U.S. primary care physician perceptions on barriers to providing guideline-driven care for UTI and recurrent UTI: a qualitative study.

BACKGROUND: Urinary tract infections (UTI) affect almost two-thirds of all women during their lives and many experience recurrent infections. There are evidence-based guidelines from multiple international societies for evaluation and treatment; however, recent claims-based analyses have demonstrated that adherence to these guidelines is poor. This study seeks to understand the barriers experienced by U.S. primary care providers (PCPs) to providing guideline-based care for UTI and recurrent UTI (rUTI). METHODS: Semi-structured interviews of 18 PCPs, recruited from the greater Los Angeles area, examined real-world clinical management of UTI/rUTI episodes, decisions to refer to subspecialty care, and resources guiding counseling and management. Grounded theory methodology served to analyze interview transcripts and identify preliminary and major themes. RESULTS: Participants expressed the desire to obtain urine cultures for each cystitis episode, but felt pressured to make compromises by patient demands or barriers to care. PCPs had lower thresholds to empirical treatment if patients had a history of rUTIs, were elderly, or declined evaluation. Laboratory data was minimally utilized in clinical decision-making: urinalyses were infrequently considered when interpreting culture data. PCPs treated a broad set of urologic and non-urologic symptoms as UTI, even with negative cultures. PCPs did not feel comfortable initiating UTI prophylaxis, instead seeking specialist evaluation for anatomic causes. They were unaware of management guidelines, typically utilizing UpToDate® as their primary resource. Few evidence-based UTI prevention interventions were recommended by providers. CONCLUSIONS: Low availability of succinct and clear professional guidelines are substantial barriers to appropriate UTI/rUTI care. Poor useability of clinical guidance documents results in substantial confusion about the role of preventative measures and additional diagnostic testing. Difficulties in patient access to care providers lead to expectations for presumptive treatment. Future studies are needed to determine if improved educational materials for providers and/or management algorithms can improve guideline concordance of UTI management.

Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation.

INTRODUCTION: Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. RESULTS: CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. DISCUSSION: The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. HIGHLIGHTS: Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

Suicide after colorectal cancer-a national population-based study.

AIM: A cancer diagnosis is often associated with physical as well as emotional distress. Previous studies indicate a higher risk for suicide in patients diagnosed with cancer. The aim of this study was to investigate the prevalence of death by suicide in a national cohort of patients with newly diagnosed colorectal cancer compared with a matched control group to determine if patients with colorectal cancer had an increased incidence of death by suicide. METHOD: This national Swedish cohort was retrieved from the register-based research database CRCBaSe, which includes all patients diagnosed with colorectal cancer between 1997-2006 (rectal) and 2008-2016 (colon) and six controls for each patient matched by age, sex, and county. Cause specific mortality due to suicide was modelled using Cox proportional hazards model and adjusted for known risk factors. RESULTS: The main analysis included patients operated for colorectal cancer, 55 578 patients compared with 307 888 controls. The first year after diagnosis the hazard ratio (HR) for suicide among patients operated for colorectal cancer was 1.86 (CI: 1.18-2.95) compared to controls. Suicide was more common among men than women (HR 2.08; 1.26-3.42 vs. 1.09; 0.32-3.75). A subgroup analysis of the 9198 patients who did not undergo surgery after diagnoses found a seven-fold increase of suicide (HR 7.03; 3.10-15.91). CONCLUSION: Suicide after surgery for colorectal cancer was almost twice as high as in the control group, mainly driven by excess mortality among men. Although the cases were few in the subgroup of nonoperated patients, the considerably higher risk of suicide indicates that more resources might be needed in this group. Evaluation of risk factors for suicide among patients with colorectal cancer should be performed for early identification of individuals at risk.

Bowel Dysfunction After Colon Cancer Surgery: A Prospective, Longitudinal, Multicenter Study.

