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To investigate the effect of timing of chemoprophylaxis on VTE and bleeding rates in patients undergoing major abdominal surgery.Postoperative bleeding and venous thromboembolisms (VTE) incur significant morbidity, mortality and healthcare costs. Chemoprophylaxis is used routinely to prevent VTEs but increases bleeding risk. The perioperative timing of chemoprophylaxis initiation may influence both VTE and bleeding risks. The optimal window for commencing chemoprophylaxis in the perioperative period is unclear.MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched using PRISMA guidelines. Randomized trials and cohort studies published between 01 January 2000 to 10 May 2022 which reported on chemoprophylaxis timing as well as the incidence of VTE and bleeding following elective abdominal surgery were meta-analyzed.From 6,175 studies, 14 (24,922 patients) were meta-analyzed. Bariatric (4 studies), antireflux (1 study), hepato-pancreatic-biliary (5 studies), colorectal (1 study), ventral hernia (1 study), and major intra-abdominal surgeries (2 studies) were included. Chemoprophylaxis was initiated before skin closure in 10,403 patients, and postoperatively in 14,519 patients. Both symptomatic (RR 0.81, 95% CI 0.45-1.43, P=0.460) and overall (RR 0.74, 95% CI 0.45-1.24, P=0.250) VTE rates were comparable between study groups. Compared with postoperative chemoprophylaxis, early usage increased the risk of all bleeding (RR 1.56, 95% CI 1.13-2.15, P=0.007), major bleeding (RR 1.63, 95% CI 1.16-2.28, P=0.005), blood transfusion (RR 1.48, 95% CI 1.24-1.76, P0.001) and reintervention (RR 1.94, 95% CI 1.19-3.18, P=0.008).Our findings advocate for initiating chemoprophylaxis postoperatively in elective abdominal surgery to minimize bleeding risk without compromising VTE protection.

Introduction At a national level, understanding preventable mortality after oesophago-gastric cancer surgery can direct quality-improvement efforts. Accordingly, utilizing the Australian and New Zealand Audit of Surgical Mortality (ANZASM), we aimed to: (1) determine the causes of death following oesophago-gastric cancer resections in Australia, (2) quantify the proportion of potentially preventable deaths, and (3) identify clinical management issues contributing to preventable mortality. Methods All in-hospital mortalities following oesophago-gastric cancer surgery from 1 January 2010 to 31 December 2020 were analysed using ANZASM data. Potentially preventable and non-preventable cases were compared. Thematic analysis with a data-driven approach was used to classify clinical management issues. Results Overall, 636 complications and 123 clinical management issues were identified in 105 mortalities. The most common causes of death were cardio-respiratory in aetiology. Forty-nine (46.7%) deaths were potentially preventable. These cases were characterized by higher rates of sepsis (59.2% vs 33.9%, p = 0.011), multiorgan dysfunction syndrome (40.8% vs 25.0%, p = 0.042), re-operation (63.3% vs 41.1%, p = 0.031) and other complications compared with non-preventable mortality. Potentially preventable mortalities also had more clinical management issues per patient [median (IQR): 2 (1–3) vs 0 (0–1), p p = 0.002), intraoperative (18.4% vs 5.4%, p = 0.037) and postoperative (51.0% vs 17.9%, p Conclusions Almost 50% of deaths following oesophago-gastric cancer resections were potentially preventable. These were characterized by higher complication rates and clinical management issues. We highlight recurrent themes in patient management to improve future quality of care.

Gene List from siRNA screen with APR-246 growth inhibition in H1299 p53-null (Sheet 1) and p53-R273H (Sheet 2)

Figure S5 shows MYC directly regulates SLC7A11 levels and APR-246 sensitivity.

Supplemental Table 1, 2, 3. Supplemental Materials and Methods.

