Management of unscheduled bleeding on HRT: A joint guideline on behalf of the British Menopause Society, Royal College Obstetricians and Gynaecologists, British Gynaecological Cancer Society, British Society for Gynaecological Endoscopy, Faculty of Sexual and Reproductive Health, Royal College of General Practitioners and Getting it Right First Time.

Unscheduled bleeding on hormone replacement therapy (HRT) can affect up to 40% of users. In parallel with the increase in HRT prescribing in the UK, there has been an associated increase in referrals to the urgent suspicion of cancer pathway for unscheduled bleeding. On behalf of the British Menopause Society (BMS) an expert review panel was established, including primary and secondary care clinicians with expertise in the management of menopause, with representatives from key related organisations, including the Royal College of Obstetricians & Gynaecologists, the British Gynaecological Cancer Society, British Society for Gynaecological Endoscopy, Royal College of General Practitioners and Faculty of Sexual and Reproductive Health, and service development partners from NHS England and GIRFT (Getting it Right First Time). For each topic, a focused literature review was completed to develop evidence led recommendations, where available, which were ratified by consensus review within the panel and by guideline groups.

Sialyl-Tn serves as a potential therapeutic target for ovarian cancer.

BACKGROUND: Ovarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer. METHODS: We aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples. RESULTS: Our in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis. CONCLUSIONS: Our preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.

Digital health interventions for postoperative recovery in children: a systematic review.

BACKGROUND: Digital health interventions offer a promising approach for monitoring during postoperative recovery. However, the effectiveness of these interventions remains poorly understood, particularly in children. The objective of this study was to assess the efficacy of digital health interventions for postoperative recovery in children. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with the use of automation tools for searching and screening. We searched five electronic databases for randomised controlled trials or non-randomised studies of interventions that utilised digital health interventions to monitor postoperative recovery in children. The study quality was assessed using Cochrane Collaboration's Risk of Bias tools. The systematic review protocol was prospectively registered with PROSPERO (CRD42022351492). RESULTS: The review included 16 studies involving 2728 participants from six countries. Tonsillectomy was the most common surgery and smartphone apps (WeChat) were the most commonly used digital health interventions. Digital health interventions resulted in significant improvements in parental knowledge about the child's condition and satisfaction regarding perioperative instructions (standard mean difference=2.16, 95% confidence interval 1.45-2.87; z=5.98, P<0.001; I2=88%). However, there was no significant effect on children's pain intensity (standard mean difference=0.09, 95% confidence interval -0.95 to 1.12; z=0.16, P=0.87; I2=98%). CONCLUSIONS: Digital health interventions hold promise for improving parental postoperative knowledge and satisfaction. However, more research is needed for child-centric interventions with validated outcome measures. Future work should focus development and testing of user-friendly digital apps and wearables to ease the healthcare burden and improve outcomes for children. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42022351492).

Cardiovascular disease risk communication and prevention: a meta-analysis.

BACKGROUND AND AIMS: Knowledge of quantifiable cardiovascular disease (CVD) risk may improve health outcomes and trigger behavioural change in patients or clinicians. This review aimed to investigate the impact of CVD risk communication on patient-perceived CVD risk and changes in CVD risk factors. METHODS: PubMed, Embase, and PsycINFO databases were searched from inception to 6 June 2023, supplemented by citation analysis. Randomized trials that compared any CVD risk communication strategy versus usual care were included. Paired reviewers independently screened the identified records and extracted the data; disagreements were resolved by a third author. The primary outcome was the accuracy of risk perception. Secondary outcomes were clinician-reported changes in CVD risk, psychological responses, intention to modify lifestyle, and self-reported changes in risk factors and clinician prescribing of preventive medicines. RESULTS: Sixty-two trials were included. Accuracy of risk perception was higher among intervention participants (odds ratio = 2.31, 95% confidence interval = 1.63 to 3.27). A statistically significant improvement in overall CVD risk scores was found at 6-12 months (mean difference = -0.27, 95% confidence interval = -0.45 to -0.09). For primary prevention, risk communication significantly increased self-reported dietary modification (odds ratio = 1.50, 95% confidence interval = 1.21 to 1.86) with no increase in intention or actual changes in smoking cessation or physical activity. A significant impact on patients' intention to start preventive medication was found for primary and secondary prevention, with changes at follow-up for the primary prevention group. CONCLUSIONS: In this systematic review and meta-analysis, communicating CVD risk information, regardless of the method, reduced the overall risk factors and enhanced patients' self-perceived risk. Communication of CVD risk to patients should be considered in routine consultations.