BACKGROUND: Longitudinal studies on functional outcome after colon resection are limited. OBJECTIVE: Examine bowel dysfunction and related distress one and three years after colon resection utilizing the low anterior resection syndrome score as well as specific validated items. DESIGN: This study presents the long-term results of bowel dysfunction and related distress based on the quality of life in colon cancer study, an observational, prospective multicenter study of patients with newly diagnosed colon cancer. SETTINGS: The study was conducted at 21 Swedish and Danish surgical centers between 2015 and 2019. PATIENTS: All patients who underwent right- or left-sided colon resection were considered eligible. Exclusion criteria were age below 18, cognitive impairment or inability to understand Swedish/Danish. Patients completed extensive questionnaires at diagnosis, and after one and three years. Clinical data were supplemented by national quality registries. MAIN OUTCOME MEASURES: The low anterior resection syndrome score, specific bowel symptoms and the patient-reported distress were assessed. RESULTS: Of 1,221 patients (83% response rate), 17% reported major LARS one year after either type of resection, consistent at 3 years (17% right, 16% left). In the long-term, the only significant difference between types of resection was a high occurrence of loose stools following right-sided resections. Overall, less than one-fifth of patients experienced distress, with women reporting more frequent symptoms and greater distress. In particular, incontinence and loose stools correlated strongly with distress. LIMITATIONS: Absence of pre-diagnosis bowel function data. CONCLUSIONS: Our study indicates that bowel function remains largely intact following colon resection, with only a minority reporting significant distress. Adverse outcomes were more common among women. The occurrence of loose stools following right-sided resection and the association between incontinence, loose stools, and distress highlights a need for postoperative evaluations and more thorough assessments beyond the LARS score when evaluating colon cancer patients. See Video Abstract.

The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation.

TIMELESS (TIM) in the fork protection complex acts as a scaffold of the replisome to prevent its uncoupling and ensure efficient DNA replication fork progression. Nevertheless, its underlying basis for coordinating leading and lagging strand synthesis to limit single-stranded DNA (ssDNA) exposure remains elusive. Here, we demonstrate that acute degradation of TIM at ongoing DNA replication forks induces the accumulation of ssDNA gaps stemming from defective Okazaki fragment (OF) processing. Cells devoid of TIM fail to support the poly(ADP-ribosyl)ation necessary for backing up the canonical OF processing mechanism mediated by LIG1 and FEN1. Consequently, recruitment of XRCC1, a known effector of PARP1-dependent single-strand break repair, to post-replicative ssDNA gaps behind replication forks is impaired. Physical disruption of the TIM-PARP1 complex phenocopies the rapid loss of TIM, indicating that the TIM-PARP1 interaction is critical for the activation of this compensatory pathway. Accordingly, combined deficiency of FEN1 and the TIM-PARP1 interaction leads to synergistic DNA damage and cytotoxicity. We propose that TIM is essential for the engagement of PARP1 to the replisome to coordinate lagging strand synthesis with replication fork progression. Our study identifies TIM as a synthetic lethal target of OF processing enzymes that can be exploited for cancer therapy.

Morbidity and mortality in patients with stage IV pancreatic adenocarcinoma and acute cholangitis: Outcomes and risk prognostication.

