Intensive pre-operative information course (IPIC) and pre-operative weight loss results in long-term sustained weight loss following bariatric surgery: 11 years results from a tertiary referral centre.

INTRODUCTION: Outcomes of long-term (5-10-year) weight loss have not been investigated thoroughly and the role of pre-operative weight loss on long-term weight loss, among other factors, are unknown. Our regional bariatric service introduced a 12 week intensive pre-operative information course (IPIC) to optimise pre-operative weight loss and provide education prior to bariatric surgery. The present study determines the effect of pre-operative weight loss and an intense pre-operative information course (IPIC), on long-term weight outcomes and sustained weight loss post-bariatric surgery. METHODS: Data were collected prospectively from a bariatric center (2008-2022). Excess weight loss (EWL) ≥ 50% and ≥ 70% were considered outcome measures. Survival analysis and logistic regression identified variables associated with overall and sustained EWL ≥ 50% and ≥ 70%. RESULTS: Three hundred thirty-nine patients (median age, 49 years; median follow-up, 7 years [0.5-11 years]; median EWL%, 49.6%.) were evaluated, including 158 gastric sleeve and 161 gastric bypass. During follow-up 273 patients (80.5%) and 196 patients (53.1%) achieved EWL ≥ 50% and ≥ 70%, respectively. In multivariate survival analyses, pre-operative weight loss through IPIC, both < 10.5% and > 10.5% EWL, were positively associated with EWL ≥ 50% (HR 2.23, p < 0.001) and EWL ≥ 70% (HR 3.24, p < 0.001), respectively. After a median of 6.5 years after achieving EWL50% or EWL70%, 56.8% (154/271) had sustained EWL50% and 50.6% (85/168) sustained EWL70%. Higher pre-operative weight loss through IPIC increased the likelihood of sustained EWL ≥ 50% (OR, 2.36; p = 0.013) and EWL ≥ 70% (OR, 2.03; p = 0.011) at the end of follow-up. CONCLUSIONS: IPIC and higher pre-operative weight loss improve weight loss post-bariatric surgery and reduce the likelihood of weight regain during long-term follow-up.

Critical shortfalls in the management of PBC: Results of a UK-wide, population-based evaluation of care delivery.

Background & Aims: Guidelines for the management of primary biliary cholangitis (PBC) were published by the British Society of Gastroenterology in 2018. In this study, we assessed adherence to these guidelines in the UK National Health Service (NHS). Methods: All NHS acute trusts were invited to contribute data between 1 January 2021 and 31 March 2022, assessing clinical care delivered to patients with PBC in the UK. Results: We obtained data for 8,968 patients with PBC and identified substantial gaps in care across all guideline domains. Ursodeoxycholic acid (UDCA) was used as first-line treatment in 88% of patients (n = 7,864) but was under-dosed in one-third (n = 1,964). Twenty percent of patients who were UDCA-untreated (202/998) and 50% of patients with inadequate UDCA response (1,074/2,102) received second-line treatment. More than one-third of patients were not assessed for fatigue (43%; n = 3,885) or pruritus (38%; n = 3,415) in the previous 2 years. Fifty percent of all patients with evidence of hepatic decompensation were discussed with a liver transplant centre (222/443). Appropriate use of second-line treatment and referral for liver transplantation was significantly better in specialist PBC treatment centres compared with non-specialist centres (p <0.001). Conclusions: Poor adherence to guidelines exists across all domains of PBC care in the NHS. Although specialist PBC treatment centres had greater adherence to guidelines, no single centre met all quality standards. Nationwide improvement in the delivery of PBC-related healthcare is required. Impact and implications: This population-based evaluation of primary biliary cholangitis, spanning four nations of the UK, highlights critical shortfalls in care delivery when measured across all guideline domains. These include the use of liver biopsy in diagnosis; referral practice for second-line treatment and/or liver transplant assessment; and the evaluation of symptoms, extrahepatic manifestations, and complications of cirrhosis. The authors therefore propose implementation of a dedicated primary biliary cholangitis care bundle that aims to minimise heterogeneity in clinical practice and maximise adherence to key guideline standards.

Portomesenteric Vein Thrombosis in Patients Undergoing Sleeve Gastrectomy: an Updated Systematic Review and Meta-Analysis of 101,914 Patients.