Evaluating Sex Differences in the Characteristics and Outcomes of Lupus Nephritis: A Systematic Review and Meta-Analysis.

Introduction: More frequent and severe lupus nephritis (LN) has been reported in men compared to women, but data are limited and inconsistent. We conducted a meta-analysis of the literature to compare the histopathologic findings and outcomes between men and women with biopsy-proven LN. Methods: A systematic search of MEDLINE, Embase, Cochrane, and Web of Science databases was conducted through February 2021. Clinical information was extracted and synthesized from 25 studies that met inclusion criteria (1,210 men and 6,635 women). Pooled odds ratios (OR) with corresponding 95% confidence intervals (CIs) were generated via meta-analysis, and meta-regression was performed to assess the impact of several covariates, both using random-effects models. Results: Twenty studies reported kidney histopathology, eleven reported kidney outcomes, and eight reported mortality rates. Men had greater odds of class IV ± V LN (OR 1.26, 95% CI: 1.01-1.56), and the composite of end-stage kidney disease, persistent eGFR <15 mL/min or doubling of serum creatinine (OR 2.20, 95% CI: 1.59-3.06), and lower odds of complete remission (OR 0.52, 95% CI: 0.39-0.68). Mortality was not statistically significantly different between sexes (OR 1.50, 95% CI: 0.92-2.46). Meta-regression did not reveal statistically significant study-level relationships between sex differences in any of the covariates that could account for the greater odds of worse kidney outcome in males. Conclusion: Our analysis confirms the association between male sex and increased severity of LN as well as worse kidney outcomes. Larger prospective studies are needed to validate this association and inform treatment strategies adapted to this population.

Comparison of Telephone and Video Telehealth Consultations: Systematic Review.

BACKGROUND: Telehealth has been used for health care delivery for decades, but the COVID-19 pandemic greatly accelerated the uptake of telehealth in many care settings globally. However, few studies have carried out a direct comparison among different telehealth modalities, with very few studies having compared the effectiveness of telephone and video telehealth modalities. OBJECTIVE: This study aimed to identify and synthesize randomized controlled trials (RCTs) comparing synchronous telehealth consultations delivered by telephone and those conducted by video with outcomes such as clinical effectiveness, patient safety, cost-effectiveness, and patient and clinician satisfaction with care. METHODS: PubMed (MEDLINE), Embase, and CENTRAL were searched via the Cochrane Library from inception until February 10, 2023, for RCTs without any language restriction. Forward and backward citation searches were conducted on included RCTs. The Cochrane Risk of Bias 2 tool was used to assess the quality of the studies. We included studies carried out in any health setting-involving all types of outpatient cohorts and all types of health care providers-that compared synchronous video consultations directly with telephone consultations and reported outcomes specified in the objective. We excluded studies of clinician-to-clinician telehealth consults, hospitalized patients, and asynchronous consultations. RESULTS: Sixteen RCTs-10 in the United States, 3 in the United Kingdom, 2 in Canada, and 1 in Australia involving 1719 participants-were included in the qualitative and quantitative analyses. Most of the telehealth interventions were for hospital-based outpatient follow-ups, monitoring, and rehabilitation (n=13). The 3 studies that were conducted in the community all focused on smoking cessation. In half of the studies, nurses delivered the care (n=8). Almost all included studies had high or unclear risk of bias, mainly due to bias in the randomization process and selection of reported results. The trials found no substantial differences between telephone and video telehealth consultations with regard to clinical effectiveness, patient satisfaction, and health care use (cost-effectiveness) outcomes. None of the studies reported on patient safety or adverse events. We did not find any study on telehealth interventions for diagnosis, initiating new treatment, or those conducted in a primary care setting. CONCLUSIONS: Based on a small set of diverse trials, we found no notable differences between telephone and video consultations for the management of patients with an established diagnosis. There is also a significant lack of telehealth research in primary care settings despite its high uptake.

