Hyperkinetic Biliary Dyskinesia: An Underrecognized Problem With Good Surgical Outcomes After Cholecystectomy.

Introduction While surgical indications for symptomatic cholelithiasis and biliary hypokinesia are clear, hyperkinetic biliary dyskinesia (HBD) is an underrecognized condition with poorly defined symptomology and management guidelines. HBD is typically defined as a gallbladder ejection fraction (EF) ≥ 80% on a hepatobiliary iminodiacetic acid (HIDA) scan. We aimed to identify the prevalence and radiographic reporting of HBD, physician referral patterns, and clinical outcomes following cholecystectomy. Methods  A retrospective cohort study of patients with HIDA scans completed over 21 years at our tertiary care hospital was performed. Demographics, symptomatology, referral patterns, and operative data were collected. HBD was defined as HIDA EF ≥80%. Patients with HBD who underwent cholecystectomy were analyzed. ANOVA and chi-square tests were used to compare variables among patients with or without symptom improvement using Statistical Product and Service Solutions (SPSS; IBM SPSS Statistics for Windows, Armonk, NY). Results Of 1,997 patients (73% female, mean age 51.7 years) who had HIDA scans with reported EF, 730 (36.6%) had an EF≥80%. Only 13.7% of HIDA scans with EF≥80% were reported as hyperkinetic, and the rest are "normal". Cholecystectomy was performed in 57 (7.8%) patients with EF≥80%, most being elective (89.5%) and all minimally invasive. Primary care physicians (PCPs) referred most elective cases to surgery (61.4%). The median time from HIDA to cholecystectomy was 146 days. Chronic cholecystitis was common in pathology (82.5%), while 38.6% had cholelithiasis. Overall, 53 patients (93.0%) reported symptom improvement at a median follow-up of 17.0 days. Patients without improvement had a higher prevalence of chronic gastrointestinal conditions (p<0.05), but not significantly more cholelithiasis, cholecystitis, time to surgery, or elective surgery status. Conclusions HBD is common but often underdiagnosed and thus likely underrecognized by treating physicians. Most HBD patients benefit from cholecystectomy, regardless of cholelithiasis. Patients with persistent symptoms after cholecystectomy may have confounding gastrointestinal diagnoses. Increased awareness among radiologists, referring PCPs, gastroenterologists, and surgeons about HBD and postoperative outcomes is needed to ensure that HBD is adequately treated.

Eastern Association for the Surgery of Trauma (EAST) vs Western Trauma Association (WTA): How a Level 1 Trauma Center Splits the Difference in Resuscitative Thoracotomy.

Background Resuscitative thoracotomy (RT) is performed in severe trauma cases as a final lifesaving effort. Prominent, yet differing, practice management guidelines exist from Eastern Association for the Surgery of Trauma (EAST) and Western Trauma Association (WTA). This study evaluates all RTs performed from 2012 to 2019 at an urban Level 1 trauma center for management guideline indication and subsequent outcomes. Methods Our trauma registry was queried to identify RT cases from 2012 to 2019. Data was collected on patient demographics, prehospital presentation, cardiopulmonary resuscitation (CPR) requirements, and resuscitation provided. Survival to the operating room, intensive care unit, and overall were recorded. Information was compared with regard to EAST and WTA criteria. Results Eighty-seven patients who underwent RTs were included. WTA guidelines were met in 78/87 (89.7%) of cases, comparatively EAST guidelines were met in every case. Within the EAST criteria, conditional and strong recommendations were met in 70/87 (80.4%) and 17/87 (19.5%) of cases, respectively. In nine cases (10.3%) indications were discordant, each meeting conditional indication by EAST and no indication by WTA. All patients that survived to the operating room (OR), ICU admission, and overall met EAST criteria. Conclusion All RTs performed at our Level 1 trauma center met indications provided by EAST criteria. WTA guidelines were not applicable in nine salvaging encounters due to the protracted duration of CPR before proceeding to RT. Furthermore, more patients that survived to OR and ICU admission met EAST guidelines suggesting an improved potential for patient survivability. As increased data is derived, management guidelines will likely be re-established for optimized patient outcomes.

