A prospective evaluation of the prostate microbiome in malignant and benign tissue using transperineal biopsy.

BACKGROUND: The link between the prostate microbiome and prostate cancer remains unclear. Few studies have analyzed the microbiota of prostate tissue, and these have been limited by potential contamination by transrectal biopsy. Transperineal prostate biopsy offers an alternative and avoids fecal cross-contamination. We aim to characterize the prostate microbiome using transperineal biopsy. METHODS: Patients with clinical suspicion for prostate cancer who were to undergo transperineal prostate biopsy with magnetic resonance imaging (MRI) fusion guidance were prospectively enrolled from 2022 to 2023. Patients were excluded if they had Prostate Imaging Reporting and Data System lesions with scores ≤ 3, a history of prostate biopsy within 1 year, a history of prostate cancer, or antibiotic use within 30 days of biopsy. Tissue was collected from the MRI target lesions and nonneoplastic transitional zone. Bacteria were identified using 16S ribosomal RNA gene sequencing. RESULTS: Across the 42 patients, 76% were found to have prostate cancer. Beta diversity indices differed significantly between the perineum, voided urine, and prostate tissue. There were no beta diversity differences between cancerous or benign tissue, or between pre- and postbiopsy urines. There appear to be unique genera more abundant in cancerous versus benign tissue. There were no differences in alpha diversity indices relative to clinical findings including cancer status, grade, and risk group. CONCLUSIONS: We demonstrate a rigorous method to better characterize the prostate microbiome using transperineal biopsy and to limit contamination. These findings provide a framework for future large-scale studies of the microbiome of prostate cancer.

Linear and discrete foreign body small intestinal obstruction outcomes, complication risk factors, and single incision red rubber catheter technique success in cats.

OBJECTIVE: To compare survival and report perioperative complications in cats undergoing surgery for small intestinal (SI) linear (LFBO) and discrete (DFBO) foreign body obstructions (FBO). To report success of a red rubber catheter technique (RRCT) to remove LFBOs. STUDY DESIGN: Retrospective study. ANIMALS: Client-owned cats (n = 169). METHODS: Medical records of cats undergoing surgery for SI FBO from a veterinary teaching hospital between February 2012 and January 2023 were classified as LFBO, DFBO, or both linear and discrete FBO (BFBO). Signalment and perioperative data were collected. RESULTS: Preoperative hypoalbuminemia (LFBO: n = 1/6; DFBO: n = 5/6) and septic peritonitis (LFBO: n = 2/4; DFBO: n = 0/4; BFBO: n = 2/4) were rare. Intraoperative hypotension did not differ between LFBOs and DFBOs (p = .4756). RRCT was successful in 20/24 attempts of LFBO removal. Three cats were euthanized intraoperatively (LFBO: 1; DFBO: 1; BFBO: 1). Postoperatively, two cats (DFBO) experienced intestinal dehiscence and two cats (DFBO) died or were euthanized. Survival to discharge (p = 1.0000) and postoperative complications (p = .1386) did not differ between LFBOs and DFBOs. CONCLUSIONS: Postoperative complications and survival did not differ between cats with LFBOs and DFBOs. Intestinal dehiscence secondary to FBO in cats is rare. A RRCT can be successful in many cats with LFBOs. CLINICAL SIGNIFICANCE: Cats with LFBOs and DFBOs have similar postoperative complication rates and survival to discharge when preoperative septic peritonitis is not present. Intestinal dehiscence is rare, which is important when discussing surgical prognosis with owners. A RRCT can be considered to remove LFBOs when there is concern for multiple enterotomies.

The ball's in your court: Trends, causes, outcomes, and costs of patient transfer for pediatric testicular torsion.