IL-6 RTPCR primers

Selected compounds for secondary screen

Primary hits-JHOC-5

Primary hits-TOV21G

RPPA Antibody List

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target. Here we use CRISPR/Cas9 and conditional short hairpin interfering RNA to perform loss-of-function studies in human OCCA cell lines to explore the requirement for IL6 in vitro and in vivo. While reduction of IL6 expression exerted limited effects in vitro, its attenuation significantly impaired tumor growth and neovascularization in vivo. In contrast to typical signaling via STAT3, IL6 in OCCA signaled via a noncanonical pathway involving gp130, Src, and the Hippo pathway protein YAP. A high-throughput combination drug screen identified agents that enhanced cell killing following reduction of IL6 signaling. Intersection of screen hits obtained from two cell lines and orthogonal approaches to attenuation of IL6 yielded AKT and EGFR inhibitors as enhancers of the inhibitory monoclonal IL6 receptor antibody tocilizumab. This study defines for the first time the requirements for, and mechanisms of, signaling by IL6 in human OCCA cell lines and identifies potential combinatory therapeutic approaches. Given the molecular diversity of OCCA, further in vitro and in vivo studies are warranted to determine whether such approaches will overcome the limited efficacy of tocilizumab observed in ovarian cancer to date.Significance:This study defines the requirements for and mechanisms of noncanonical signaling by IL6 in human ovarian clear cell adenocarcinoma cell lines and identifies combinatory therapeutic approaches to be explored clinically.

Supplementary Figures

Background Abdominal visceral resections incur relatively higher rates of postoperative bleeding and venous thromboembolism (VTE). While guidelines recommend the use of perioperative chemical thromboprophylaxis, the most appropriate time for its initiation is unknown. Here, we investigated whether early (before skin closure) versus postoperative commencement of chemoprophylaxis affected VTE and bleeding rates following abdominal visceral resection. Methods Retrospective review of all elective abdominal visceral resections undertaken between January 1, 2018, and June 30, 2019, across four tertiary-referral hospitals. Major bleeding was defined as the need for blood transfusion, reintervention, or > 20 g/L fall in hemoglobin from baseline. Clinical VTE was defined as imaging-proven symptomatic disease Results A total of 945 cases were analyzed. Chemoprophylaxis was given early in 265 (28.0%) patients and postoperatively in 680 (72.0%) patients. Mean chemoprophylaxis exposure doses were similar between the two groups. Clinical VTE developed in 14 (1.5%) patients and was unrelated to chemoprophylaxis timing. Postoperative bleeding occurred in 71 (7.5%) patients, with 57 (80.3%) major bleeds, requiring blood transfusion in 48 (67.6%) cases and reintervention in 31 (43.7%) cases. Bleeding extended length-of-stay (median (IQR), 12 (7–27) versus 7 (5–11) days, p p = 0.038) and independently predicted its occurrence. Conclusions The risk of bleeding following elective abdominal visceral resections is substantial and is higher than the risk of clinical VTE. Compared with early chemoprophylaxis, postoperative initiation reduces bleeding risk without an increased risk of clinical VTE.

To determine whether early (before skin closure) versus postoperative chemoprophylaxis affects the incidence of venous thromboembolism (VTE) and bleeding following major abdominal surgery, in a high thromboembolic risk population.Major abdominal surgery incurs both VTE and bleeding risks. Patients with high preoperative VTE risk derive the most benefit from chemoprophylaxis, but carry an increased risk of bleeding. The optimal window for chemoprophylaxis in the perioperative period, whereby both VTE and bleeding risks are minimized, is unknown.Analysis of pooled data from five multicenter studies including only high thromboembolic risk (Caprini score4) patients. Clinical VTE was defined as radiographically-proven symptomatic disease30 days post-surgery. Major bleeding was defined as the need for blood transfusion, reintervention, or20 g/L fall in hemoglobin.From 5501 cases, chemoprophylaxis was initiated early in 1752 (31.8%) patients and postoperatively in 3749 (68.2%) patients. Baseline characteristics were similar between study groups. The incidence of clinical VTE was not associated with chemoprophylaxis timing (early 0.7% vs. postop 0.7%, OR 1.11, 95% CI 0.60-2.15, P=0.730). Contrastingly, compared with postoperative chemoprophylaxis, early usage increased the risk of all bleeding (5.1% vs. 2.6%, OR 2.04, 95% CI 1.52-2.73, P0.001) major bleeding (3.6% vs. 1.8%, OR 1.99, 95% CI 1.40-2.81, P0.001), and reintervention (2.0% vs. 1.0%, OR 2.10, 95% CI 1.32-3.35, P=0.003). Early chemoprophylaxis independently predicted postoperative bleeding (OR 1.71, 95% CI 1.25-2.34, P0.001), but not VTE.In high VTE risk patients undergoing major abdominal surgery, chemoprophylaxis commenced postoperatively reduces bleeding risk without affecting clinical VTE risk.