Ultra-clean pure shift NMR with optimal water suppression for analysis of aqueous pharmaceutical samples.

Pure shift NMR experiments greatly enhance spectral resolution by collapsing multiplet structures into singlets and, with water suppression, can be used for aqueous samples. Here, we combine ultra-clean pure-shift NMR (SAPPHIRE) with two different internally encoded water suppression schemes to achieve optimal performance for small molecule and macrocyclic peptide pharmaceuticals in water and acetonitrile-water mixtures.

Coronary artery bypass grafting in octogenarians: an Australian experience.

BACKGROUND: The aims of this study were to describe early and mid-term morbidity and mortality in octogenarian patients undergoing CABG, to determine if outcomes are comparable to younger patients undergoing the same procedure. METHODS: We conducted a retrospective analysis of the first 901 patients who underwent cardiac surgery at a large newly established tertiary hospital in Western Australia from February 2015 to September 2019. Inclusion criteria involved all patients undergoing coronary artery bypass grafting. Exclusion criteria included patients who underwent concomitant valve or aortic procedure. RESULTS: From a cohort of 901 patients, 37 octogenarian patients underwent CABG. Octogenarian patients had a higher rate of post-operative transfusion 35.1% versus 21.4% (P = 0.048), a higher rate of post-op acute kidney injury 40.5% versus 17.2% (P < 0.0001), a higher rate of post-operative atrial arrythmia requiring treatment 40.5% versus 22.5% (P = 0.011) and higher rate of return to theatre (13.5% versus 4.7%, P = 0.018), with bleeding/tamponade being the most likely reason (10.8% versus 2.7%). Octogenarian patients had a longer post-operative length of stay (LOS) with a median LOS of 10 versus 7 days (P < 0.0001). There was no increase in hospital readmission rate, in-hospital mortality or 1 year mortality in octogenarian patients. 24-month and 36-month survivals were 95.2% and 89.6% in octogenarians and 95.3% and 91.5% in the younger group. CONCLUSIONS: Despite an increase in post-operative morbidity and LOS, there was no difference in hospital readmission, in-hospital mortality or 1 year mortality in octogenarian patients who underwent CABG. CABG is safe and remains an important management option for these patients.

Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.

Pathogenic heterozygous loss of function variants in CTNNB1 are associated with CTNNB1 neurodevelopmental disorder. We report the clinical phenotype of individuals with CTNNB1 neurodevelopmental disorder using both caregiver-reported data (medical history, adaptive function, quality of life, and behavior issues) and in-person clinical assessments (neurological, motor, and cognitive function) in 32 individuals with likely pathogenic or pathogenic CTNNB1 variants. Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord. Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy. Half of individuals walked without an assistive device. The mean Gross Motor Functional Measure-66 score was 56.6 (SD = 14.8). Average time to complete Nine-Hole Peg Test was slower than norms. Mean general conceptual ability composite scores from Differential Ability Scales Second Edition were very low (M = 58.3, SD = 11.3). Fifty-five percent of individuals had low adaptive functioning based on the Vineland Adaptive Behavioral Scales. Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges. The mean overall Quality of Life Inventory-Disability score was 81.7 (SD = 11.9). These data provide a detailed characterization of clinical features in individuals with CTNNB1 neurodevelopmental disorder.

Barriers to Healthcare for Latinx Autistic Children and Adolescents.

PURPOSE: To understand the ways in which autistic Latinx children experience disparities in diagnosis, healthcare, and receipt of specialty services. METHODS: 417 individuals who identified as Latinx caregivers of autistic children who were members of the same integrated healthcare system in Northern California were surveyed. Responses were analyzed using the child's insurance coverage (Government or Commercial) and caregiver's primary language (Spanish or English). RESULTS: Compared to the commercially-insured, government-insured participants accessed several services at a higher rate and were less likely to cite the high cost of co-pays as a barrier. CONCLUSION: There were no significant differences in service access by language status, but Spanish speakers were more likely to cite health literacy as a barrier to receiving care.