INTRODUCTION: Portomesenteric vein thrombosis (PMVT) is a rare but potentially fatal complication of sleeve gastrectomy (SG). The rising prevalence of SG has led to a surge in the occurrence of PMVT, while the associated risk factors have not been fully elucidated. This study aims to determine the incidence and risk factors of PMVT in patients undergoing SG. METHODS: A comprehensive literature search was performed in PubMed and EMBASE databases. Proportion and regression meta-analyses were conducted. RESULTS: In a total of 76 studies including 101,914 patients undergoing SG, we identified 357 patients with PMVT. Mean follow-up was 14.4 (SD: 16.3) months. The incidence of PMVT was found to be 0.50% (95%CI: 0.40-0.61%). The majority of the population presented with abdominal pain (91.8%) at an average of 22.4 days postoperatively and PMVT was mainly diagnosed with computed tomography (CT) (96.0%). Hematologic abnormalities predisposing to thrombophilia were identified in 34.9% of the population. Advanced age (p=0.02) and low center volume (p <0.0001) were significantly associated with PMVT, while gender, BMI, hematologic abnormality, prior history of deep vein thrombosis or pulmonary embolism, type of prophylactic anticoagulation, and duration of prophylactic anticoagulation were not associated with the incidence of PMVT in meta-regression analyses. Treatment included therapeutic anticoagulation in 93.4% and the mortality rate was 4/357 (1.1%). CONCLUSION: PMVT is a rare complication of sleeve gastrectomy with an incidence rate <1% that is associated with low center volume and advanced age but is not affected by the duration or type of thromboprophylaxis administered postoperatively.

Performance of Nuclear Magnetic Resonance-Based Estimated Glomerular Filtration Rate in a Real-World Setting.

An accurate estimate of glomerular filtration rate (eGFR) is essential for proper clinical management, especially in patients with kidney dysfunction. This prospective observational study evaluated the real-world performance of the nuclear magnetic resonance (NMR)-based GFRNMR equation, which combines creatinine, cystatin C, valine, and myo-inositol with age and sex. We compared GFRNMR performance to that of the 2021 CKD-EPI creatinine and creatinine-cystatin C equations (CKD-EPI2021Cr and CKD-EPI2021CrCys), using 115 fresh routine samples of patients scheduled for urinary iothalamate clearance measurement (mGFR). Median bias to mGFR of the three eGFR equations was comparably low, ranging from 0.4 to 2.0 mL/min/1.73 m2. GFRNMR outperformed the 2021 CKD-EPI equations in terms of precision (interquartile range to mGFR of 10.5 vs. 17.9 mL/min/1.73 m2 for GFRNMR vs. CKD-EPI2021CrCys; p = 0.01) and accuracy (P15, P20, and P30 of 66.1% vs. 48.7% [p = 0.007], 80.0% vs. 60.0% [p < 0.001] and 95.7% vs. 86.1% [p = 0.006], respectively, for GFRNMR vs. CKD-EPI2021CrCys). Clinical parameters such as etiology, comorbidities, or medications did not significantly alter the performance of the three eGFR equations. Altogether, this study confirmed the utility of GFRNMR for accurate GFR estimation, and its potential value in routine clinical practice for improved medical care.

Impact of race-independent equations on estimating glomerular filtration rate for the assessment of kidney dysfunction in liver disease.

BACKGROUND: Altered hemodynamics in liver disease often results in overestimation of glomerular filtration rate (GFR) by creatinine-based GFR estimating (eGFR) equations. Recently, we have validated a novel eGFR equation based on serum myo-inositol, valine, and creatinine quantified by nuclear magnetic resonance spectroscopy in combination with cystatin C, age and sex (GFRNMR). We hypothesized that GFRNMR could improve chronic kidney disease (CKD) classification in the setting of liver disease. RESULTS: We conducted a retrospective multicenter study in 205 patients with chronic liver disease (CLD), comparing the performance of GFRNMR to that of validated CKD-EPI eGFR equations, including eGFRcr (based on creatinine) and eGFRcr-cys (based on both creatinine and cystatin C), using measured GFR as reference standard. GFRNMR outperformed all other equations with a low overall median bias (-1 vs. -6 to 4 ml/min/1.73 m2 for the other equations; p < 0.05) and the lowest difference in bias between reduced and preserved liver function (-3 vs. -16 to -8 ml/min/1.73 m2 for other equations). Concordant classification by CKD stage was highest for GFRNMR (59% vs. 48% to 53%) and less biased in estimating CKD severity compared to the other equations. GFRNMR P30 accuracy (83%) was higher than that of eGFRcr (75%; p = 0.019) and comparable to that of eGFRcr-cys (86%; p = 0.578). CONCLUSIONS: Addition of myo-inositol and valine to creatinine and cystatin C in GFRNMR further improved GFR estimation in CLD patients and accurately stratified liver disease patients into CKD stages.

GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia.

Cancer cachexia is a disorder characterized by involuntary weight loss and impaired physical performance. Decline in physical performance of patients with cachexia is associated with poor quality of life, and currently there are no effective pharmacological interventions that restore physical performance. Here we examine the effect of GDF15 neutralization in a mouse model of cancer-induced cachexia (TOV21G) that manifests weight loss and muscle function impairments. With comprehensive assessments, our results demonstrate that cachectic mice treated with the anti-GDF15 antibody mAB2 exhibit body weight gain with near-complete restoration of muscle mass and markedly improved muscle function and physical performance. Mechanistically, the improvements induced by GDF15 neutralization are primarily attributed to increased caloric intake, while altered gene expression in cachectic muscles is restored in caloric-intake-dependent and -independent manners. The findings indicate potential of GDF15 neutralization as an effective therapy to enhance physical performance of patients with cachexia.

Laparoscopic Lumen-guided cholecystectomy in face of the difficult gallbladder.

BACKGROUND: Where the critical view of safety cannot be established during cholecystectomy, certain salvage techniques are indicated to reduce the likelihood of bile duct injury. The present study describes a salvage technique termed the "laparoscopic lumen-guided cholecystectomy" (LLC) and reports its peri-operative outcomes. METHOD: A summary of the technique is as follows: (1) Hartmann's pouch is incised and stones are evacuated; (2) the cystic anatomy is inspected from the inside of the gallbladder; (3) the lumen is used to guide retrograde dissection towards the cystic pedicle; (4) cystic duct control is achieved if deemed safe. LLC cases performed between June 2020 and January 2022 in a single health board were included. The operative details and peri-operative outcomes of the technique are reported and compared to cases of similar difficulty where the LLC was not attempted. RESULTS: LLC was performed in 4.6% (27/587) of cases. In all 27 cases, LLC was performed for a "frozen" cholecystohepatic triangle. Hartmann's pouch was completely excised in all cases (27/27) and cystic duct control was achieved in 85.2% of cases (23/27). No cases of bile leak or ductal injury were reported. Rates of bile leak, post-operative complications and ERCP were lower following LLC compared to the group where LLC was not attempted (p < 0.01). CONCLUSION: LLC is a safe salvage technique and should be considered in cases where the critical view of safety cannot be established. The technique achieves cystic duct control in the majority of cases and favourable outcomes in the face of a difficult cholecystectomy.

A Systematic Review of Patient and Public Involvement (PPI) in Bariatric Research Trials: The Need for More Work.

Patient and public involvement (PPI) has gained increased attention in research circles. The consistency of PPI reporting has been addressed by the development of validated checklists such as GRIPP and GRIPP2. The primary aim of this study was to identify the incidence of PPI reporting in bariatric research. MEDLINE/PubMed, EMBASE, and CINAHL/Cochrane databases were searched for publications between 1st January 2018 to 31st December 2021 for "bariatric surgery" OR "weight loss surgery" OR "obesity surgery" AND "randomized controlled trials." Ninety studies fulfilled exclusion criteria; two studies reported direct PPI involvement, one indirectly used PPI and one reported not using PPI methods. No other study made direct or indirect mention of PPI. Concluding, that GRIPP2 and PPI reporting in bariatric surgery trials is lacking.

Exposure to bile and gastric juice can impact the aerodigestive microbiome in people with cystic fibrosis.

Studies of microbiota reveal inter-relationships between the microbiomes of the gut and lungs. This relationship may influence the progression of lung disease, particularly in patients with cystic fibrosis (CF), who often experience extraoesophageal reflux (EOR). Despite identifying this relationship, it is not well characterised. Our hypothesis is that the gastric and lung microbiomes in CF are related, with the potential for aerodigestive pathophysiology. We evaluated gastric and sputum bacterial communities by culture and 16S rRNA gene sequencing in 13 CF patients. Impacts of varying levels of bile acids, pepsin and pH on patient isolates of Pseudomonas aeruginosa (Pa) were evaluated. Clonally related strains of Pa and NTM were identified in gastric and sputum samples from patients with symptoms of EOR. Bacterial diversity was more pronounced in sputa compared to gastric juice. Gastric and lung bile and pepsin levels were associated with Pa biofilm formation. Analysis of the aerodigestive microbiomes of CF patients with negative sputa indicates that the gut can be a reservoir of Pa and NTM. This combined with the CF patient's symptoms of reflux and potential aspiration, highlights the possibility of communication between microorganisms of the gut and the lungs. This phenomenon merits further research.