Comparing proficiency of obstetrics and gynaecology trainees with general surgery trainees using simulated laparoscopic tasks in Health Education England, North-West: a prospective observational study.

BACKGROUND: Training programmes for obstetrics and gynaecology (O&G) and general surgery (GS) vary significantly, but both require proficiency in laparoscopic skills. We sought to determine performance in each specialty. DESIGN: Prospective, observational study. SETTING: Health Education England North-West, UK. PARTICIPANTS: 47 surgical trainees (24 O&G and 23 GS) were subdivided into four groups: 11 junior O&G, 13 senior O&G, 11 junior GS and 12 senior GS trainees. OBJECTIVES: Trainees were tested on four simulated laparoscopic tasks: laparoscopic camera navigation (LCN), hand-eye coordination (HEC), bimanual coordination (BMC) and suturing with intracorporeal knot tying (suturing). RESULTS: O&G trainees completed LCN (p<0.001), HEC (p<0.001) and BMC (p<0.001) significantly slower than GS trainees. Furthermore, O&G found fewer number of targets in LCN (p=0.001) and dropped a greater number of pins than the GS trainees in BMC (p=0.04). In all three tasks, there were significant differences between O&G and GS trainees but no difference between the junior and senior groups within each specialty. Performance in suturing also varied by specialty; senior O&G trainees scored significantly lower than senior GS trainees (O&G 11.4±4.4 vs GS 16.8±2.1, p=0.03). Whilst suturing scores improved with seniority among O&G trainees, there was no difference between the junior and senior GS trainees (senior O&G 11.4±4.4 vs junior O&G 3.6±2.1, p=0.004). DISCUSSION: GS trainees performed better than O&G trainees in core laparoscopic skills, and the structure of O&G training may require modification. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05116332).

Functional Genomics of Gastrointestinal Escherichia coli Isolated from Patients with Cancer and Diarrhea.

We describe the epidemiology and clinical characteristics of 29 patients with cancer and diarrhea in whom Enteroaggregative Escherichia coli (EAEC) was initially identified by GI BioFire panel multiplex. E. coli strains were successfully isolated from fecal cultures in 14 of 29 patients. Six of the 14 strains were identified as EAEC and 8 belonged to other diverse E. coli groups of unknown pathogenesis. We investigated these strains by their adherence to human intestinal organoids, cytotoxic responses, antibiotic resistance profile, full sequencing of their genomes, and annotation of their functional virulome. Interestingly, we discovered novel and enhanced adherence and aggregative patterns for several diarrheagenic pathotypes that were not previously seen when co-cultured with immortalized cell lines. EAEC isolates displayed exceptional adherence and aggregation to human colonoids compared not only to diverse GI E. coli , but also compared to prototype strains of other diarrheagenic E. coli . Some of the diverse E. coli strains that could not be classified as a conventional pathotype also showed an enhanced aggregative and cytotoxic response. Notably, we found a high carriage rate of antibiotic resistance genes in both EAEC strains and diverse GI E. coli isolates and observed a positive correlation between adherence to colonoids and the number of metal acquisition genes carried in both EAEC and the diverse E. coli strains. This work indicates that E. coli from cancer patients constitute strains of remarkable pathotypic and genomic divergence, including strains of unknown disease etiology with unique virulomes. Future studies will allow for the opportunity to re-define E. coli pathotypes with greater diagnostic accuracy and into more clinically relevant groupings.

Class-Driven Synergy and Antagonism between a Pseudomonas Phage and Antibiotics.