BACKGROUND: Acute cholangitis (AC) is a common complication of pancreatic ductal adenocarcinoma (PDAC). Herein, we evaluated outcomes after the first AC episode and predictors of mortality and AC recurrence in patients with stage IV PDAC. METHODS: We conducted a single-center, retrospective observational study using institutional databases. Clinical data and outcomes for patients with stage IV PDAC and at least one documented episode of AC, were assessed. Overall survival (OS) was estimated using the Kaplan-Meier method, and Cox regression model was employed to identify predictors of AC recurrence and mortality. RESULTS: One hundred and twenty-four patients with stage IV PDAC and AC identified between January 01, 2014 and October 31, 2020 were included. Median OS after first episode of AC was 4.1 months (95 % CI, 4.0-5.5), and 30-day, 6, and 12-month survival was 86.2 % (95 % CI, 80.3-92.5), 37 % (95 % CI, 29.3-46.6 %) and 18.9 % (95 % CI, 13.1-27.3 %), respectively. Primary tumor in pancreatic body/tail (HR 2.29, 95 % CI: 1.26 to 4.18, p = 0.011), concomitant metastases to liver and other sites (HR 1.96, 95 % CI: 1.16 to 3.31, p = 0.003) and grade 3 AC (HR 2.26, 95 % CI: 1.45 to 3.52, p < 0.001), predicted worse outcomes. Intensive care unit admission, sepsis, systemic therapy, treatment regimen, and time to intervention did not predict survival or risk of recurrence of AC. CONCLUSIONS: AC confers significant morbidity and mortality in advanced PDAC. Worse outcomes are associated with higher grade AC, primary tumor location in pancreatic body/tail, and metastases to liver and other sites.

Preoperative beta blockers and other drugs in relation to anastomotic leakage after anterior resection for rectal cancer.

AIM: Previous research has indicated that preoperative beta blocker therapy is associated with a decreased risk of complications after surgery for rectal cancer. This is thought to arise because of the anti-inflammatory activity of the drug. These results need to be reproduced and analyses extended to other drugs with such properties, as this information might be useful in clinical decision-making. The main aim of this work was to replicate previous findings of beta blocker use as a prognostic marker for postoperative leakage. We also investigated whether drug exposure might induce anastomotic leaks. METHOD: This is a retrospective multicentre cohort study, comprising 1126 patients who underwent anterior resection for rectal cancer between 2014 and 2018. The use of any preoperative beta blocker was treated as the primary exposure, while anastomotic leakage within 12 months of surgery was the outcome. Secondary exposures comprised angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins and metformin. Using multivariable regression, we performed a replication analysis with a predictive aim for beta blockers only, while adjustment for confounding was done in more causally oriented analyses for all drugs. We estimated incidence rate ratio (IRR) and relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Anastomotic leakage occurred in 20.6% of patients. Preoperative beta blockers were used by 22.7% of the cohort, while the leak distribution was almost identical between exposure groups. In the main replication analysis, no association could be detected (IRR 0.95, 95% CI 0.68-1.33). In the causally oriented analyses, only metformin affected the risk of leakage (RR 1.59, 95% Cl 1.31-1.92). CONCLUSION: While previous research has suggested that preoperative beta blocker use could be prognostic of anastomotic leakage, this study could not detect any such association. On the contrary, our results indicate that preoperative beta blocker use neither predicts nor causes anastomotic leakage after anterior resection for rectal cancer.

Poly(ADP-ribosyl)ation of TIMELESS limits DNA replication stress and promotes stalled fork protection.

Poly(ADP-ribosyl)ation (PARylation), catalyzed mainly by poly(ADP-ribose) polymerase (PARP)1, is a key posttranslational modification involved in DNA replication and repair. Here, we report that TIMELESS (TIM), an essential scaffold of the replisome, is PARylated, which is linked to its proteolysis. TIM PARylation requires recognition of auto-modified PARP1 via two poly(ADP-ribose)-binding motifs, which primes TIM for proteasome-dependent degradation. Cells expressing the PARylation-refractory TIM mutant or under PARP inhibition accumulate TIM at DNA replication forks, causing replication stress and hyper-resection of stalled forks. Mechanistically, aberrant engagement of TIM with the replicative helicase impedes RAD51 loading and protection of reversed forks. Accordingly, defective TIM degradation hypersensitizes BRCA2-deficient cells to replication damage. Our study defines TIM as a substrate of PARP1 and elucidates how the control of replisome remodeling by PARylation is linked to stalled fork protection. Therefore, we propose a mechanism of PARP inhibition that impinges on the DNA replication fork instability caused by defective TIM turnover.