BACKGROUND: The transfer of pediatric patients with testicular torsion from community hospitals to pediatric centers can be a time and resource-intensive step toward emergent surgical intervention. OBJECTIVE: We sought to describe trends of patient transfer in our state and compare clinical outcomes and health system costs between patients transferred and treated primarily at a pediatric center. STUDY DESIGN: This retrospective cohort study compared patients aged 1-18 years who presented directly to a pediatric center to those transferred for acute testicular torsion from 2018 to 2023. Exclusion criteria included age <1 year, non-urgent surgery, and admission from clinic. Patient age, BMI, Tanner stage, ASA class, insurance coverage, and presentation time were covariates. Group characteristics and times from symptom onset to initial ED presentation to surgery were compared via two-sided Student's t-tests. Clinical outcomes (orchiectomy, testicular atrophy) were compared via Fisher's exact tests. Costs from transferring hospitals were estimated from costs at our institution, and medical transport costs were extrapolated from contract prices between transport agencies and the pediatric center to compare total episode-of-care cost. RESULTS: A total of 133 cases (37 primaries, 96 transfers) met inclusion criteria. Transfers increased over the study period (67%-75%). There were no significant differences in age, Tanner stage, ASA score, BMI, or time of day of presentation between groups. Median transfer distance was 12 miles (IQR 7-22) and time was 1 h (IQR 1-2). More than half of cases (53%) were transferred due to hospital policy regarding surgical treatment of minors, and 25% due to lack of urology coverage. Time from initial ED site to OR was nearly doubled for the transfer group (median 4.5 vs 2.5 h, p = 0.02). Despite a higher rate of orchiectomy in the primary group (43 vs 22%, p = 0.01), this difference was not significant after stratification by symptom duration. The estimated average cost of care for patients transferred was twice that of primary patients ($15,082 vs $6898). DISCUSSION: Transfer of pediatric patients in our state for testicular torsion has increased in recent years. Hospital policies and local urology coverage are primary drivers of patient transfer which nearly doubled time to surgical intervention and more than doubled cost of care. Clinical outcomes were driven by delayed presentation. CONCLUSION: Transfer of pediatric patients for testicular torsion nearly doubles time to surgical intervention and more than doubles cost of care. Restrictive hospital policies and gaps in rural hospital urology coverage present opportunities to improve the quality and efficiency of care for these children.

Antenatal creatine supplementation reduces persistent fetal lung inflammation and oxidative stress in an ovine model of chorioamnionitis.

Chorioamnionitis is a common antecedent of preterm birth and induces inflammation and oxidative stress in the fetal lungs. Reducing inflammation and oxidative stress in the fetal lungs may improve respiratory outcomes in preterm infants. Creatine is an organic acid with known anti-inflammatory and antioxidant properties. The objective of the study was to evaluate the efficacy of direct fetal creatine supplementation to reduce inflammation and oxidative stress in fetal lungs arising from an in utero proinflammatory stimulus. Fetal lambs (n = 51) were instrumented at 90 days gestation to receive a continuous infusion of creatine monohydrate (6 mg·kg-1·h-1) or saline for 17 days. Maternal chorioamnionitis was induced with intra-amniotic lipopolysaccharide (LPS; 1 mg, O55:H6) or saline 7 days before delivery at 110 days gestation. Tissue creatine content was assessed with capillary electrophoresis, and inflammatory markers were analyzed with Luminex Magpix and immunohistochemistry. Oxidative stress was measured as the level of protein thiol oxidation. The effects of LPS and creatine were analyzed using a two-way ANOVA. Fetal creatine supplementation increased lung creatine content by 149% (PCr < 0.0001) and had no adverse effects on lung morphology. LPS-exposed groups showed increased levels of interleukin-8 in the bronchoalveolar lavage (PLPS < 0.0001) and increased levels of CD45+ leukocytes (PLPS < 0.0001) and MPO+ (PLPS < 0.0001) cells in the lung parenchyma. Creatine supplementation significantly reduced the levels of CD45+ (PCr = 0.045) and MPO+ cells (PCr = 0.012) in the lungs and reduced thiol oxidation in plasma (PCr < 0.01) and lung tissue (PCr = 0.02). In conclusion, fetal creatine supplementation reduced markers of inflammation and oxidative stress in the fetal lungs arising from chorioamnionitis.NEW & NOTEWORTHY We evaluated the effect of antenatal creatine supplementation to reduce pulmonary inflammation and oxidative stress in the fetal lamb lungs arising from lipopolysaccharide (LPS)-induced chorioamnionitis. Fetal creatine supplementation increased lung creatine content and had no adverse effects on systemic fetal physiology and overall lung architecture. Importantly, fetuses that received creatine had significantly lower levels of inflammation and oxidative stress in the lungs, suggesting an anti-inflammatory and antioxidant benefit of creatine.

Temporal tracking of cysteine 34 oxidation of plasma albumin as a biomarker of muscle damage following a bout of eccentric exercise.