The ubiquitous bacterial pathogen Pseudomonas aeruginosa is responsible for severe infections in patients with burns, cystic fibrosis, and neutropenia. Biofilm formation gives physical refuge and a protected microenvironment for sessile cells, rendering cure by antibiotics a challenge. Bacteriophages have evolved to prey on these biofilms over millions of years, using hydrolases and depolymerases to penetrate biofilms and reach cellular targets. Here, we assessed how a newly discovered KMV-like phage (ΦJB10) interacts with antibiotics to treat P. aeruginosa more effectively in both planktonic and biofilm forms. By testing representatives of four classes of antibiotics (cephalosporins, aminoglycosides, fluoroquinolones, and carbapenems), we demonstrated class-dependent interactions between ΦJB10 and antibiotics in both biofilm clearance and P. aeruginosa killing. Despite identifying antagonism between some antibiotic classes and ΦJB10 at early time points, all classes showed neutral to favorable interactions with the phage at later time points. In one notable example where the antibiotic alone had poor activity against both biofilm and high-density planktonic cells, we found that addition of ΦJB10 demonstrated synergy and resulted in effective treatment of both. Further, ΦJB10 seemed to act as an adjuvant to several antibiotics, reducing the concentration of antibiotics required to ablate the biofilm. This report shows that phages such as ΦJB10 may be valuable additions to the armamentarium against difficult-to-treat biofilm-based infections.

Effectiveness of discharge education for patients undergoing general surgery: A systematic review and meta-analysis.

BACKGROUND: There is some evidence to suggest that discharge education may reduce the risk of postoperative complications, however, a critical evaluation of the body of evidence is needed. OBJECTIVE: To assess the effect of discharge education interventions versus standard education given to general surgery patients prior to, or up to 30-days of hospital discharge on clinical and patient-reported outcomes. DESIGN: Systematic review and meta-analysis. Clinical outcomes were 30-day surgical site infection incidence and re-admission up to 28 days. Patient-reported outcomes included patient knowledge, self-confidence, satisfaction, and quality of life. SETTING: Participants were recruited from hospitals. PARTICIPANTS: Adult general surgical patients. METHODS: MEDLINE (Pubmed), CINAHL (EBSCO), EMBASE (Elsevier) and the Cochrane Library were searched in February 2022. Randomised controlled trials and non-randomised studies of interventions published between 2010 and 2022, with adults undergoing general surgical procedures receiving discharge education on surgical recovery, including wound management, were eligible for inclusion. Quality appraisal was undertaken using the Cochrane Risk of Bias 2 and the Risk of Bias Assessment Tool for Nonrandomised Studies. The Grading of Assessment, Development, Recommendations, and Evaluation was used to assess the certainty of the body of evidence based on the outcomes of interest. RESULTS: Ten eligible studies (eight randomised control trials and two non-randomised studies of interventions) with 965 patients were included. Six randomised control trials assessed the effect of discharge education interventions on 28-day readmission (Odds ratio 0.88, 95 % confidence interval 0.56-1.38). Two randomised control trials assessed the effect of discharge education interventions on surgical site infection incidence (Odds ratio = 0.84, 95 % confidence interval 0.39-1.82). The results of the non-randomised studies of interventions were not pooled due to heterogeneity in outcome measures. The risk of bias was either moderate or high for all outcomes, and the body of evidence using GRADE was judged as very low for all outcomes studied. CONCLUSIONS: The impact of discharge education on the clinical and patient-reported outcomes of patients undergoing general surgery cannot be determined due to the uncertainty of the evidence base. Despite the increased use of web-based interventions to deliver discharge education to general surgery patients, larger samples in more rigorous multicentre randomised control trials with parallel process evaluations are needed to better understand the effect of discharge education on clinical and patient-reported outcomes. REGISTRATION: PROSPERO CRD42021285392. TWEETABLE ABSTRACT: Discharge education may reduce the likelihood of surgical site infection and hospital readmission but the body of evidence is inconclusive.

Overuse of medications in low- and middle-income countries: a scoping review.

