographic pulmonary opacities. Multivariable logistic regression analyses adjusting for available confounders were performed to identify predictors of mortality. RESULTS: A total of 235 patients were included. The median (interquartile range [IQR]) Sequential Organ Failure Assessment score was 5 (3-8), and the median (IQR) PaO2/FiO2 was 208 (146-300) with 86.4% of patients meeting criteria for ARDS. The median (IQR) follow-up was 92 (86-99) days, and the median ICU length of stay was 16 (8-25) days; 62.1% of patients were proned, 49.8% required neuromuscular blockade, and 3.4% required extracorporeal membrane oxygenation. The most common complications were shock (88.9%), acute kidney injury (AKI) (69.8%), secondary bacterial pneumonia (70.6%), and pressure ulcers (51.1%). As of July 8, 2020, 175 patients (74.5%) were discharged alive (61.7% to skilled nursing or rehabilitation facility), 58 (24.7%) died in the hospital, and only 2 patients were still hospitalized, but out of the ICU. Age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.04-1.12), higher median Sequential Organ Failure Assessment score at ICU admission (OR, 1.24; 95% CI, 1.06-1.43), elevated creatine kinase of ≥1,000 U/L at hospital admission (OR, 6.64; 95% CI, 1.51-29.17), and severe ARDS (OR, 5.24; 95% CI, 1.18-23.29) independently predicted hospital mortality.Comorbidities, steroids, and hydroxychloroquine treatment did not predict mortality. CONCLUSION: We present here the outcomes of critically ill patients with COVID-19. Age, acuity of disease, and severe ARDS predicted mortality rather than comorbidities. LEVEL OF EVIDENCE: Prognostic, level III.