PURPOSE: Exercise-induced muscle damage (EIMD) results in the generation of reactive oxygen species (ROS), but little is known about the temporal profile of change in ROS post-EIMD and how ROS levels relate to the onset of and recovery from EIMD. Our primary aim was to examine the effect of EIMD on the pattern of change in the blood level of thiol-oxidised albumin, a marker of oxidative stress. METHODS: Seven male participants were subjected on separate days to eccentric muscle contraction to cause EIMD or a no-exercise condition. After each session, the participants collected daily dried blood spots to measure thiol-oxidised albumin and returned to the laboratory every 2 days for the assessment of indirect markers of EIMD, namely maximal voluntary contraction (MVC), delayed onset muscle soreness (DOMS), creatine kinase (CK), and myoglobin. RESULTS: Eccentric exercise resulted in a significant decrease in MVC and increase in DOMS, CK, myoglobin, and thiol-oxidised albumin with the latter reaching above baseline level within 24-48 h post-exercise. All the markers of EIMD returned to baseline level within 6 days post-exercise, but not the level of thiol-oxidised albumin which remained elevated for 10 days after exercise. There was a moderate correlation between changes in thiol-oxidised albumin and DOMS, but no significant relationship between any other markers of muscle damage. CONCLUSION: The levels of thiol-oxidised albumin increase in response to EIMD and remain elevated for several days post-exercise. The temporal pattern of change in the level of thiol-oxidised albumin suggests that this may be a useful biomarker of muscle repair post-EIMD.

Identifying co-morbidities and risk in people with epilepsy: The Maltese experience.

BACKGROUND: People with epilepsy are at increased risk of multiple co-morbidities that may influence risk of adverse outcomes including impact on quality of life and premature mortality. These risk factors include potentially modifiable clinical characteristics associated with sudden unexpected death in epilepsy (SUDEP). For services to tackle risk, the clinical complexity of the target epilepsy population needs to be defined. While this has been comprehensively studied in large, economically developed countries little knowledge of these issues exist in small economically developed countries, like Malta (population: 500,000). METHODS: This was a single centre study focused exclusively on patients attending Gozo General Hospital (GGH) Malta. STROBE guidance for reporting cross sectional studies was used to design and report the study. This was a retrospective review of standard care and SUDEP and seizure risks provided to all adults (over 18 years) with epilepsy attending GGH (2018-2021). RESULTS: The review identified 68 people and 92% were compliant with their anti-seizure medication. A fifth (21%) had an intellectual disability. Despite only one patient having a psychotic illness, 19% were on antipsychotic medication. Only 18% of patients had a specific epilepsy care plan, 6% nocturnal surveillance and none had received advice on SUDEP. DISCUSSION: Patient outcomes may be improved with increasing rates of personalized epilepsy care plans, appropriate nocturnal surveillance and reducing the prescription of antipsychotic medication as it is associated with greater risk of mortality. Issues such as stigma and shame appear to play a significant role in small communities and their access to care.

Robotic transperitoneal versus retroperitoneal approach for anterior renal mass nephron-sparing surgery.