Objective: To identify and summarize the evidence about the extent of overuse of medications in low- and middle-income countries, its drivers, consequences and potential solutions. Methods: We conducted a scoping review by searching the databases PubMed®, Embase®, APA PsycINFO® and Global Index Medicus using a combination of MeSH terms and free text words around overuse of medications and overtreatment. We included studies in any language published before 25 October 2021 that reported on the extent of overuse, its drivers, consequences and solutions. Findings: We screened 3489 unique records and included 367 studies reporting on over 5.1 million prescriptions across 80 low- and middle-income countries - with studies from 58.6% (17/29) of all low-, 62.0% (31/50) of all lower-middle- and 60.0% (33/55) of all upper-middle-income countries. Of the included studies, 307 (83.7%) reported on the extent of overuse of medications, with estimates ranging from 7.3% to 98.2% (interquartile range: 30.2-64.5). Commonly overused classes included antimicrobials, psychotropic drugs, proton pump inhibitors and antihypertensive drugs. Drivers included limited knowledge of harms of overuse, polypharmacy, poor regulation and financial influences. Consequences were patient harm and cost. Only 11.4% (42/367) of studies evaluated solutions, which included regulatory reforms, educational, deprescribing and audit-feedback initiatives. Conclusion: Growing evidence suggests overuse of medications is widespread within low- and middle-income countries, across multiple drug classes, with few data of solutions from randomized trials. Opportunities exist to build collaborations to rigorously develop and evaluate potential solutions to reduce overuse of medications.

Metabolic aspects of surgical subcutaneous fat removal: An umbrella review and implications for future research.

Although obesity is a preventable disease, maintaining a normal body weight can be very challenging and difficult, which has led to a significant increase in the demand for surgical subcutaneous fat removal (SSFR) to improve physical appearance. The need for SSFR is further exacerbated because of the global rise in the number of bariatric surgeries, which is currently the single most durable intervention for mitigating obesity. Fat tissue is now recognized as a vital endocrine organ that produces several bioactive proteins. Thus, SSFR-mediated weight (fat) loss can potentially have significant metabolic effects; however, currently, there is no consensus on this issue. This review focuses on the metabolic sequelae after SSFR interventions for dealing with cosmetic body appearance. Data was extracted from existing systematic reviews and the diversity of possible metabolic changes after SSFR are reported along with gaps in the knowledge and future directions for research and practice. We conclude that there is a potential for metabolic sequelae after SSFR interventions and their clinical implications for the safety of the procedures as well as for our understanding of subcutaneous adipose tissue biology and insulin resistance are discussed.

Metabolic changes after surgical fat removal: A dose-response meta-analysis.

BACKGROUND: Bariatric surgery averts obesity-induced insulin resistance and the metabolic syndrome. By contrast, surgical fat removal is considered merely an esthetic endeavor. The aim of this article was to establish whether surgical fat removal, similar to bariatric surgery, exerts measurable, lasting metabolic benefits. METHODS: PubMed, Embase, and Scopus were searched using the Polyglot Search Translator to find studies examining quantitative expression of metabolic markers. Quality assessment was done using the MethodologicAl STandard for Epidemiological Research scale. The robust-error meta-regression model was employed for this synthesis. RESULTS: Twenty-two studies with 493 participants were included. Insulin sensitivity improved gradually with a maximum reduction in fasting insulin and homeostatic model assessment for insulin resistance of 17 pmol/L and 1 point, respectively, at postoperative day 180. Peak metabolic benefits manifest as a reduction of 2 units in body mass index, 3 kg of fat mass, 5 cm of waist circumference, 15 µg/L of serum leptin, 0.75 pg/ml of tumor necrosis factor-alpha, 0.25 mmol/L of total cholesterol, and 3.5 mmHg of systolic and diastolic blood pressure that were observed at day 50 but were followed by a return to preoperative levels by day 180. Serum high-density lipoproteins peaked at 50 days post-surgery before falling below the baseline. No significant changes were observed in lean body mass, serum adiponectin, resistin, interleukin-6, C-reactive protein, triglyceride, low-density lipoproteins, free fatty acids, and fasting blood glucose. CONCLUSION: Surgical fat removal exerts several metabolic benefits in the short term, but only improvements in insulin sensitivity last beyond 6 months.

Metabolic changes after nonsurgical fat removal: A dose response meta-analysis.