Incidence of collagenous colitis in NHS Lothian: a population-based study.

Objective: Increases in incidence of collagenous colitis (CC) have been documented across Europe; however, previous data from NHS Lothian (1998-2003) demonstrated this to be a low-prevalence area. We aimed to assess incidence of CC in NHS Lothian over time by comparing a more recent cohort (2013-2018) with our existing cohort. Methods: All histologically confirmed diagnoses of CC between 2013 and 2018 were obtained from the NHS Lothian colorectal pathology department (Western General Hospital, Edinburgh). Case record review was performed to obtain relevant demographic and clinical data. Data were also collected regarding the availability of colonoscopy in NHS Lothian. Results: 224 cases of CC were diagnosed between 2013 and 2018, compared with 25 between 1998 and 2003. Mean annual incidence rose from 0.5/100 000 population to 4.3/100 000 population. Incidence in females ≥60 years old rose from 2.3/100 000 population to 22.4/100 000 population (p<0.001). The total number of colonoscopies performed increased by 179.1% from 15 262 (1998-2003) to 42 600 (2013-2018), with the number of CC cases per 1000 colonoscopies performed rising from 1.7 to 5.3 (p<0.001). Conclusion: We describe the increasing incidence of CC in Southeast Scotland, with temporal trends comparable to other European countries. The increase is particularly marked in older females and parallels increasing numbers of colonoscopies being performed.

cSurvival: a web resource for biomarker interactions in cancer outcomes and in cell lines.

Survival analysis is a technique for identifying prognostic biomarkers and genetic vulnerabilities in cancer studies. Large-scale consortium-based projects have profiled >11 000 adult and >4000 pediatric tumor cases with clinical outcomes and multiomics approaches. This provides a resource for investigating molecular-level cancer etiologies using clinical correlations. Although cancers often arise from multiple genetic vulnerabilities and have deregulated gene sets (GSs), existing survival analysis protocols can report only on individual genes. Additionally, there is no systematic method to connect clinical outcomes with experimental (cell line) data. To address these gaps, we developed cSurvival (https://tau.cmmt.ubc.ca/cSurvival). cSurvival provides a user-adjustable analytical pipeline with a curated, integrated database and offers three main advances: (i) joint analysis with two genomic predictors to identify interacting biomarkers, including new algorithms to identify optimal cutoffs for two continuous predictors; (ii) survival analysis not only at the gene, but also the GS level; and (iii) integration of clinical and experimental cell line studies to generate synergistic biological insights. To demonstrate these advances, we report three case studies. We confirmed findings of autophagy-dependent survival in colorectal cancers and of synergistic negative effects between high expression of SLC7A11 and SLC2A1 on outcomes in several cancers. We further used cSurvival to identify high expression of the Nrf2-antioxidant response element pathway as a main indicator for lung cancer prognosis and for cellular resistance to oxidative stress-inducing drugs. Altogether, these analyses demonstrate cSurvival's ability to support biomarker prognosis and interaction analysis via gene- and GS-level approaches and to integrate clinical and experimental biomedical studies.

How safe bariatric surgery is-An update on perioperative mortality for clinicians and patients.

Bariatric, metabolic or weight loss surgery produces sustained weight loss and imporovement in obesity related diseases. Bariatric surgery has existed for decades but there is limited reliable data on the risk of perioperative mortality following the procedures. This commentary focuses on a recent meta-analysis which has produced contemporaneous mortality data, and the findings are significant. Utilising data from 3.6 million patients the study has shown an overall pooled perioperative mortality of 0.08%, a significantly reduced risk compared to previous, smaller studies. This finding increases our knowledge of surgical risk for these procedures and should now equip health care groups to challenge barriers to uptake of bariatric surgery. Barriers currently include a worldwide lack of focus on treating obesity, lack of funding and resource from commissioners, and a general public and professional view that bariatric surgery may be high risk. In reality, this figure equates to mortality risk for procedures generally considered 'safe' such as laparoscopic cholecystectomy and knee arthroplasty. Bariatric surgery is a safe option for achieving sustained weight-loss and the treatment of obesity related diseases, and refusing access to surgery on the grounds of perioperative safety should now be an outdated premise.