Robotic nephron-sparing surgery is traditionally performed via a transperitoneal (TP) approach. However, the retroperitoneal (RP) approach has gained popularity, particularly for posterolateral renal masses. The RP approach is associated with shorter operative time, less blood loss, and shorter length of stay, while preserving oncologic outcomes in selected masses. Here, we aim to assess the feasibility of the RP approach in excising anterior renal masses. Patients ≥ 18 years of age who underwent robotic nephron-sparing surgery for anterior renal masses were retrospectively identified (2008-2022). Baseline demographics, tumor characteristics, and perioperative data were collected and characterized based on TP vs RP approaches. Wilcoxon rank sum test and Pearson's Chi-squared test were used to compare continuous and categorical variables, respectively. Two hundred and sixteen patients were included-178 (82.4%) underwent TP approach and 38 (17.6%) underwent RP approach. Baseline demographics, preoperative tumor size, and renal nephrometry scores were similar. The RP approach was associated with shorter operative (150 vs 203 min, p < 0.001) and warm ischemia time (12 vs 21 min, p < 0.001), and less blood loss (20 vs 100 cc, p = 0.002) (Table 1). The RP approach was associated with shorter length of stay (1 vs 2 days, p < 0.001) and less total complications (5.3% vs 19.1%, p = 0.038). Major complication (Clavien-Dindo Grade > 3) rates were similar. There was no difference in positive surgical margin rates or pathologic characteristics. Robotic RP approach for nephron-sparing surgery is feasible for eligible anterior tumors and is associated with favorable perioperative outcomes with preserved negative surgical margin rates. Table 1 Patient baseline demographics Overall Transperitoneal Retroperitoneal p value Median/N IQR/% Median/N IQR/% Median/N IQR/% N 216 178 82.4% 38 17.6% Age (years) 60.5 (52.1-67.7) 60.4 (52.8-67.7) 61.6 (49.1-69.2) 0.393 Sex Male 126 58.3% 100 56.2% 26 68.4% Female 90 41.7% 78 43.8% 12 31.6% 0.165 Race White 162 75.0% 137 77.0% 25 65.8% Asian 4 1.9% 2 1.1% 2 5.3% Black 21 9.7% 18 10.1% 3 7.9% Hispanic 26 12.0% 18 10.1% 8 21.1% Other 2 0.9% 2 1.1% 0 0.0% 0.197 Body mass index (kg/m2) < 25 32 14.8% 25 14.0% 7 18.4% 25-30 68 31.5% 55 30.9% 13 34.2% 30-35 60 27.8% 50 28.1% 10 26.3% 35 + 56 25.9% 48 27.0% 8 21.1% 0.808 Prior abdominal surgery Yes 118 54.6% 104 58.4% 14 36.8% No 98 45.4% 74 41.6% 24 63.2% 0.015 Prior kidney surgery Yes 10 4.6% 9 5.1% 1 2.6% No 206 95.4% 169 94.9% 37 97.4% 0.518 Chronic kidney disease stage ≥ 3 Yes 45 20.8% 38 21.3% 7 18.4% No 171 79.2% 140 78.7% 31 81.6% 0.687 Charlson comorbidity index 0 138 63.9% 116 65.2% 22 57.9% 1 46 21.3% 38 21.4% 8 21.1% 2 19 8.8% 13 7.3% 6 15.8% ≥ 3 13 6.0% 11 6.2% 2 5.3% 0.412 Tumor size (cm) 2.7 (2-3.6) 2.8 (2-3.5) 2.55 (2-3.7) 0.796 Tumor laterality Left 100 46.3% 78 43.8% 22 57.9% Right 116 53.7% 100 56.2% 16 42.1% 0.114 Clinical T stage cT1a 186 86.1% 152 85.4% 34 89.5% cT1b 30 13.9% 26 14.6% 4 10.5% 0.509 RENAL Nephrometry score Low (4 to 6) 94 43.5% 76 42.7% 18 47.4% Intermediate (7 to 9) 112 51.9% 94 52.8% 18 47.4% High (≥ 10) 19 4.6% 8 4.5% 2 5.3% 0.829 TE tumor enucleation, SPN standard margin partial nephrectomy, IQR interquartile range.

Fluorescence Lifetime Imaging for Quantification of Targeted Drug Delivery in Varying Tumor Microenvironments.

Rationale: Trastuzumab (TZM) is a monoclonal antibody that targets the human epidermal growth factor receptor (HER2) and is clinically used for the treatment of HER2-positive breast tumors. However, the tumor microenvironment can limit the access of TZM to the HER2 targets across the whole tumor and thereby compromise TZM's therapeutic efficacy. An imaging methodology that can non-invasively quantify the binding of TZM-HER2, which is required for therapeutic action, and distribution within tumors with varying tumor microenvironments is much needed. Methods: We performed near-infrared (NIR) fluorescence lifetime (FLI) Forster Resonance Energy Transfer (FRET) to measure TZM-HER2 binding, using in vitro microscopy and in vivo widefield macroscopy, in HER2 overexpressing breast and ovarian cancer cells and tumor xenografts, respectively. Immunohistochemistry was used to validate in vivo imaging results. Results: NIR FLI FRET in vitro microscopy data show variations in intracellular distribution of bound TZM in HER2-positive breast AU565 and AU565 tumor-passaged XTM cell lines in comparison to SKOV-3 ovarian cancer cells. Macroscopy FLI (MFLI) FRET in vivo imaging data show that SKOV-3 tumors display reduced TZM binding compared to AU565 and XTM tumors, as validated by ex vivo immunohistochemistry. Moreover, AU565/XTM and SKOV-3 tumor xenografts display different amounts and distributions of TME components, such as collagen and vascularity. Therefore, these results suggest that SKOV-3 tumors are refractory to TZM delivery due to their disrupted vasculature and increased collagen content. Conclusion: Our study demonstrates that FLI is a powerful analytical tool to monitor the delivery of antibody drug tumor both in cell cultures and in vivo live systems. Especially, MFLI FRET is a unique imaging modality that can directly quantify target engagement with potential to elucidate the role of the TME in drug delivery efficacy in intact live tumor xenografts.