BACKGROUND: Obesity-induced insulin resistance leads to the metabolic syndrome. Both bariatric surgery and surgical fat removal have been shown to improve metabolic health, but the metabolic benefits of nonsurgical fat removal remain uncertain. The aim of this paper is to establish whether nonsurgical fat removal exerts measurable, lasting metabolic benefits by way of changes to serum lipid profiles. METHODS: PubMed, Cochrane CENTRAL, Embase, and clinical trials registers were searched using the Polyglot Search Translator to find studies examining quantitative changes in metabolic markers after nonsurgical body contouring procedures. The MethodologicAl STandard for Epidemiological Research (MASTER) scale was adopted for the quality assessment of the included studies. The robust-error meta-regression (REMR) model was employed. RESULTS: Twenty-two studies and 676 participants were included. Peak body compositions measures manifest as a reduction of 2 units in body mass index (BMI), 1 kg of body weight (BW), 5 cm in waist circumference (WC) and 1.5 cm in abdominal fat thickness (FT), sustained up to 60 days postprocedure. Transient increases of 15 mg/dL in low-density lipoprotein (LDL), 10 mg/dl in triglycerides (TG), and 15 mg/dl in total cholesterol (TC) were observed at 2 weeks postprocedure. CONCLUSION: While nonsurgical fat removal exerts sustained effects on body anthropometrics, changes to serum lipid profiles were transient. There is no compelling evidence at present to support the conclusion that nonsurgical fat removal is metabolically beneficial.

Overdiagnosis and overuse of diagnostic and screening tests in low-income and middle-income countries: a scoping review.

OBJECTIVE: Overdiagnosis and overuse of healthcare services harm individuals, take resources that could be used to address underuse, and threaten the sustainability of health systems. These problems are attracting increasing attention in low-income and middle-income countries (LMICs). Unaware of any review of relevant evidence, we conducted a scoping review of the evidence around overdiagnosis and overuse of diagnostic and screening tests in LMICs. DESIGN: Scoping review. METHODS: We searched PubMed, Embase, PsycINFO, Global Index Medicus for relevant studies published until 24 May 2021, with no restrictions on date or language. We categorised included studies by major focus (overdiagnosis, overuse of tests, or both) and main themes (presence or estimates of extent; drivers; consequences and solutions). RESULTS: We identified 2763 unique records and included 162 articles reporting on 154 studies across 55 countries, involving over 2.8 million participants and/or requests for tests. Almost half the studies focused on overdiagnosis (70; 45.5%), one-third on overuse of tests (61; 39.6%) and one-fifth on both (23; 14.9%). Common overdiagnosed conditions included malaria (61; 39.6%) and thyroid cancer (25; 16.2%), estimated to be >70% in China. Overused tests included imaging (n=25 studies) such as CT and MRI; laboratory investigations (n=18) such as serological tests and tumour markers; and procedures (n=14) such as colonoscopy. Drivers included fear of conflict with patients and expanding disease definitions. Common consequences included unnecessary treatments such as antimalarials, and wasted resources, with costs of malaria overdiagnosis estimated at US$86 million in Sudan in 1 year alone. Only 9% of studies discussed solutions, which included addressing inappropriately lowered diagnostic thresholds and reforming test-ordering processes. CONCLUSIONS: Overdiagnosis and overuse of tests are widespread in LMICs and generate significant harm and waste. Better understanding of the problems and robust evaluation of solutions is needed, informed by a new global alliance of researchers and policy-makers.

Is There a Doctors' Effect on Patients' Physical Health, Beyond the Intervention and All Known Factors? A Systematic Review.