Obesity is common and adversely impacts quality-of-life and healthcare cost. In Australia, less than 10% of bariatric surgeries are performed in the public sector. This study reports our 10-year experience from a high volume public bariatric service which delivers multi-disciplinary care for primary and revisional procedures with mid- to long-term follow-up.A prospectively maintained database of all patients who underwent bariatric surgery from January 2010 to January 2020 at a tertiary metropolitan hospital was analysed. We analysed patient demographics, comorbidities, perioperative outcomes, 2- and 5-year weight loss as well as comorbidities reduction.A total of 995 patients underwent 1086 (674 primary and 412 revisional) bariatric procedures with mean age of 46.9 years, mean BMI of 49.6 ± 9.1 kg/mThis study confirms that bariatric surgery in Australia can be delivered effectively in resource constrained public health system with outcomes similar to private sector.

Wound complications are a common cause of postoperative morbidity and incur significant healthcare costs. Recent studies have shown that negative pressure wound dressings reduce wound complication rates, particularly surgical site infections, after elective laparotomies. The clinical utility of prophylactic negative pressure wound dressings for closed emergency laparotomy incisions remains controversial. This meta-analysis investigated the rates of wound complications after emergency laparotomy when a negative pressure wound dressing was applied.A systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Cochrane Registry, Web of Science, and Clinialtrials.gov databases were searched from January 1, 2005, to April 1, 2022. All studies comparing negative pressure wound dressings to standard dressings on closed emergency laparotomy incisions were included.A total of 1,199 (negative pressure wound dressings: 566, standard dressing: 633) patients from 7 (prospective: 4, retrospective: 3) studies were identified. Overall, the surgical site infection (superficial/deep) rate was 13.6% (77/566) vs 25.1% (159/633) in the negative pressure wound dressing versus standard dressing groups, respectively (odds ratio 0.43, 95% confidence interval 0.30-0.62). Wound breakdown (skin/fascial dehiscence) was significantly lower in the negative pressure wound dressing (7.7%) group compared to the standard dressing (16.9%) group (odds ratio 0.36, 95% confidence interval 0.19-0.72). The incidence of overall wound complications was significantly lower in the negative pressure wound dressing (15.9%) group compared to the standard dressing (30.4%) group (odds ratio 0.41, 95% confidence interval 0.28-0.59). No significant differences were found in hospital length-of-stay and readmission rates.Prophylactic negative pressure wound dressings for closed emergency laparotomy incisions were associated with a significant reduction in surgical site infections, wound breakdown, and overall wound complications, thus supporting its clinical use.

To provide an updated evaluation of radiology residency program websites in light of virtual interviewing during the COVID-19 pandemic and encourage programs to improve the quality of their online website presence.We evaluated the websites of 197 US radiology residency programs between November and December 2021 for the presence or absence of 30 metrics. The metrics chosen are those considered important by applicants when choosing a program and have been used in other similar papers.Of the 197 programs, 192 (97.5%) had working websites. The average radiology residency website had 16 of 30 (54%) metrics listed on their websites. Five programs did not have accessible websites and were not included in the analysis. The most comprehensive website had 29 of 30 (97%) of metrics listed and the least comprehensive website had 2 of 30 (7%). There is a statistically significant difference in website comprehensiveness between top 20 and non-top 20 radiology program websites.Although radiology residency program websites have generally become more comprehensive over time, there is still room for improvement, especially in times of virtual interviews when residency applicants are becoming more and more reliant on program websites to gain essential information about a program. Some key areas to include are diversity and inclusion initiatives, resident wellness, applicant information, program benefits, and showcase of people in the program.