Urinary comprehensive genomic profiling predicts urothelial carcinoma recurrence and identifies responders to intravesical therapy.

Intravesical therapy (IVT) is the standard of care to decrease risk of recurrence and progression for high-grade nonmuscle-invasive bladder cancer. However, post-IVT recurrence remains common and the ability to risk-stratify patients before or after IVT is limited. In this prospectively designed and accrued cohort study, we examine the utility of urinary comprehensive genomic profiling (uCGP) for predicting recurrence risk following transurethral resection of bladder tumor (TURBT) and evaluating longitudinal IVT response. Urine was collected before and after IVT instillation and uCGP testing was done using the UroAmp™ platform. Baseline uCGP following TURBT identified patients with high (61%) and low (39%) recurrence risk. At 24 months, recurrence-free survival (RFS) was 100% for low-risk and 45% for high-risk patients with a hazard ratio (HR) of 9.3. Longitudinal uCGP classified patients as minimal residual disease (MRD) Negative, IVT Responder, or IVT Refractory with 24-month RFS of 100%, 50%, and 32%, respectively. Compared with MRD Negative patients, IVT Refractory patients had a HR of 10.5. Collectively, uCGP enables noninvasive risk assessment of patients following TURBT and induction IVT. uCGP could inform surveillance cystoscopy schedules and identify high-risk patients in need of additional therapy.

Neurotechnological solutions for post-traumatic stress disorder: A perspective review and concept proposal.

Post-traumatic stress disorder (PTSD) is an anxiety condition caused by exposure to severe trauma. It is characterised by nightmares, flashbacks, hyper-vigilance and avoidance behaviour. These all lead to impaired functioning reducing quality of life. PTSD affects 2-5% of the population globally. Most sufferers cannot access effective treatment, leading to impaired psychological functioning reducing quality of life. Eye movement desensitisation and reprocessing (EMDR) is a non-invasive brain stimulation treatment that has shown significant clinical effectiveness in PTSD. Another treatment modality, that is, trauma-focused cognitive behavioural therapy is also an effective intervention. However, both evidence-based treatments are significantly resource intensive as they need trained therapists to deliver them. A concept of a neuro-digital tool for development is proposed to put to clinical practice of delivering EMDR to improve availability, efficiency and effectiveness of treatment. The evidence in using new technologies to measure sleep, geolocation and conversational analysis of social media to report objective outcome measures is explored. If achieved, this can be fed back to users with data anonymously collated to evaluate and improve the tool. Coproduction would be at the heart of product development so that the tool is acceptable and accessible to people with the condition.

Generic professional capabilities hub: developing leadership and management skills in trainees.

High quality leadership is key to delivering high standards of patient care. For many reasons, doctors in training are not currently well represented in leadership positions and struggle to access opportunities to develop these skills. As a key cohort within the medical workforce, using existing present opportunities within clinical training programmes would allow them to engage in leadership development and support them to lead on projects within their trusts and make sustainable changes within their own organisation.Within our anaesthetic department, we designed the Generic Professional Capabilities Hub (GPC hub)-a framework that aims to address some of the barriers to engagement in clinical leadership. Involvement in the GPC hub can be at three different levels, which allows for flexibility around other training needs. Currently, there are seven workstreams within the framework, with trainees being involved through symposia attendance, leading on projects linked to the hub or becoming a trainee workstream lead. We share our learning from setting up this framework, the benefits it brings to trainees and departments, initial evaluation results and our next steps which include regional roll out to four other anaesthetic departments.

Characterization of Methyl- and Acetyl-Ni Intermediates in Acetyl CoA Synthase Formed during Anaerobic CO2 and CO Fixation.

The Wood-Ljungdahl Pathway is a unique biological mechanism of carbon dioxide and carbon monoxide fixation proposed to operate through nickel-based organometallic intermediates. The most unusual steps in this metabolic cycle involve a complex of two distinct nickel-iron-sulfur proteins: CO dehydrogenase and acetyl-CoA synthase (CODH/ACS). Here, we describe the nickel-methyl and nickel-acetyl intermediates in ACS completing the characterization of all its proposed organometallic intermediates. A single nickel site (Nip) within the A cluster of ACS undergoes major geometric and redox changes as it transits the planar Nip, tetrahedral Nip-CO and planar Nip-Me and Nip-Ac intermediates. We propose that the Nip intermediates equilibrate among different redox states, driven by an electrochemical-chemical (EC) coupling process, and that geometric changes in the A-cluster linked to large protein conformational changes control entry of CO and the methyl group.