The Influence of Specific Activity on the Biodistribution of 18F-rhPSMA-7.3: A Retrospective Analysis of Clinical PET Data.

We investigated whether the time between synthesis and injection and the resulting decrease in specific activity affects the normal-organ and tumor uptake of the PSMA ligand 18F-rhPSMA-7.3 in patients with prostate cancer. Methods: The biodistribution of 18F-rhPSMA-7.3 on PET/CT scans obtained with a high specific activity (median, 178.9 MBq/µg; n = 42) and a low specific activity (median, 19.3 MBq/µg; n = 42) was compared. Results: Tracer uptake by the parotid gland, submandibular gland, and spleen was moderately but significantly lower in the low-specific-activity group than in the high-specific-activity group (median SUVmean, 16.7 vs. 19.2; 18.1 vs. 22.3; and 7.8 vs. 9.6, respectively). No other statistically significant differences were found for normal organs or tumor lesions. Conclusion: A 10-fold decrease in specific activity has only minor effects on the biodistribution of 18F-rhPSMA-7.3. These findings suggest that 18F-labeled PSMA ligands can be centrally produced and shipped to PET clinics in a similar way to 18F-FDG.

Tumor Sink Effect in 68Ga-PSMA-11 PET: Myth or Reality?

We aimed to systematically determine the impact of tumor burden on 68Ga-prostate-specific membrane antigen-11 (68Ga-PSMA) PET biodistribution by the use of quantitative measurements. Methods: This international multicenter, retrospective analysis included 406 men with prostate cancer who underwent 68Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into a very low (quintile 1, ≤25 cm3), low (quintile 2, 25-189 cm3), moderate (quintile 3, 189-532 cm3), high (quintile 4, 532-1,355 cm3), or very high (quintile 5, ≥1,355 cm3) total PSMA-positive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semiautomatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as a control group. Normal organs, which included salivary glands, liver, spleen, and kidneys, were semiautomatically segmented using 68Ga-PSMA PET images, and SUVmean was obtained. Correlations between the SUVmean of normal organs and PSMA-VOL as continuous and categoric variables by quintiles were evaluated. Results: The median PSMA-VOL was 302 cm3 (interquartile range [IQR], 47-1,076 cm3). The median SUVmean of salivary glands, kidneys, liver, and spleen was 10.0 (IQR, 7.7-11.8), 26.0 (IQR, 20.0-33.4), 3.7 (IQR, 3.0-4.7), and 5.3 (IQR, 4.0-7.2), respectively. PSMA-VOL showed a moderate negative correlation with the SUVmean of the salivary glands (r = -0.44, P < 0.001), kidneys (r = -0.34, P < 0.001), and liver (r = -0.30, P < 0.001) and a weak negative correlation with the spleen SUVmean (r = -0.16, P = 0.002). Patients with a very high PSMA-VOL (quintile 5, ≥1,355 cm3) had a significantly lower PSMA uptake in the salivary glands, kidneys, liver, and spleen than did the control group, with an average difference of -38.1%, -40.0%, -43.2%, and -34.9%, respectively (P < 0.001). Conclusion: Tumor sequestration affects 68Ga-PSMA biodistribution in normal organs. Patients with a very high tumor load showed a significantly lower uptake of 68Ga-PSMA in normal organs, confirming a tumor sink effect. As similar effects might occur with PSMA-targeted radioligand therapy, these patients might benefit from increased therapeutic activity without exceeding the radiation dose limit for organs at risk.

Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study.

BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022). INTERPRETATION: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option. FUNDING: Prostate Cancer Foundation.

Discovery of Surfactins as Inhibitors of MicroRNA Processing Using Cat-ELCCA.