Retrospective comparative study. To compare complications before and after implementation of the Multi-D screening protocol in complex pediatric patients undergoing spinal instrumentation for non-idiopathic scoliosis. Pediatric patients undergoing surgery for non-idiopathic scoliosis experience significantly more complications than those with idiopathic scoliosis. Operating on these patients can lead to serious complications including death. Recent reports have demonstrated the benefits of establishing a multidisciplinary-based system to reduce complications in adult spinal deformity during the perioperative period. However, there are limited studies examining these benefits in a complex pediatric spine population. This was a retrospective review of all cases involving spinal instrumentation at our institution for 2 years before and after the initiation of our Neuromuscular Spine Surgery Care Plan in July 2014. Study sample was n = 129 cases (107 patients) prior to the initiation of the process and n = 122 cases (109 patients) thereafter. Primary outcome measures included: mortality at 30 days and 1 year; post-operative neurologic deficit, and surgical site infections (SSI). Secondary outcome measures included: instrument failure in 1 year; readmission in 30 days; return to OR in 90 days. The study populations were matched by age and gender. Patients passing the Multi-D conference had higher BMI. Implementation of the Multi-D conference reduced mortality at 30 days (2 vs 0, p = 0.17) and at 1 year (4 vs 0, p = 0.04), as well as reduced post-operative neurologic deficit (2 vs 0, p = 0.17). The rate of SSI remained unchanged. All other secondary outcome measures also remained unchanged. Implementation of a Multi-D conference led to a significant reduction in mortality at 1 year, and is an important safety process to reduce serious complications after non-idiopathic scoliosis surgery. Level III.

The purpose of the present study was to validate a new spinal sagittal classification. We retrospectively included 105 consecutive AIS patients who underwent posterior spinal fusion. Preoperative long-standing EOS radiographs were available on all patients. Patients were classified according to the four suggested sagittal patterns: type 1, 2a, 2b or 3. Several predetermined sagittal parameters were compared between the groups. The mean preoperative Cobb angle was 64° ± 12°, and 73% of the patients were female. Of 105 patients, 51 were type 1, 14 were type 2a, one was type 2b and 39 were type 3. The distribution of the four sagittal patterns was significantly different compared with the original publication (p

Major ventral hernia surgeries are commonly performed. Despite guideline recommendations for chemo-thromboprophylaxis in the perioperative period, the optimal timing for its initiation is unknown. We characterized the variability in perioperative chemoprophylaxis in elective major ventral hernia surgery and determine whether timing of chemoprophylaxis affects bleeding and symptomatic venous thromboembolism.Retrospective analysis of all elective major ventral hernia surgery undertaken between January 1, 2014, and December 31, 2019, at 14 hospitals across Australia. Major bleeding was defined as the need for blood transfusion, reoperation, or20 g/L fall in hemoglobin. Clinical venous thromboembolism was defined as imaging-proven symptomatic disease30 days postsurgery. Propensity score matched analysis was used to validate primary findings.In the study, 3,384 hernia repairs were analyzed. Chemoprophylaxis was administered early (before skin closure), postoperatively, or not given in 856 (25.3%), 1,701 (50.3%), and 827 (24.4%) patients, respectively. This varied between surgeons, trainees, and institutions. Clinical venous thromboembolism occurred in 6 (0.2%) patients and was unrelated to chemoprophylaxis timing. 134 (4.0%) patients had postoperative bleeding, with 67 (50%) major bleeds, requiring surgical control in 41 (30.6%) cases. Bleeding extended duration of stay (mean [standard deviation], 7.0 (13.9) vs 2.6 (4.7) days, P.001). Notably, compared with postoperative (odds ratio 1.98; 95% confidence interval, 1.36-2.88; P.001) and no (odds ratio 2.83; 95% confidence interval, 1.70-4.89; P.001) chemoprophylaxis, early initiation significantly increased bleeding risk and independently predicted its occurrence.The incidence of clinical venous thromboembolism after elective major ventral hernia repair is low. Variability in perioperative thromboprophylaxis is high. Early chemoprophylaxis increases bleeding risk without appreciable additional protection from venous thromboembolism.