Metachronous colorectal cancer metastasis: Who, what, when and what to do about it.

Metachronous colorectal cancer (CRC) metastasis occurs due to micrometastatic disease, in up to 23% of patients who have undergone curative-intent treatment. Metachronous metastasis tends to occur within 2 years of initial treatment. Diagnosis relies on posttreatment surveillance strategies. Care for patients with metachronous CRC metastasis is complex and requires careful multidisciplinary consideration. Those with isolated and technically resectable diseases are recommended to undergo metastasectomy with adjunct chemotherapy, however, survival, even after curative-intent resection, is poor.

Adjuvant chemotherapy improves survival amongst octogenarians following resection of colorectal adenocarcinoma.

BACKGROUND: The Australian population is ageing, with an increasing number of patients diagnosed with colorectal cancer in their eighth decade. This group represents a challenging cohort to deliver multidisciplinary care, with increased morbidity and mortality related to surgical and oncological therapies. This project aimed to compare surgical and oncological outcomes in octogenarian and non-octogenarian patients with colorectal cancer. METHODS: A matched case-control retrospective review of a prospectively maintained institutional database of colorectal cancer patients treated between 2005 and 2021 was conducted. Patient demographics, treatment details, peri-operative complications, and long-term survival were reported. The primary outcome, cancer-specific survival, was investigated using time-to-event analysis and interrogated with multivariate regression. RESULTS: There were 747 patients included in the study. There was no difference in five-year cancer-specific survival and recurrence-free survival between cohorts. Multivariate analysis for octogenarians confirmed a significant hazard signal associated with worsening cancer stage and a survival benefit associated with the administration of adjuvant therapy. However, we noted that stage-matched octogenarian patients received less adjuvant treatment compared to non-octogenarians. CONCLUSION: Octogenarians undergoing treatment for colorectal cancer have similar cancer-specific survival and recurrence-free survival to non-octogenarians. Our study demonstrates a survival benefit when adjuvant therapy is provided to octogenarians, despite only half of this cohort receiving therapy compared to their younger peers. Further research into adjuvant therapy with surgical resection for CRC in older Australians is required.

Perforated pre-pyloric ulcer in the gastric remnant over a decade after Roux-en-Y gastric bypass: A case report.

INTRODUCTION AND IMPORTANCE: Roux-en-Y gastric bypass (RYGB) is one of the two most common weight loss surgeries. Surgical emergencies after gastric bypass can be complicated by devastating events that are often difficult to diagnose and manage. Perforated ulcers are a very rare complication after a RYGB. CASE PRESENTATION: In this report, the diagnosis and surgical management of a 59-year-old immunosuppressed male patient who presented with late perforation of a pre-pyloric ulcer in the gastric remnant after RYGB is presented. The perforation was repaired transversely in a running horizontal mattress fashion and patched with a piece of well-vascularized omentum. CLINICAL DISCUSSION: This case illustrates the potential for gastric remnant ulceration, even a decade after RYGB. A high degree of suspicion for the diagnosis of perforated remnant stomach is required, especially in the absence of pneumoperitoneum and free fluid. Patient-specific factors, such as immunosuppression in this case, may blunt normal physiologic response. CONCLUSION: Considering the location of the ulcer in the pre-pyloric area, we caution that the typical paradigm of marginal ulceration of the gastro-jejunal anastomosis does not always apply when evaluating gastric complications after RYGB.

Optimising multiplex immunofluorescence staining for characterising the tumour immune micro-environment.