Purpose: Despite billions of doctor visits worldwide each year, little is known on whether doctors themselves affect patients' physical health after accounting for intervention and confounders such as patients' and doctors' data, hospital effects, nor how strong that doctors' effect is. Knowledge of surgeons' and psychotherapists' effects exists, but not for 102 other medical specialties notwithstanding the importance of such knowledge. Methods: Eligibility Criteria: Randomized controlled trials (RCTs), case-control, and cohort studies including medical doctors except surgeons for any intervention, reporting the proportion of variance in patients' outcomes owing to the doctors (random effects), or the fixed effects of grading doctors by outcomes, after multivariate adjustment. Exclusions: studies of <15 doctors or solely reporting doctors' effects for known variables. Sources: Medline, Embase, PsycINFO, inception to June 2020. Manual search for papers referring/referred to by resulting studies. Risk of Bias: Using Newcastle-Ottawa scale. Results: Despite all medical interventions bar surgery being eligible, only thirty cohort papers were found, covering 36,239 doctors, with 10 specialties, 21 interventions, 60 outcomes (17 unique). Studies reported doctors' effects by grading doctors from best to worst, or by diversely calculating the doctor-attributed percentage of patients' outcome variation, ie the intra-class correlation coefficient (ICC). Sixteen studies presented fixed effects, 18 random effects, and 3 another approach. No RCTs found. Thirteen studies reported exceptionally good and/or poor performers with confidence intervals wholly outside the average performance. ICC range 0 to 33%, mean 3.9%. Highly diverse reporting, meta-analysis therefore not applicable. Conclusion: Doctors, on their own, can affect patients' physical health for many interventions and outcomes. Effects range from negligible to substantial, even after accounting for all known variables. Many published cohorts may reveal valuable information by reanalyzing their data for doctors' effects. Positive and negative doctor outliers appear regularly. Therefore, it can matter which doctor is chosen.

Is There a Surgeons' Effect on Patients' Physical Health, Beyond the Intervention, That Requires Further Investigation? A Systematic Review.

Objective: To find and review published papers researching surgeons' effects on patients' physical health. Clinical outcomes of surgery patients with similar prognoses cannot be fully explained by surgeon skill or experience. Just as there are "hospital" and "psychotherapist" effects, there may be "surgeons" effects that persist after controlling for known variables like patient health and operation riskiness. Methods: Cohort studies and randomized controlled trials (RCTs) of any surgical intervention, which, after multivariate adjustment, either showed proportion of variance in patients' physical health outcomes due to surgeons (random effects) or graded surgeons from best to worst (fixed effects). Studies with <15 surgeons or only ascribing surgeons' effects to known variables excluded. Medline, PubMed, Embase, and PsycINFO were used for search until June 2020. Manual search for papers referring/referred by resulting studies. Risk of bias assessed by Cochrane risk-of-bias tool and Newcastle-Ottawa Scale. Results: Included studies: 52 cohort studies and three RCTs of 52,436+ surgeons covering 102 outcomes (33 unique). Studies either graded surgeons from best to worst or calculated the intra-class correlation coefficient (ICC), the percentage of patients' variation due to surgeons, in diverse ways. Sixteen studies showed exceptionally good and/or bad performers with confidence intervals wholly above or below the average performance. ICCs ranged from 0 to 47%, median 4.0%. There are no well-established reporting standards; highly heterogeneous reporting, therefore no meta-analysis. Discussion: Interpretation: There is a surgeons' effect on patients' physical health for many types of surgeries and outcomes, ranging from small to substantial. Surgeons with exceptional patient outcomes appear regularly even after accounting for all known confounding variables. Many existing cohort studies and RCTs could be reanalyzed for surgeons' effects especially after methodological reporting guidelines are published. Conclusion: In terms of patient outcomes, it can matter which surgeon is chosen. Surgeons with exceptional patient outcomes are worth studying further.

Long Term Survivals in Aggressive Primary Brain Malignancies Treated With an Adjuvant Ketogenic Diet.

Aggressive primary brain tumors (APBT) glioblastoma multiforme and grade IV astrocytoma are treated with multimodality treatments that include surgery to remove as much tumor as possible without sacrificing neurological function followed by radiation therapy and chemotherapy usually temozolomide. Survivals in adults are in the range of 8-16 months. The addition of a ketogenic diet (KD) to rodents with transplanted brain tumors increased survival in nine of 11 animals to over 299 days compared to survival in untreated controls of 33 days and radiation only controls of 38 days. We treated humans with APBT with standard of care neurosurgery immediately followed by 6 weeks of an adjuvant ketogenic diet concurrent with radiation therapy and temozolomide. Twice daily measurements of blood ketones and glucose were recorded and the patients' diet was modified toward the goal of maintaining blood ketone levels approaching 3 mM. Of the nine patients who completed the protocol three younger patients age 32, 28, and 22 at enrollment are alive and employed with clinically stable disease and brain images 74, 58, and 52 months since diagnosis. All the six older patients mean age 55 have died with disease progression detected on average 8 months after Dx. In conclusion: 1. It is possible to implement and maintain dietary induced ketosis in patients with APBT; 2. The longer survivals observed in younger patients treated with KD need to be confirmed in larger studies that should be focused on younger patients possibly under age 40.