Patients with scleroderma often suffer from dysphagia and gastroesophageal reflux disease (GERD). Partial fundoplication is a validated anti-reflux procedure for GERD but may worsen dysphagia in scleroderma patients. Its utility in these patients is unknown. Here, we evaluate the efficacy and acceptability of partial fundoplication for the treatment of medically refractory GERD in patients with scleroderma.Analysis of a prospectively maintained database of patients who underwent fundoplication across 14 hospitals between 1991 and 2019. Perioperative outcomes, reintervention rates, heartburn, dysphagia, and patient satisfaction were assessed at 3 months, 1- and 3-years post-surgery.A total of 17 patients with scleroderma were propensity score matched to 526 non-scleroderma controls. All underwent a partial fundoplication. Perioperative outcomes including complication rate, length of stay, and need for reoperation were similar between the two groups. Compared to baseline, both groups reported significantly improved heartburn at 3 months, 1- and 3-years following partial fundoplication. Surgery was equally effective at controlling heartburn across all follow-up timepoints in patients with or without scleroderma. Dysphagia to solids was more common in patients with scleroderma than controls at 3-months post-surgery, but was not significantly different to controls at 1- and 3-year follow-up. Satisfaction scores were high and comparable between both groups across all postoperative timepoints, with 100% of patients with scleroderma reporting that their initial choice to undergo surgery was correct.Partial fundoplication controls reflux and is associated with a transient period of dysphagia to solids in patients with scleroderma. This approach is safe, effective and acceptable for patients with scleroderma and medically refractory GERD.

The incidence of and associated risk factors for implant removal following the plate-and-screw fixation of metacarpal shaft fractures have not been well described. The primary objective of our study was to identify implant-related radiographic parameters associated with implant removal in patients treated with the plate-and-screw fixation of isolated, displaced metacarpal fractures at 2 years of follow-up. The secondary objective of our study was to identify patient-related factors associated with implant removal.A retrospective study of all patients who underwent open treatment of a metacarpal fracture with a plate-and-screw construct from January 1, 2000, to April 30, 2019, at 2 level-1 trauma centers was conducted. After the application of exclusion criteria, we identified 138 patients with a single isolated metacarpal fracture of a nonthumb digit treated with open reduction and internal fixation using a plate-and-screw construct. Our study endpoint was the removal of the plate-and-screw construct or a minimum of 2 years of follow-up without the removal of the hardware. Twenty-three patients achieved our study endpoint as determined using their electronic medical records, and 58 additional patients were reached via telephone to confirm their implant removal status. A bivariate analysis was used to screen for factors associated with implant removal, and variables significant in the bivariate screen were included in a multivariable stepwise logistic regression model.Twenty-three out of 81 patients (28%) in our final cohort underwent implant removal by the final follow-up visit. In the logistic regression analysis, the distance between the plate and metacarpophalangeal joint, the distance between the plate and carpometacarpal joint, and active smoking were independently associated with implant removal.The proximity of metacarpal plates to adjacent joints is associated with subsequent implant removal. Patients may be counseled about the higher risk of implant removal when periarticular metacarpal plating is performed.Prognosis IV.