Exploring the tumour microenvironment provides insight into the unique interaction between the host and tumour. Ultimately, its study improves understanding of how an individual mounts and achieves an anti-tumour immune response. In the context of colorectal cancer, immune biomarkers within the tumour microenvironment outperform traditional histopathological staging in predicting disease recurrence. Multiplex immunofluorescence enables simultaneous assessment of multiple markers to provide a highly accurate classification of immune cells and their spatial characterisation relative to tumour tissue. Further, automated slide staining provides staining consistency and reduces labour costs. Image acquisition using a non-spectral scanner allows more researchers to utilise multiplexed immunofluorescence for translational research. Herein we describe the optimisation process of conducting automated staining using a five-colour, tyramide signal amplification-based multiplex immunofluorescence panel. Using antibodies against CD3, CD8, CD103 and cytokeratin, the panel characterises T cell populations within human colorectal adenocarcinoma tissue. We provide an overview of primary antibody titration and the development of tyramide signal amplification immunofluorescence monoplex assays. We detail the processes of antibody stripping and the role of exogenous horseradish peroxidase inhibition to facilitate multiplexing. An account of determining the staining sequence and fluorophore assignment is provided. We describe image acquisition using a standard fluorescence microscope slide scanner and the management of spectral crosstalk using this system. Finally, we briefly document the digital image analysis required to characterise cells and determine their spatial distribution within the colorectal tumour microenvironment.

Combination of Lactate and Base Deficit Levels at Admission to Predict Mortality in Blunt Trauma Patients.

INTRODUCTION: Elevated lactate levels are associated with increased mortality in both trauma and non-trauma patients. The relation between base deficit (BD) and mortality is less clear. Traumatologists debate the utility of elevated lactate (EL) versus BD in predicting mortality. We hypothesized that EL (2mmol/L to 5mmol/L) and BD (≤-2mmol/L) in combination could predict mortality in blunt trauma patients.  Methods: This is a retrospective analysis of the trauma registry from 2012 to 2021 at a level 1 trauma center. Blunt trauma patients with admission lactate and BD values were included in the analysis. Exclusion criteria were age <18, penetrating trauma, unknown mortality, and unknown lactate or BD. Logistics regression of the total 5153 charts showed 93% of the patients presented with lactate levels <5mmol/L, therefore patients with lactate >5mmol/L were excluded as outliers. The primary outcome was mortality. RESULTS: A total of 4794 patients (151 non-survivors) were included in the analysis. Non-survivors had higher rates of EL + BD (35.8% vs. 14.4%, p <0.001). When comparing survivors and non-survivors, EL + BD (OR 5.69), age >65 (5.17), injury severity score (ISS) >25 (8.87), Glasgow coma scale <8 (8.51), systolic blood pressure (SBP) <90 (4.2), and ICU admission (2.61) were significant predictors of mortality. Other than GCS <8 and ISS >25, EL + BD had the highest odds of predicting mortality. CONCLUSION: Elevated lactate + BD on admission in combination represents a 5.6-fold increase in mortality in blunt trauma patients and can be used to predict a patient's outcome on admission. This combination variable provides an additional early data point to identify patients at elevated risk of mortality at the moment of admission.

Perineal fibroadenoma masquerading as a soft-tissue sarcoma: a case report.

We report a case of a perineal fibroadenoma initially diagnosed on ultrasound and magnetic resonance imaging as a soft tissue sarcoma in a 35-year-old female. Following wide local excision, histopathology revealed the lesion as a vulval fibroadenoma. We provide an overview of the literature and highlight the need to consider fibroadenoma, arising from ectopic breast tissue, as an important differential for general surgeons and gynaecologists caring for patients with perineal masses.

Synthesis of a Complex and Highly Potent PCSK9 Inhibitor.

The solution-based gram-scale synthesis of complex and highly potent proprotein convertase subtilisin-like/kexin type 9 (PCSK9) inhibitor 1 is presented. Construction of Northern fragment 2, followed by stepwise installation of Eastern 3, Southern 4, and Western 5 fragments, provided macrocyclic precursor 19. This intermediate was cross-linked via an intramolecular azide-alkyne click reaction, which preceded macrolactamization to afford the core framework of compound 1. Finally, coupling with poly(ethylene glycol) side-chain-based 6 gave the PCSK9 inhibitor 1.