Sortilin enhances secretion of apolipoprotein(a) through effects on apolipoprotein B secretion and promotes uptake of lipoprotein(a).

Elevated plasma lipoprotein(a) (Lp(a)) is an independent, causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Lp(a) is formed in or on hepatocytes from successive noncovalent and covalent interactions between apo(a) and apoB, although the subcellular location of these interactions and the nature of the apoB-containing particle involved remain unclear. Sortilin, encoded by the SORT1 gene, modulates apoB secretion and LDL clearance. We used a HepG2 cell model to study the secretion kinetics of apo(a) and apoB. Overexpression of sortilin increased apo(a) secretion, while siRNA-mediated knockdown of sortilin expression correspondingly decreased apo(a) secretion. Sortilin binds LDL but not apo(a) or Lp(a), indicating that its effect on apo(a) secretion is likely indirect. Indeed, the effect was dependent on the ability of apo(a) to interact noncovalently with apoB. Overexpression of sortilin enhanced internalization of Lp(a), but not apo(a), by HepG2 cells, although neither sortilin knockdown in these cells or Sort1 deficiency in mice impacted Lp(a) uptake. We found several missense mutations in SORT1 in patients with extremely high Lp(a) levels; sortilin containing some of these mutations was more effective at promoting apo(a) secretion than WT sortilin, though no differences were found with respect to Lp(a) internalization. Our observations suggest that sortilin could play a role in determining plasma Lp(a) levels and corroborate in vivo human kinetic studies which imply that secretion of apo(a) and apoB are coupled, likely within the hepatocyte.

Apo(a) and ApoB Interact Noncovalently Within Hepatocytes: Implications for Regulation of Lp(a) Levels by Modulation of ApoB Secretion.

BACKGROUND: Elevated plasma Lp(a) (lipoprotein(a)) levels are associated with increased risk for atherosclerotic cardiovascular disease and aortic valve stenosis. However, the cell biology of Lp(a) biosynthesis remains poorly understood, with the locations of the noncovalent and covalent steps of Lp(a) assembly unclear and the nature of the apoB-containing particle destined for Lp(a) unknown. We, therefore, asked if apo(a) and apoB interact noncovalently within hepatocytes and if this impacts Lp(a) biosynthesis. METHODS: Using human hepatocellular carcinoma cells expressing 17K (17 kringle) apo(a), or a 17KΔLBS7,8 variant with a reduced ability to bind noncovalently to apoB, we performed coimmunoprecipitation, coimmunofluorescence, and proximity ligation assays to document intracellular apo(a):apoB interactions. We used a pulse-chase metabolic labeling approach to measure apo(a) and apoB secretion rates. RESULTS: Noncovalent complexes containing apo(a)/apoB are present in lysates from cells expressing 17K but not 17KΔLBS7,8, whereas covalent apo(a)/apoB complexes are absent from lysates. 17K and apoB colocalized intracellularly, overlapping with staining for markers of endoplasmic reticulum trans-Golgi, and early endosomes, and less so with lysosomes. The 17KΔLBS7,8 had lower colocalization with apoB. Proximity ligation assays directly documented intracellular 17K/apoB interactions, which were dramatically reduced for 17KΔLBS7,8. Treatment of cells with PCSK9 (proprotein convertase subtilisin/kexin type 9) enhanced, and lomitapide reduced, apo(a) secretion in a manner dependent on the noncovalent interaction between apo(a) and apoB. Apo(a) secretion was also reduced by siRNA-mediated knockdown of APOB. CONCLUSIONS: Our findings explain the coupling of apo(a) and Lp(a)-apoB production observed in human metabolic studies using stable isotopes as well as the ability of agents that inhibit apoB biosynthesis to lower Lp(a) levels.