Surgery is the only effective treatment strategy for a symptomatic pharyngeal pouch. However, octo- and nonagenarians are often denied referral to a surgeon because of perceived increased risks. Here, we compare the outcomes of pharyngeal pouch surgery in octo- and nonagenarians with patients under 80 years-of-age and determine the factors which predict post-operative complications and improvement in swallowing.Analysis of a prospectively maintained database of patients who underwent pharyngeal pouch surgery across seven hospitals over 15 years.In total, 113 patients (≥80 years-of-age: 27,80 years-of-age: 86) underwent endoscopic or open pharyngeal pouch surgery. Despite more comorbidities and a longer hospital stay (median: one extra day), patients ≥80 years-of-age had comparable operative time, complication profile, intensive care admission, emergency reoperation, and revisional pouch surgery as their younger counterparts. Furthermore, the severity of complications was not significantly different between the two age cohorts. No surgical mortality was recorded. Multivariate analysis demonstrated that diverticulectomy combined with cricopharyngeal myotomy independently predicted higher rates of complications (OR: 4.53, 95% CI: 1.43-14.33, p = 0.010), but also greater symptomatic improvement (OR: 4.36, 95% CI: 1.50-12.67, p = 0.007). Importantly, a greater proportion of octo- and nonagenarians experienced improved swallowing than patients 80 years-of-age (96.3% vs. 74.4%, p = 0.013). Moreover, advanced age was not predictive of post-operative complications on multivariate analysis.Pharyngeal pouch surgery in octo- and nonagenarians is safe and effective. Surgical correction in this age group alleviates symptoms and improves quality-of-life for most patients. These patients should not be denied surgery on the basis of advanced age alone.

APR-246 (eprenetapopt) is in clinical development with a focus on hematologic malignancies and is promoted as a mutant-p53 reactivation therapy. Currently, the detection of at least one

OBJECTIVE Lateral lumbar corpectomy with interbody fusion has been well described via a transpsoas approach in the lateral position, as has lumbar interbody fusion with posterior fixation in the prone position. However, no previous report has described the use of both an open posterior approach and a lateral transpsoas approach simultaneously in the prone position. Here, the authors describe their technique of performing transpsoas lumbar corpectomy in the prone position in order to have simultaneous posterior and lateral access for difficult clinical scenarios, and they report their early clinical experience. METHODS The surgical technique for simultaneous posterior and lateral transpsoas access to the lumbar spine was reviewed and described in detail. The cases of 2 patients who underwent simultaneous posterior and lateral access in the prone position for complex lumbar pathology were retrospectively reviewed. Clinical presentation, preoperative radiographs, postoperative course, and postoperative radiographs were reviewed. RESULTS The first patient presented after previous transforaminal lumbar interbody fusion that was complicated by significant subsidence of the intervertebral cage, vertebral body split fracture, rotational instability, and resulting spinal stenosis. A simultaneous posterior and lateral transpsoas approach in the prone position allowed for removal of the previous cage, lumbar corpectomy, and rigid posterior fixation with direct decompression. The second patient had a significant pathologic burst fracture secondary to a plasmacytoma with retropulsion, resulting in vertebra plana and significant canal stenosis. Simultaneous approaches allowed for complete resection of the plasmacytoma, restoration of lumbar alignment, rigid fixation, and direct posterior decompression. There were no short-term complications, and both patients had resolution of their preoperative symptoms. CONCLUSIONS Simultaneous posterior and lateral transpsoas access to the lumbar spine in the prone position is a previously unreported technique that allows a safe surgical approach to difficult clinical scenarios.

Purpose :Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusión: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals. Sin financiación 8.822 JCR(2020) Q1, 15/176 Genetics & Heredity 3.509 SJR (2020) Q1, 7/96 Genetics (clinical) No data IDR 2020 UEM

Midgut volvulus in pregnancy is rare but life-threatening, resulting in high maternal and fetal mortality. This surgical emergency commonly masquerades as symptoms of pregnancy, which together with its low incidence often leads to delay in diagnosis and definitive treatment. Here, we review the last three decades of the literature, discuss the challenges in managing this rare condition, and raise awareness among clinicians to minimise loss of life.