Anastomotic Leakage in Relation to Type of Mesorectal Excision and Defunctioning Stoma Use in Anterior Resection for Rectal Cancer.

BACKGROUND: Anastomotic leakage after anterior resection for rectal cancer is more common after total mesorectal excision compared to partial mesorectal excision but might be mitigated by a defunctioning stoma. OBJECTIVE: The aim is to assess how anastomotic leakage is affected by type of mesorectal excision and defunctioning stoma use. DESIGN: This is a retrospective multicenter cohort study evaluating anastomotic leakage after anterior resection. Multivariable Cox regression with HRs and 95% CIs was used to contrast mesorectal excision types and defunctioning stoma use with respect to anastomotic leakage, with adjustment for confounding. SETTINGS: This multicenter study included patients from 11 Swedish hospitals between 2014 and 2018. PATIENTS: Patients who underwent anterior resection for rectal cancer were included. MAIN OUTCOMES MEASURES: Anastomotic leakage rates within and after 30 days of surgery are described up to 1 year after surgery. RESULTS: Anastomotic leakage occurred in 24.2% and 9.0% of 1126 patients operated with total and partial mesorectal excision, respectively. Partial compared to total mesorectal excision was associated with a reduction in leakage, with an adjusted HR of 0.46 (95% CI, 0.29-0.74). Early leak rates within 30 days were 14.9% with and 12.5% without a stoma, whereas late leak rates after 30 days were 7.5% with and 1.9% without a stoma. After adjustment, defunctioning stoma was associated with a lower early leak rate (HR 0.47; 95% CI, 0.28-0.77). However, the late leak rate was nonsignificantly higher in patients with defunctioning stomas (HR 1.69; 95% CI, 0.59-4.85). LIMITATIONS: This study was limited by its retrospective observational study design. CONCLUSIONS: Anastomotic leakage is common up to 1 year after anterior resection for rectal cancer, where partial mesorectal excision is associated with a lower leak rate. Defunctioning stomas seem to decrease the occurrence of leakage, although partially by only delaying the diagnosis. See Video Abstract . FUGA ANASTOMTICA SEGN EL TIPO DE EXCISIN MESORRECTAL Y LA CONFECCIN DE OSTOMA DE PROTECCIN EN LA RESECCIN ANTERIOR POR CNCER DE RECTO: ANTECEDENTES:La fuga anastomótica después de una resección anterior por cáncer de recto es más frecuente después de la excisión total del mesorrecto comparada con la excisión parcial del mismo, pero podría mitigarse con la confección de ostomías de protección.OBJETIVO:El objetivo es evaluar cómo la fuga anastomótica se ve afectada según el tipo de excisión mesorrectal y la confección de una ostomía de protección.DISEÑO:Estudio de cohortes multicéntrico y retrospectivo que evalúa la fuga anastomótica después de la resección anterior. Se aplicó la regresión multivariada de Cox con los índices de riesgo (HR) y los intervalos de confianza (IC) al 95% para contrastar los tipos de excisión mesorrectal y el uso de otomías de protección con respecto a la fuga anastomótica, realizando ajustes respecto a las variables de confusión.AJUSTES:El presente estudio multicéntrico incluyó pacientes de 11 hospitales suecos entre 2014 y 2018.PACIENTES:Se incluyeron todos aquellos sometidos a resección anterior por cáncer de recto.PRINCIPALES MEDIDAS DE RESULTADOS:Las tasas de fuga anastomótica dentro y después de los 30 días de la cirugía fueron descritos hasta un año mas tarde al acto quirúrgico.RESULTADOS:La fuga anastomótica ocurrió en el 24,2% y el 9,0% de 1126 pacientes operados por excisión total y parcial del mesorrecto respectivamente.La excisión parcial del mesorrecto en comparación con la total se asoció con una reducción de la fuga, HR ajustado de 0,46 (IC del 95 %: 0,29 a 0,74). Las tasas de fuga temprana dentro de los 30 días fueron del 14,9 % con y el 12,5 % sin estoma, mientras que las tasas de fuga tardía después de 30 días fueron del 7,5 % con y el 1,9 % sin estoma.Después del ajuste de variables de confusión, las ostomías de protección se asociaron con una tasa de fuga temprana más baja (HR 0,47; IC 95 %: 0,28-0,77). Sin embargo, la tasa de fuga tardía no fue significativamente mayor en pacientes ostomizados (HR 1,69; IC 95%: 0,59-4,85).LIMITACIONES:Las limitaciones del presente estudio estuvieron vinculadas con el diseño de tipo observacional y retrospectivo.CONCLUSIONES:La fuga anastomótica es común hasta un año después de la resección anterior por cáncer de recto, donde la excisión parcial del mesorrecto se asocia con una menor tasa de fuga. La confección de ostomías de protección parece disminuir la aparición de fuga anastomótica, aunque en parte sólo retrasen el diagnóstico. (Traducción-Dr. Xavier Delgadillo ).

Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes.

INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: ß = 2.44, p < 0.001, M7: ß = 2.57, p < 0.001) and executive function performance (M4: ß = -2.00, p = 0.005, M7: ß = -2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

Splenic flexure mobilization and anastomotic leakage in anterior resection for rectal cancer: A multicentre cohort study.

BACKGROUND AND OBJECTIVE: Some colorectal surgeons advocate routine splenic flexure mobilization (SFM) when performing anterior resection for rectal cancer to ensure a tension-free anastomosis. Meta-analyses of smaller studies suggest that this approach does not influence anastomotic leakage rates, but larger multicentre studies are needed to confirm the safety of a selective strategy. The aim of this study is to evaluate the impact of SFM on anastomotic leakage. METHODS: This is a retrospective multicentre cohort study, comprising 1109 patients operated with anterior resection for rectal cancer in 2014-2018. Exposure was SFM, while anastomotic leakage within a year constituted the outcome. Stratified analyses were performed for type of mesorectal excision and surgical approach, as well as sensitivity analysis considering vascular tie placement. Multivariable Cox regression with hazard ratios (HRs) and 95% confidence intervals (CIs) was employed to adjust for confounding, while multiple imputation was used for missing data. RESULTS: SFM was performed in 381 patients (34.4%). Anastomotic leakage occurred in 83 (21.8%) and 123 (20.3%) patients operated with and without SFM, respectively. SFM was neither clearly detrimental nor beneficial regarding anastomotic leakage (adjusted HR = 0.82; 95% CI: 0.59-1.15), with no apparent differences for total or partial mesorectal excision and minimally invasive or open surgery. Concurrent high vascular ligation did not impact these results, and there was no evidence of interaction from centers with a more common use of SFM. CONCLUSIONS: SFM did not seem to influence the risk of anastomotic leakage after anterior resection for rectal cancer, regardless of type of mesorectal excision, use of minimally invasive surgery, or high vascular ligation.

The modified Glasgow Prognostic Score indicates an increased risk of anastomotic leakage after anterior resection for rectal cancer.