Unequivocal identification of two-bond heteronuclear correlations in natural products at nanomole scale by i-HMBC.

HMBC is an essential NMR experiment for determining multiple bond heteronuclear correlations in small to medium-sized organic molecules, including natural products, yet its major limitation is the inability to differentiate two-bond from longer-range correlations. There have been several attempts to address this issue, but all reported approaches suffer various drawbacks, such as restricted utility and poor sensitivity. Here we present a sensitive and universal methodology to identify two-bond HMBC correlations using isotope shifts, referred to as i-HMBC (isotope shift detection HMBC). Experimental utility was demonstrated at the sub-milligram / nanomole scale with only a few hours of acquisition time required for structure elucidation of several complex proton-deficient natural products, which could not be fully elucidated by conventional 2D NMR experiments. Because i-HMBC overcomes the key limitation of HMBC without significant reduction in sensitivity or performance, i-HMBC can be used as a complement to HMBC when unambiguous identifications of two-bond correlations are needed.

DELTA50: A Highly Accurate Database of Experimental 1H and 13C NMR Chemical Shifts Applied to DFT Benchmarking.

Density functional theory (DFT) benchmark studies of 1H and 13C NMR chemical shifts often yield differing conclusions, likely due to non-optimal test molecules and non-standardized data acquisition. To address this issue, we carefully selected and measured 1H and 13C NMR chemical shifts for 50 structurally diverse small organic molecules containing atoms from only the first two rows of the periodic table. Our NMR dataset, DELTA50, was used to calculate linear scaling factors and to evaluate the accuracy of 73 density functionals, 40 basis sets, 3 solvent models, and 3 gauge-referencing schemes. The best performing DFT methodologies for 1H and 13C NMR chemical shift predictions were WP04/6-311++G(2d,p) and ωB97X-D/def2-SVP, respectively, when combined with the polarizable continuum solvent model (PCM) and gauge-independent atomic orbital (GIAO) method. Geometries should be optimized at the B3LYP-D3/6-311G(d,p) level including the PCM solvent model for the best accuracy. Predictions of 20 organic compounds and natural products from a separate probe set had root-mean-square deviations (RMSD) of 0.07 to 0.19 for 1H and 0.5 to 2.9 for 13C. Maximum deviations were less than 0.5 and 6.5 ppm for 1H and 13C, respectively.

Locally performed postoperative circulating tumour DNA testing performed during routine clinical care to predict recurrence of colorectal cancer.

BACKGROUND: Identifying patients at high risk for colorectal cancer recurrence is essential for improving prognosis. In the postoperative period, circulating tumour DNA (ctDNA) has been demonstrated as a significant prognostic indicator of recurrence. These results have been obtained under the strict rigours of clinical trials, but not validated in a real-world setting using in-house testing. We report the outcomes of locally performed postoperative ctDNA testing conducted during routine clinical care and the association with the recurrence of colorectal cancer. METHODS: We recruited 36 consecutive patients with newly diagnosed colorectal cancer between 2018 and 2020. Postoperative plasma samples were collected at the first outpatient review following resection. Tumour-informed ctDNA analysis was performed using droplet digital polymerase chain reaction or targeted next-generation sequencing. RESULTS: At the time of surgery, there were 24 patients (66.7%) with localized cancer, nine (25%) with nodal spread, and three (8.3%) with metastatic disease. The median time from surgery to plasma sample donation was 22 days (IQR 20-28 days). At least one somatic mutation was identified in primary tumour tissue for 28 (77.8%) patients. Postoperative ctDNA was detected in five patients (13.9%). The median duration of follow-up was 32.0 months (IQR 27.2-38.1 months). Two patients (5.56%) developed metastatic recurrence. However, neither had detectable postoperative ctDNA. There were no instances of loco-regional recurrence. CONCLUSION: Analysis of postoperative ctDNA testing can be performed locally, however this study did not reproduce the adverse association between detectable postoperative ctDNA and the development of colorectal cancer recurrence seen in clinical trials.

