Rates and risk factors for anastomotic leak following blunt trauma-associated bucket handle intestinal injuries: a multicenter study.

Objectives: The risk factors for anastomotic leak (AL) after resection and primary anastomosis for traumatic bucket handle injury (BHI) have not been previously defined. This multicenter study was conducted to address this knowledge gap. Methods: This is a multicenter retrospective study on small intestine and colonic BHIs from blunt trauma between 2010 and 2021. Baseline patient characteristics, risk factors, presence of shock and transfusion, operative details, and clinical outcomes were compared using R. Results: Data on 395 subjects were submitted by 12 trauma centers, of whom 33 (8.1%) patients developed AL. Baseline details were similar, except for a higher proportion of patients in the AL group who had medical comorbidities such as diabetes, hypertension, and obesity (60.6% vs. 37.3%, p=0.015). AL had higher rates of surgical site infections (13.4% vs. 5.3%, p=0.004) and organ space infections (65.2% vs. 11.7%, p<0.001), along with higher readmission and reoperation rates (48.4% vs. 9.1%, p<0.001, and 39.4% vs. 11.6%, p<0.001, respectively). There was no difference in intensive care unit length of stay or mortality (p>0.05). More patients with AL were discharged with an ostomy (69.7% vs. 7.3%, p<0.001), and the mean duration until ostomy reversal was 5.85±3 months (range 2-12.4 months). The risk of AL significantly increased when the initial operation was a damage control procedure, after adjusting for age, sex, injury severity, presence of one or more comorbidities, shock, transfusion of >6 units of packed red blood cells, and site of injury (adjusted RR=2.32 (1.13, 5.17)), none of which were independent risk factors in themselves. Conclusion: Damage control surgery performed as the initial operation appears to double the risk of AL after intestinal BHI, even after controlling for other markers of injury severity. Level of evidence: III.

The Impact of Neighborhood Socioeconomic Disadvantage on Operative Outcomes after Single-Level Lumbar Fusion.

INTRODUCTION: The relationship between socioeconomic status and neurosurgical outcomes has been investigated with respect to insurance status or median household income, but few studies have considered more comprehensive measures of socioeconomic status. This study examines the relationship between Area Deprivation Index (ADI), a comprehensive measure of neighborhood socioeconomic disadvantage, and short-term postoperative outcomes after lumbar fusion surgery. METHODS: 1861 adult patients undergoing single-level, posterior-only lumbar fusion at a single, multihospital academic medical center were retrospectively enrolled. An ADI matching protocol was used to identify each patient's 9-digit zip code and the zip code-associated ADI data. Primary outcomes included 30- and 90-day readmission, emergency department visits, reoperation, and surgical complication. Coarsened exact matching was used to match patients on key demographic and baseline characteristics known to independently affect neurosurgical outcomes. Odds ratios (ORs) were computed to compare patients in the top 10% of ADI versus lowest 40% of ADI. RESULTS: After matching (n = 212), patients in the highest 10% of ADI (compared to the lowest 40% of ADI) had significantly increased odds of 30- and 90-day readmission (OR = 5.00, P < 0.001 and OR = 4.50, P < 0.001), ED visits (OR = 3.00, P = 0.027 and OR = 2.88, P = 0.007), and reoperation (OR = 4.50, P = 0.039 and OR = 5.50, P = 0.013). There was no significant association with surgical complication (OR = 0.50, P = 0.63). CONCLUSIONS: Among otherwise similar patients, neighborhood socioeconomic disadvantage (measured by ADI) was associated with worse short-term outcomes after single-level, posterior-only lumbar fusion. There was no significant association between ADI and surgical complications, suggesting that perioperative complications do not explain the socioeconomic disparities in outcomes.

Emergency department thoracotomy in children: A Pediatric Trauma Society, Western Trauma Association, and Eastern Association for the Surgery of Trauma systematic review and practice management guideline.