MicroRNAs (miRNAs) are a family of small noncoding RNAs that regulate gene expression. Due to their important activity in the fine-tuning of protein translation, abnormal expression of miRNAs has been linked to many human diseases, making the targeting of miRNAs attractive as a novel therapeutic strategy. Accordingly, researchers have been heavily engaged in the discovery of small molecule modulators of miRNAs. With an interest in the identification of new chemical space for targeting miRNAs, we developed a high-throughput screening (HTS) technology, catalytic enzyme-linked click chemistry assay (cat-ELCCA), aimed at the discovery of small molecule ligands for pre-miR-21, a miRNA that is frequently overexpressed in human cancers. From our HTS campaign, we found that natural products, a source of many impactful human medicines, may be a promising source of potential pre-miR-21-selective maturation inhibitors. Herein we describe our first efforts in natural product inhibitor discovery leading to the identification of a depsipeptide class of natural products as RNA-binding inhibitors of Dicer-mediated miRNA processing.

Online Information About the Effectiveness of Shoulder Surgery Is Not Based on the Best Available Evidence: A Content Analysis.

OBJECTIVE: To summarize the proportion of consumer webpages on subacromial decompression and rotator cuff repair surgery that make an accurate portrayal of the evidence for these operations (primary outcome), mention the benefits and harms of surgery, outline alternatives to surgery, and make various surgical recommendations. DESIGN: Content analysis. SETTING: Online consumer information about subacromial decompression and rotator cuff repair surgery. Webpages were identified through (1) Google searches using terms synonymous with "shoulder pain" and "shoulder surgery" and searching "orthopedic surgeon" linked to each Australian capital city and (2) websites of relevant professional associations (eg, Australian Orthopaedic Association). Two reviewers independently identified webpages and extracted data. PARTICIPANTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Whether the webpage made an accurate portrayal of the evidence for subacromial decompression or rotator cuff repair surgery (primary outcome), mentioned benefits and harms of surgery, outlined alternatives to surgery, and made various surgical recommendations (eg, delay surgery). Outcome data were summarized using counts and percentages. RESULTS: A total of 155 webpages were analyzed (n=89 on subacromial decompression, n=90 on rotator cuff repair, n=24 on both). Only 18% (n=16) and 4% (n=4) of webpages made an accurate portrayal of the evidence for subacromial decompression and rotator cuff repair surgery, respectively. For subacromial decompression and rotator cuff repair, respectively, 85% (n=76) and 80% (n=72) of webpages mentioned benefits, 38% (n=34) and 47% (n=42) mentioned harms, 94% (n=84) and 92% (n=83) provided alternatives to surgery, and 63% (n=56) and 62% (n=56) recommended delayed surgery (the most common recommendation). CONCLUSIONS: Most online information about subacromial decompression and rotator cuff repair surgery does not accurately portray the best available evidence for surgery and may be inadequate to inform patient decision making.

Optical Hemodynamic Imaging of Jugular Venous Dynamics During Altered Central Venous Pressure.

OBJECTIVE: An optical imaging system is proposed for quantitatively assessing jugular venous response to altered central venous pressure. METHODS: The proposed system assesses sub-surface optical absorption changes from jugular venous waveforms with a spatial calibration procedure to normalize incident tissue illumination. Widefield frames of the right lateral neck were captured and calibrated using a novel flexible surface calibration method. A hemodynamic optical model was derived to quantify jugular venous optical attenuation (JVA) signals, and generate a spatial jugular venous pulsatility map. JVA was assessed in three cardiovascular protocols that altered central venous pressure: acute central hypovolemia (lower body negative pressure), venous congestion (head-down tilt), and impaired cardiac filling (Valsalva maneuver). RESULTS: JVA waveforms exhibited biphasic wave properties consistent with jugular venous pulse dynamics when time-aligned with an electrocardiogram. JVA correlated strongly (median, interquartile range) with invasive central venous pressure during graded central hypovolemia (r = 0.85, [0.72, 0.95]), graded venous congestion (r = 0.94, [0.84, 0.99]), and impaired cardiac filling (r = 0.94, [0.85, 0.99]). Reduced JVA during graded acute hypovolemia was strongly correlated with reductions in stroke volume (SV) (r = 0.85, [0.76, 0.92]) from baseline (SV: 79 ± 15 mL, JVA: 0.56 ± 0.10 a.u.) to -40 mmHg suction (SV: 59 ± 18 mL, JVA: 0.47 ± 0.05 a.u.; p 0.01). CONCLUSION: The proposed non-contact optical imaging system demonstrated jugular venous dynamics consistent with invasive central venous monitoring during three protocols that altered central venous pressure. SIGNIFICANCE: This system provides non-invasive monitoring of pressure-induced jugular venous dynamics in clinically relevant conditions where catheterization is traditionally required, enabling monitoring in non-surgical environments.