Midgut volvulus complicating congenital malrotation is a rare but life-threatening condition that can occur in pregnancy. We present a case of intestinal infarction resulting from midgut volvulus in a healthy 32-week pregnant woman who underwent emergency laparotomy and small bowel resection in the setting of fetal death in utero. This case highlights several challenging issues in diagnosing and managing this uncommon condition which leads to increased adverse perinatal outcomes. Prompt investigation and definitive surgical treatment are required when pregnant women present with bilious vomiting and new-onset abdominal or back pain especially beyond the first trimester.

Unfortunately, the names of the members of the Texas Children’s Hospital Spine Study Group have not been mentioned in the published article.

Two Argentinean siblings (a boy and a girl) from a nonconsanguineous family presented with hypercalcemia, hypercalciuria, hypophosphatemia, low parathyroid hormone (PTH), and nephrocalcinosis.The goal of this study was to identify genetic causes of the clinical findings in the two siblings.Whole exome sequencing was performed to identify disease-causing mutations in the youngest sibling, and a candidate variant was screened in other family members by Sanger sequencing. In vitro experiments were conducted to determine the effects of the mutation that was identified.Affected siblings (2 y.o. female and 10 y.o male) and their parents were included in the study. Informed consent was obtained for genetic studies.A novel homozygous mutation in the gene encoding the renal sodium-dependent phosphate transporter SLC34A1 was identified in both siblings (c.1484GA, p.Arg495His). In vitro studies showed that the p.Arg495His mutation resulted in decreased phosphate uptake when compared to wild-type SLC34A1.The homozygous GA transition that results in the substitution of histidine for arginine at position 495 of the renal sodium-dependent phosphate transporter, SLC34A1, is involved in disease pathogenesis in these patients. Our report of the second family with two mutated SLC34A1 alleles expands the known phenotype of this rare condition.

Shohat-type spondyloepimetaphyseal dysplasia (SEMD) is a skeletal dysplasia that affects cartilage development. Similar skeletal disorders, such as spondyloepiphyseal dysplasias, are linked to mutations in type II collagen (COL2A1), but the causative gene in SEMD is not known. Here, we have performed whole-exome sequencing to identify a recurrent homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK domain containing 1 (DDRGK1) in 4 families affected by SEMD. In zebrafish, ddrgk1 deficiency disrupted craniofacial cartilage development and led to decreased levels of the chondrogenic master transcription factor sox9 and its downstream target, col2a1. Overexpression of sox9 rescued the zebrafish chondrogenic and craniofacial phenotype generated by ddrgk1 knockdown, thus identifying DDRGK1 as a regulator of SOX9. Consistent with these results, Ddrgk1-/- mice displayed delayed limb bud chondrogenic condensation, decreased SOX9 protein expression and Col2a1 transcript levels, and increased apoptosis. Furthermore, we determined that DDRGK1 can directly bind to SOX9 to inhibit its ubiquitination and proteasomal degradation. Taken together, these data indicate that loss of DDRGK1 decreases SOX9 expression and causes a human skeletal dysplasia, identifying a mechanism that regulates chondrogenesis via modulation of SOX9 ubiquitination.

The advent of multi-omic profiling of tumors, together with the increasing affordability of high-throughput drug screening programs, has helped usher in a new era of molecular targeted therapies for many solid malignancies. However, there has been limited success in esophageal adenocarcinoma. Until recently, preclinical drug development for this cancer has been largely limited to a small number of cell line models. Now, the increasing availability of patient-derived xenografts and novel metastatic models are helping to bridge the gap between scientific discovery and patient care. These platforms are valuable adjuncts for drug testing. Nevertheless, further work is required to develop systems that model the tumor microenvironment, including cancer cell interactions with the immune system, which will be particularly relevant for the translation of novel immunotherapies for esophageal adenocarcinoma.

Li–anode protective layers were fabricated using layer-by-layer (LBL) assembly. The simple deposition on a polymer support membrane of an ionic conductive polymer and graphene oxide (GO) resulted in high ionic conductivity, controlled electrolyte permeability, and high-Li-transfer number. The uniformly coated LbL protective layer suppressed Li dendritic growth on the Li surface and improved Li electrode cyclability. This makes it possible to use Li metal for rechargeable Li batteries.