More than Means to an End: Assessing Surgical Provider Familiarity with Palliative Care.

BACKGROUND: As palliative medicine concepts emerge as essential surgical education, there has been a resulting spike in surgical palliative care research. Historic surgical dogma viewed mortality and comfort-focused care as a failure of the providers' endurance, knowledge base, or technical skill. Therefore, many providers avoided consultation to a palliative medicine service until it became evident a patient could not survive or was actively dying. As the need for surgical palliative care grows, the identification of deficits in surgical providers' understanding of the scope of palliative medicine is necessary to direct further training and development efforts. METHOD: A ten-question survey was emailed to all residents, physician assistants, nurse practitioners, and attending physicians in the general surgery and subspecialty surgical departments within the Einstein Healthcare Network. RESULTS: 30 non-trainees (attending surgeons, nurse practitioners, and physician assistants) and 26 trainees (PGY-1 to PGY-5) completed the survey. Less than half of participants reported training in conversations regarding withdrawal of life-prolonging treatments in the setting of expected poor outcomes, 55% reported receiving training in pain management, and 64% reported receiving training in delivery of bad news. 54% report being involved in five or more end-of-life discussions in the last year with trainees reporting fewer end-of-life discussions than non-trainees; 67% of trainees reported zero to four discussions while 23% of non-trainees reported over twenty discussions (P = .009). CONCLUSIONS: Despite many participants training in intensive care settings, providers lack the training to carry out major discussions regarding life-limiting illness, goals of care, and end-of-life independently.

Quantitative nuclear magnetic resonance of chloride by an accurate internal standard approach.

Chloride is the most common counterion used to improve aqueous solubility and enhance stability of small molecule active pharmaceutical ingredients. While several analytical techniques, such as titration, HPLC with charged aerosol detection, and ion chromatography, are currently utilized to assay the level of chloride, they have notable limitations, and these instruments may not be readily available. Here, we present a generally applicable 35 Cl solution NMR method to assay the level of chloride in pharmaceutical compounds. The method uses KClO4 as an internal standard for improved accuracy in comparison with external standard methods, and it was found to be robust, linear over three orders of magnitude, precise (<3% RSD), and accurate (<0.5% absolute error).

Laparoscopic Cholecystectomy in the Time of Coronavirus: A Level-1 Trauma Center's Experience.

INTRODUCTION: Laparoscopic cholecystectomy (LC), one of the most common surgical procedures performed in the U.S., offers a window into the effects of the COVID-19 pandemic on routine surgical care. The purpose of our study was to analyze the effects of the COVID-19 pandemic at a Level-1 trauma center on the performance rate of non-elective LC over time. METHODS: A retrospective chart review from July 2019 to December 2020 identified all non-elective LC cases performed at a level-1 trauma center. Patients were categorized into 4 temporal phases along the course of the pandemic based on statewide incidence data on COVID-19: pre-pandemic, peak 1, recovery, and peak 2. We compared the phases based on demographic information and outcomes. RESULTS: In total, 176 patients were reviewed. The performance rate in cases/day varied as follows: pre-pandemic .61, 1st peak .34, recovery .44, and 2nd peak .53. The complication rate was highest in the 2nd peak (16%) (P < .05). Compared to the pre-pandemic period, the intra-pandemic period had a higher incidence of complicated gallbladder disease (P < .05). In the non-elderly subgroup, complicated gallbladder disease was significantly more prevalent in the intra-pandemic period compared to the pre-pandemic period (25% vs 10%, P < .05). CONCLUSIONS: Our data suggests a learning curve throughout the course of the pandemic, reflecting a stepwise increase in the performance rate of LC. The higher incidence of complicated gallbladder disease in the intra-pandemic period may imply patient hesitancy to seek routine surgical care, especially among younger patients.