Impact of intravesical Bacillus Calmette-Guérin and chemotherapy on the bladder microbiome in patients with non-muscle invasive bladder cancer.

Introduction: Intravesical therapy (IVT), including Bacillus Calmette-Guérin (BCG), is the standard of care for high grade (HG) non-muscle invasive bladder cancer (NMIBC). Despite the use of IVT, many patients recur after treatment. The bladder microbiome and its role in disease processes has recently risen to prominence. We aim to characterize changes that occur in the bladder microbiome over the course of intravesical therapy and assess whether these changes correlate with outcomes in patients with NMIBC. Methods: Patients with NMIBC undergoing induction BCG or intravesical therapy were prospectively enrolled from January 2019 to March 2020. Patients with clinical T2 or greater pathology or active urinary tract infection at enrollment were excluded. Twenty-nine patients had catheterized (bladder) urine samples collected prior to induction intravesical therapy and prior to each IVT instillation. Twenty-seven received BCG while 2 received intravesical gemcitabine. Bacteria were identified using 16S ribosomal RNA gene sequencing. Bladder microbiome changes were evaluated and differences between patients who recurred and patients who did not recur after IVT were investigated. Results: Across the 29 patients analyzed, bacterial richness decreased significantly following intravesical therapy (Richness, P=0.01). Evenness and overall diversity did not change significantly (Pielou, P=0.62; Shannon, P=0.13). Patients who experienced recurrence had a higher relative abundance of Aerococcus in their urine (P<0.01), while those who did not recur had significantly more Ureaplasma (P=0.01) and Escherichia/Shigella species (P=0.05). Patients with decreased levels of alpha diversity were more likely to fall within the non-recurrence cohort. Conclusion: IVT for NMIBC appears to change the urinary microbiome by decreasing richness while not altering evenness or overall diversity. The presence of Aerococcus species may be predictive of a poor cancer response to IVT, while the presence of Ureaplasma and Escherichia/Shigella may predict a favorable response to IVT. Further studies are warranted to elucidate and confirm the significance of changes in the bladder microbiome.

Diagnostic models predicting paediatric viral acute respiratory infections: a systematic review.

OBJECTIVES: To systematically review and evaluate diagnostic models used to predict viral acute respiratory infections (ARIs) in children. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase were searched from 1 January 1975 to 3 February 2022. ELIGIBILITY CRITERIA: We included diagnostic models predicting viral ARIs in children (<18 years) who sought medical attention from a healthcare setting and were written in English. Prediction model studies specific to SARS-CoV-2, COVID-19 or multisystem inflammatory syndrome in children were excluded. DATA EXTRACTION AND SYNTHESIS: Study screening, data extraction and quality assessment were performed by two independent reviewers. Study characteristics, including population, methods and results, were extracted and evaluated for bias and applicability using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies and PROBAST (Prediction model Risk Of Bias Assessment Tool). RESULTS: Of 7049 unique studies screened, 196 underwent full text review and 18 were included. The most common outcome was viral-specific influenza (n=7; 58%). Internal validation was performed in 8 studies (44%), 10 studies (56%) reported discrimination measures, 4 studies (22%) reported calibration measures and none performed external validation. According to PROBAST, a high risk of bias was identified in the analytic aspects in all studies. However, the existing studies had minimal bias concerns related to the study populations, inclusion and modelling of predictors, and outcome ascertainment. CONCLUSIONS: Diagnostic prediction can aid clinicians in aetiological diagnoses of viral ARIs. External validation should be performed on rigorously internally validated models with populations intended for model application. PROSPERO REGISTRATION NUMBER: CRD42022308917.

Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure.

BACKGROUND: Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF. METHODS: This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity. RESULTS: The primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L). CONCLUSIONS: The primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.

Imaging of pediatric liver tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Primary hepatic malignancies are relatively rare in the pediatric population, accounting for approximately 1%-2% of all pediatric tumors. Hepatoblastoma and hepatocellular carcinoma are the most common primary liver malignancies in children under the age of 5 years and over the age of 10 years, respectively. This paper provides consensus-based imaging recommendations for evaluation of patients with primary hepatic malignancies at diagnosis and follow-up during and after therapy.