BACKGROUND: Preoperative inflammation might cause and also be a marker for anastomotic leakage after anterior resection for rectal cancer. Available biomarker indices such as the modified Glasgow Prognostic Score (mGPS) or the C-reactive protein-to-albumin ratio (CAR) may be clinically useful for leakage assessment. METHODS: Patients who underwent anterior resection for rectal cancer during 2014-2018 from a multicentre retrospective cohort were included. Data from the Swedish Colorectal Cancer registry and chart review at each hospital were collected. In a subset of patients, preoperative laboratory assessments were available, constituting the exposures mGPS and CAR. Anastomotic leakage within 12 months was the outcome. Causally oriented analyses were conducted with adjustment for confounding, as well as predictive models. RESULTS: A total of 418 patients were eligible for analysis. Most patients had mGPS = 0 (84.7%), while mGPS = 1 (10.8%) and mGPS = 2 (4.5%) were less common. mGPS = 2 (OR: 4.11; 95% CI: 1.69-10.03) seemed to confer anastomotic leakage, while this was not seen for mGPS = 1 (OR 1.09; 95% CI: 0.53-2.25). A cut off point of CAR > 0.36 might be indicative of leakage (OR 2.25; 95% CI: 1.21-4.19). Predictive modelling using mGPS rendered an area-under-the-curve of 0.73 (95% CI: 0.67-0.79) at most. DISCUSSION: Preoperative inflammation seems to be involved in the development of anastomotic leakage after anterior resection for cancer. Inclusion into prediction models did not result in accurate leakage prediction, but high degrees of systemic inflammation might still be important in clinical decision-making.

A cross-sectional study of anxiety and depression caseness in female competitive figure skaters in Sweden.

Objectives: Little is known about figure skaters' mental health. This study aimed to describe anxiety and depression caseness (defined as a screening condition qualifying for psychiatric examination) in competitive figure skaters and analyse factors associated with such caseness. Methods: A cross-sectional study was performed in April 2019 among all competitive figure skaters in the south-eastern region of Sweden (N=400). The primary outcomes were anxiety caseness, measured using the short-form Spielberger State-Trait Anxiety Inventory and depression caseness, measured using the WHO-5 index. Multivariable logistic regression models were employed to determine the association between anxiety caseness and explanatory factors. Results: In total, 36% (n=142) of the invited skaters participated. Only females (n=137), mean age 12.9 (SD 3.0) years) were selected for analysis. Of the participating skaters, 47% displayed anxiety caseness and 10% depression caseness. Overweight body image perception (OR 5.9; 95% CI 2.0 to 17.6; p=0.001) and older age (OR 1.2; 95% CI 1.1 to 1.4; p=0.005) were associated with anxiety caseness. Skaters reporting no caseness were younger than those reporting only anxiety caseness (mean age difference -1.9 years; 95% CI -3.1 to -0.7; p=0.001) or anxiety and depression caseness (OR -3.5 years; 95% CI -5.6 to -1.5 years; p<0.001). Conclusion: Anxiety caseness was associated with overweight body image perception and older age in female competitive figure skaters. Older skaters reported generally worse mental health. More research on the mental health of figure skaters is warranted, considering comorbidity and focusing on those needing further assessment and support.

The impact of the anastomotic configuration on low anterior resection syndrome 3 years after total mesorectal excision for rectal cancer: a national cohort study.

AIM: After low anterior resection, the bowel can be anastomosed in different ways. It is not clear which configuration is optimal from a functional and complication point of view. The primary aim was to investigate the impact of the anastomotic configuration on bowel function evaluated by the low anterior resection syndrome (LARS) score. Secondarily, the impact on postoperative complications was evaluated. METHOD: All patients who had undergone low anterior resection from 2015 to 2017 were identified in the Swedish Colorectal Cancer Registry. Three years after surgery, patients were sent an extensive questionnaire and were analysed based on anastomotic configuration ('J-pouch/side-to-end anastomosis' or 'straight anastomosis'). Inverse probability weighting by propensity score was used to adjust for confounding factors. RESULTS: Among 892 patients, 574 (64%) responded, of whom 494 patients were analysed. After weighting, the anastomotic configuration had no significant impact on the LARS score (J-pouch/side-to-end OR 1.05, 95% confidence interval [CI] 0.82-1.34). The J-pouch/side-to-end anastomosis was significantly associated with overall postoperative complications (OR 1.43, 95% CI 1.06-1.95). No significant difference was seen regarding surgical complications (OR 1.14, 95% CI 0.78-1.66). CONCLUSION: This is the first study investigating the impact of the anastomotic configuration on long-term bowel function, evaluated by the LARS score, in an unselected national cohort. Our results suggested no benefit for J-pouch/side-to-end anastomosis on long-term bowel function and postoperative complication rates. The anastomotic strategy may be based upon the anatomical conditions of the patient and surgical preference.