BACKGROUND: The role of emergency department resuscitative thoracotomy (EDT) in traumatically injured children has not been elucidated. We aimed to perform a systematic review and create evidence-based guidelines to answer the following PICO (population, intervention, comparator, and outcome) question: should pediatric patients who present to the emergency department pulseless (with or without signs of life [SOL]) after traumatic injuries (penetrating thoracic, penetrating abdominopelvic, or blunt) undergo EDT (vs. no EDT) to improve survival and neurologically intact survival? METHODS: Using Grading of Recommendations Assessment, Development and Evaluation methodology, a group of 12 pediatric trauma experts from the Pediatric Trauma Society, Western Trauma Association, and Eastern Association for the Surgery of Trauma assembled to perform a systematic review. A consensus conference was conducted, a database was queried, abstracts and manuscripts were reviewed, data extraction was performed, and evidence quality was determined. Evidence tables were generated, and the committee voted on guideline recommendations. RESULTS: Three hundred three articles were identified. Eleven studies met the inclusion criteria and were used for guideline creation, providing 319 pediatric patients who underwent EDT. No data were available on patients who did not undergo EDT. For each PICO, the quality of evidence was very low based on the serious risk of bias and serious or very serious imprecision. CONCLUSION: Based on low-quality data, we make the following recommendations. We conditionally recommend EDT when a child presents pulseless with SOL to the emergency department following penetrating thoracic injury, penetrating abdominopelvic injury and after blunt injury if emergency adjuncts point to a thoracic source. We conditionally recommend against EDT when a pediatric patient presents pulseless without SOL after penetrating thoracic and penetrating abdominopelvic injury. We strongly recommend against EDT in the patient without SOL after blunt injury.

Anastomotic leak rates after repair of mesenteric bucket-handle injuries: A multi-center retrospective cohort study.

BACKGROUND: Primary aim was to assess the relative risk (RR) of anastomotic leak (AL) in intestinal bucket-handle (BH) compared to non-BH injury. METHODS: Multi-center study comparing AL in BH from blunt trauma 2010-2021 compared to non-BH intestinal injuries. RR was calculated for small bowel and colonic injury using R. RESULTS: AL occurred in 20/385 (5.2%) of BH vs. 4/225 (1.8%) of non-BH small intestine injury. AL was diagnosed 11.6 ± 5.6 days from index operation in small intestine BH and 9.7 ± 4.3 days in colonic BH. Adjusted RR for AL was 2.32 [0.77-6.95] for small intestinal and 4.83 [1.47-15.89] for colonic injuries. AL increased infections, ventilator days, ICU & total length of stay, reoperation, and readmission rates, although mortality was unchanged. CONCLUSION: BH carries a significantly higher risk of AL, particularly in the colon, than other blunt intestinal injuries.

Pediatric emergency resuscitative thoracotomy: A Western Trauma Association, Pediatric Trauma Society, and Eastern Association for the Surgery of Trauma collaborative critical decisions algorithm.

LEVEL OF EVIDENCE: Literature synthesis and expert opinion, Level V.

Neurosurgeons Deliver Similar Quality Care Regardless of First Assistant Type: Resident Physician versus Nonphysician Surgical Assistant.

OBJECTIVE: There are limited data evaluating the outcomes of attending neurosurgeons with different types of first assistants. This study considers a common neurosurgical procedure (single-level, posterior-only lumbar fusion surgery) and examines whether attending surgeons deliver equal patient outcomes, regardless of the type of first assistant (resident physician vs. nonphysician surgical assistant [NPSA]), among otherwise exact-matched patients. METHODS: The authors retrospectively analyzed 3395 adult patients undergoing single-level, posterior-only lumbar fusion at a single academic medical center. Primary outcomes included readmissions, emergency department visits, reoperation, and mortality within 30 and 90 days after surgery. Secondary outcome measures included discharge disposition, length of stay, and length of surgery. Coarsened exact matching was used to match patients on key demographics and baseline characteristics known to independently affect neurosurgical outcomes. RESULTS: Among exact-matched patients (n = 1402), there was no significant difference in adverse postsurgical events (readmission, emergency department visits, reoperation, or mortality) within 30 days or 90 days of the index operation between patients who had resident physicians and those who had NPSAs as first assistants. Patients who had resident physicians as first assistants demonstrated a longer length of stay (mean: 100.0 vs. 87.4 hours, P < 0.001) and a shorter duration of surgery (mean: 187.4 vs. 213.8 minutes, P < 0.001). There was no significant difference between the two groups in the percentage of patients discharged home. CONCLUSIONS: For single-level posterior spinal fusion, in the setting described, there are no differences in short-term patient outcomes delivered by attending surgeons assisted by resident physicians versus NPSAs.

Evaluating the change in patterns of traumatic injury in the setting of pandemic and social distancing restrictions: An analysis of a level 1 trauma center.

BACKGROUND: Social distancing measures and quarantine during the COVID-19 pandemic have led to reported changes in traumatic injury patterns. We set to examine the effects of these restrictive guidelines in our trauma center. METHODS: This is a retrospective chart review of all patients evaluated for traumatic injuries at a Level 1 trauma center during two time periods: March-June 2020 (COVID) and March-June 2019 (Pre-COVID). RESULTS: Overall trauma volume did not differ significantly between the two time periods. Changes seen during COVID included increases in penetrating injuries (12.5% vs 6.7%, p < 0.001), particularly those due to firearms (7.5% vs 3.7%, p < 0.001). Hospital length of stay, intensive care unit length of stay, and days on the ventilator remained consistent between the two groups. Trends toward increased injuries in the home and non-accidental trauma were not statistically significant. CONCLUSION: Traumatic injury patterns have changed as a result of social distancing in both the adult and pediatric trauma populations. Analyzing the effects of social distancing on trauma can lead to a better development of preventive strategies.