Loss of bone morphogenetic protein signaling in fibroblasts results in CXCL12-driven serrated polyp development.

Mutations in Bone Morphogenetic Protein (BMP) Receptor (BMPR)1A and SMAD4 are detected in 50% of juvenile polyposis syndrome (JPS) patients, who develop stroma-rich hamartomatous polyps. The established role of stromal cells in regulating BMP activity in the intestine implies a role for stromal cells in polyp development. We used conditional Cre-LoxP mice to investigate how specific loss of BMPR1A in endothelial cells, fibroblasts, or myofibroblasts/smooth muscle cells affects intestinal homeostasis. Selective loss of BMPR1A in fibroblasts causes severe histological changes in the intestines with a significant increase in stromal cell content and epithelial cell hyperproliferation, leading to numerous serrated polyps. This phenotype suggests that crucial changes occur in the fibroblast secretome that influences polyp development. Analyses of publicly available RNA expression databases identified CXCL12 as a potential candidate. RNAscope in situ hybridization showed an evident increase of Cxcl12-expressing fibroblasts. In vitro, stimulation of fibroblasts with BMPs resulted in downregulation of CXCL12, while inhibition of the BMP pathway resulted in gradual upregulation of CXCL12 over time. Moreover, neutralization of CXCL12 in vivo in the fibroblast-specific BMPR1A KO mice resulted in a significant decrease in polyp formation. Finally, in CRC patient specimens, mRNA-expression data showed that patients with high GREMLIN1 and CXCL12 expression had a significantly poorer overall survival. Significantly higher GREMLIN1, NOGGIN, and CXCL12 expression were detected in the Consensus Molecular Subtype 4 (CMS4) colorectal cancers, which are thought to arise from serrated polyps. Taken together, these data imply that fibroblast-specific BMP signaling-CXCL12 interaction could have a role in the etiology of serrated polyp formation.

Validation of an LC-MS/MS method for the determination of sotorasib, a KRASG12C inhibitor, in human plasma.

Background: Sotorasib (AMG 510) is a first-in-class KRASG12C inhibitor that received accelerated US FDA approval in 2021 for the treatment of patients with KRASG12C-mutated locally advanced or metastatic non-small-cell lung cancer. Method: An LC-MS/MS method was developed and validated for the determination of sotorasib in human plasma to support clinical development studies. Samples were prepared using protein precipitation and analyzed by LC-MS/MS using gradient elution with a calibration standard curve range of 10.0-10,000 ng/ml. Stable isotope labeled [13C, D3]-sotorasib was used as an internal standard. Results & conclusion: The method fully met FDA guidelines for all validation parameters, including precision, accuracy, selectivity, matrix effect, recovery and stability and has been extensively used to support multiple clinical studies.

Proximal Trapezoidectomy and Scaphotrapezoid Joint Tendon Interposition at the Time of Ligament Reconstruction and Tendon Interposition for Pan Trapezial Osteoarthritis Does Not Increase Proximal Carpal Row Malalignment.

Background Surgical options for osteoarthritis (OA) of the first carpometacarpal include excision, replacement arthroplasty, and arthrodesis. However, in pan trapezial OA, optimal management of residual scaphotrapezoidal articulation has remained unclear. Purpose The purpose of this study was to evaluate whether removing the proximal trapezoid from the scaphotrapezoid joint (STJ) and interposing tendon when performing a ligament reconstruction and tendon interposition (LRTI) for pan trapezial arthritis resulted in any clinical or radiographic compromise compared with LRTI alone in isolated carpometacarpal joint arthritis. Methods In a prospective consecutive cohort, 122 thumbs were selected to generate two matched cohorts and a cross-sectional review was completed at an average of 24 months (range: 5-203 months). Fifty-six thumbs had LRTI alone and 66 thumbs also had resection of the proximal portion of the trapezoid with tendon interposition in the residual gap. Results The cohorts showed no significant differences in subjective and objective outcome measures and imaging. Excision of the STJ was not associated with poorer clinical outcomes or the development of a dorsal intercalated segment instability deformity. Conclusions The management of pan trapezial arthritis with LRTI and proximal trapezoid excision and STJ interposition appears satisfactory on short- to medium-term clinical and radiographic follow-up. Level of Evidence: This is a Level III, consecutive cross-sectional cohort study.