Technical considerations for positioning and placement of a transperineal ultrasound probe during prostate radiotherapy.

This technical evaluation aims to provide practice 'how to' guidelines for radiation therapists (RTs) when positioning a transperineal ultrasound (TPUS) probe during prostate radiotherapy. Recommendations and practical tips will be provided for the best practice in TPUS-guided workflow to obtain optimal ultrasound images for accurate interpretation and registration of the prostate gland. This will assist the RTs in making consistent and accurate clinical decision in an ultrasound-guided radiotherapy workflow for prostate treatment. The implementation process and the associated successes and challenges will also be described to assist institutions who may be investigating the potential of implementing this system.

An Unusual Case of a Filshie Clip Presenting as a Bladder Wall Abscess 12 Years After Sterilization.

BACKGROUND There is growing evidence suggesting that Filshie clip migration is a rare but significant late complication following tubal sterilization. Although most women are asymptomatic, clip migration can result in serious morbidity such as abscess formation and be a source of sepsis years later. CASE REPORT A 51-year-old woman presented with 2-week history of worsening right flank pain with fever and chills, unresponsive to oral antibiotics. CT imaging showed a 4-cm anterior bladder wall mass with a tubal ligation clip within, initially suspicious for a tumor, with secondary infection. Cystoscopy was unremarkable and tumor markers were negative. A subsequent CT urography confirmed the finding of right adnexal abscess with ligation clip within, suggesting a diagnosis of pelvic inflammatory disease. Due to failure of conservative management, she underwent a diagnostic laparoscopy, which was then converted to an exploratory laparotomy due to dense omental adhesions. A Filshie clip was found within the bladder wall abscess and removed. An inadvertent bladder dome perforation was repaired. Pain and fever resolved after the operation and she was discharged home on post-op day 4 with an indwelling catheter. A micturating cystogram a month later showed no extravasation of contrast and the catheter was removed. CONCLUSIONS This case report highlights the importance of considering Filshie clip migration as a differential diagnosis vs. pelvic inflammatory disease in women without other risk factors and who had previously undergone tubal ligation. Women should be made aware of this potential, rare late complication and its serious morbidity, which may occur years later.

J-Aggregation of Perylene Diimides in Silica Nanocapsules for Stable Near-Infrared Photothermal Conversion.

A novel near-infrared-responsive (NIR-responsive) photothermal therapy (PTT) agent based on perylene-diimide-encapsulated (PDI-encapsulated) PEGylated silica nanocapsules (SNCs) is developed. Dicyclohexylamino-PDI (DCAPDI) with electron-donating cyclohexylamino substitutes at bay positions aggregates into J-aggregation in the core of SNCs, and their electronic coupling interactions are strengthened because of the spatial confinement of SNCs, resulting in strong NIR absorption but negligible fluorescence emission which is crucial for NIR-responsive PTT. Based on our knowledge, this is the first example of generating NIR photothermal conversion by means of molecular aggregation derived from spatial confinement. Unprecedented photostability is achieved with the DCAPDI-encapsulated SNCs in response to more than 60 runs of cyclic NIR exposure with each run exposed to the 808 nm, 1 W cm-2 laser for 10 min. It overcomes the common photodegradation problem of small organic NIR dyes under continuous high-power laser irradiation thanks to the robust molecular skeleton of PDIs and their formation of structurally stable J-aggregates in SNCs. The DCAPDI-encapsulated SNCs demonstrate low cellular cytotoxicity and excellent in vivo photothermal efficacy in tumor ablation in a tumor-bearing zebrafish model, and thus allow the practical employment of a stable photothermal agent in clinical applications.

Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice.

Acquired aplastic anemia is an autoimmune-mediated bone marrow failure syndrome. The mechanism by which such an autoimmune reaction is initiated is unknown. Whether and how the genetic lesions detected in patients cause autoimmune bone marrow failure have not yet been determined. We found that mice with spontaneous deletion of the TGFß-activated kinase-1 gene in a small subset of hematopoietic cells developed bone marrow failure which resembled the clinical manifestations of acquired aplastic anemia patients. Bone marrow failure in such mice could be reversed by depletion of CD4+ T lymphocytes or blocked by knockout of interferon-γ, suggesting a Th1-cell-mediated autoimmune mechanism. The onset and progression of bone marrow failure in such mice were significantly accelerated by the inactivation of tumor necrosis factor-α signaling. Tumor necrosis factor-α restricts autoimmune bone marrow failure by inhibiting type-1 T-cell responses and maintaining the function of myeloid-derived suppressor cells. Furthermore, we determined that necroptosis among a small subset of mutant hematopoietic cells is the cause of autoimmune bone marrow failure because such bone marrow failure can be prevented by deletion of receptor interacting protein kinase-3 Our study suggests a novel mechanism to explain the pathogenesis of autoimmune bone marrow failure.

Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent.

This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K i = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.

Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK.

TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0.8nM) and exceptional kinase selectivity. The SAR indicates a strong dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide moiety delineating the geometry for 1½ type kinase inhibitor. Molecular modeling indicates the extensive and optimal contacts, mediated through H-bonds and hydrophobic interactions, are responsible for the selectivity and potency of the inhibitors. The compounds demonstrate a strong anti-proliferative activity in a panel of human cancer cell lines (HCT116 GI50<15nM) and good rodent pharmacokinetics (oral %F 97%).

Minimal access microsurgical ligation of spinal dural arteriovenous fistula with tubular retractor.

BACKGROUND: Open surgical ligation is an effective treatment of spinal dural arteriovenous fistula (SDAVF). Until recently, the procedure would require an open laminectomy, which may potentially cause significant postoperative pain, spinal deformity, and instability due to disruptions of the spinal mechanics. Development in minimal access spine surgery provides an alternative approach that can minimize bone and soft tissue trauma. CASE DESCRIPTION: We report two patients who presented with progressive paraparesis secondary to thoracolumbar SDAVF. Minimal access microsurgical ligation was successfully performed through a tubular retractor using a paramedian muscle-splitting approach. CONCLUSION: With accurate localization of the fistulous point in each patient, only a hemilaminectomy and a small dura opening were required using the tube-assisted technique. This allows direct visualization and ligation of the fistulous point while minimizing postoperative morbidities.

The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as Anticancer Agents.

The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI50 < 0.1 µM), displayed low off-target activity (>500×), and microsomal stability (T(1/2) > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.

Prevalence and Characteristics of Chinese Patients With Duchenne and Becker Muscular Dystrophy: A Territory Wide Collaborative Study in Hong Kong.

The aim of this collaborative study on Duchenne muscular dystrophy and Becker muscular dystrophy is to determine the prevalence and to develop data on such patients as a prelude to the development of registry in Hong Kong. Information on clinical and molecular findings, and patient care, was systematically collected in 2011 and 2012 from all Pediatric Neurology Units in Hong Kong. Ninety patients with dystrophinopathy were identified, and 83% has Duchenne muscular dystrophy. The overall prevalence of dystrophinopathy in Hong Kong in 2010 is 1.03 per 10 000 males aged 0 to 24 years. Among the Duchenne group, we observed a higher percentage (40.6%) of point mutations with a lower percentage (45.3%) of exon deletions in our patients when compared with overseas studies. Although we observed similar percentage of Duchenne group received scoliosis surgery, ventilation support, and cardiac treatment when compared with other countries, the percentage (25%) of steroid use is lower.

Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.

GFP transgenic medaka (Oryzias latipes) under the inducible cyp1a promoter provide a sensitive and convenient biological indicator for the presence of TCDD and other persistent organic chemicals.

Persistent organic pollutants (POPs) are resistant to environmental degradation and can cause multitude of health problems. Cytochrome P450 1A (Cyp1a) is often up-regulated by POPs through the activation of aryl hydrocarbon receptor (AhR) pathway and is thus usually used as a biomarker for xenobiotics exposure. To develop a convenient in vivo tool to monitor xenobiotic contamination in the water, we have established GFP transgenic medaka using the inducible cyp1a promoter, Tg(cyp1a:gfp). Here we tested Tg(cyp1a:gfp) medaka at three different stages, prehatching embryos, newly hatched fry and adult with 2,3,7,8-tetrachlorodiebnzo-p-dioxin (TCDD), a dioxin. While GFP induction was observed in all three stages, newly hatched fry were the most sensitive with the lowest observed effective concentration of 0.005 nM or 16.1 ng/L. The highly sensitive organs included the kidney, liver and intestine. With high concentrations of TCDD, several other organs such as the olfactory pit, tail fin, gills, lateral line neuromast cells and blood vessels also showed GFP expression. In addition, Tg(cyp1a:gfp) medaka fry also responded to two other AhR agonists, 3-methylcholanthrene and benzo[a]pyrene, for GFP induction, but no significant GFP induction was observed towards several other chemicals tested, indicating the specificity of this transgenic line. The GFP inducibility of Tg(cyp1a:gfp) medaka at both fry and adult stages may be useful for development of high-throughput assays as well as online water monitoring system to detect xenobiotic toxicity.