The Practice and Feasibility of Screening, Treatment, and Referral for Gaming Problems in Gambling, Alcohol and Other Drugs, and Youth Services.

Screening, brief intervention, and referral to treatment (SBIRT) is a comprehensive approach to identifying people at risk of addiction, but its feasibility for gaming disorder is unknown. This study surveyed 88 clinicians from gambling, alcohol and other drugs, and youth services in New Zealand. Results indicated that the most frequent GD screening method was an unstructured interview (61%), but 74% stated they would use a standardized tool if available. Responsivity to the detection of GD was an immediate intervention (84%), and rates of referral were low (28%). Around 50% of clinicians indicated high confidence in administering motivational approaches and relapse prevention. There was strong support for screening training (85%), treatment guidelines (88%), self-help materials (92%), and access to internet-delivered CBT that could be used in conjunction with other treatment (84%). Clinicians appear motivated and willing to implement SBIRT for GD but report lacking necessary training and resources, including access to screening tools and treatment guidelines.

A genetically encoded fluorescent sensor for manganese(II), engineered from lanmodulin.

The design of selective metal-binding sites is a challenge in both small-molecule and macromolecular chemistry. Selective recognition of manganese (II)-the first-row transition metal ion that tends to bind with the lowest affinity to ligands, as described by the Irving-Williams series-is particularly difficult. As a result, there is a dearth of chemical biology tools with which to study manganese physiology in live cells, which would advance understanding of photosynthesis, host-pathogen interactions, and neurobiology. Here we report the rational re-engineering of the lanthanide-binding protein, lanmodulin, into genetically encoded fluorescent sensors for MnII, MnLaMP1 and MnLaMP2. These sensors with effective Kd(MnII) of 29 and 7 µM, respectively, defy the Irving-Williams series to selectively detect MnII in vitro and in vivo. We apply both sensors to visualize kinetics of bacterial labile manganese pools. Biophysical studies indicate the importance of coordinated solvent and hydrophobic interactions in the sensors' selectivity. Our results establish lanmodulin as a versatile scaffold for design of selective protein-based biosensors and chelators for metals beyond the f-block.

Content and Effectiveness of Web-Based Treatments for Online Behavioral Addictions: Systematic Review.

BACKGROUND: Very few people seek in-person treatment for online behavioral addictions including gaming and gambling or problems associated with shopping, pornography use, or social media use. Web-based treatments have the potential to address low rates of help seeking due to their convenience, accessibility, and capacity to address barriers to health care access (eg, shame, stigma, cost, and access to expert care). However, web-based treatments for online behavioral addictions have not been systematically evaluated. OBJECTIVE: This review aimed to systematically describe the content of web-based treatments for online behavioral addictions and describe their therapeutic effectiveness on symptom severity and consumption behavior. METHODS: A database search of MEDLINE, Embase, PsycInfo, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar was conducted in June 2022. Studies were eligible if the study design was a randomized controlled trial or a pre-post study with at least 1 web-based intervention arm for an online behavioral addiction and if the study included the use of a validated measure of problem severity, frequency, or duration of online behavior. Data on change techniques were collected to analyze intervention content, using the Gambling Intervention System of CharacTerization. Quality assessment was conducted using the Effective Public Health Practice Project Quality Assessment Tool. RESULTS: The review included 12 studies with 15 intervention arms, comprising 7 randomized controlled trials and 5 pre-post studies. The primary focus of interventions was gaming (n=4), followed by internet use inclusive of screen time and smartphone use (n=3), gambling (n=3), and pornography (n=2). A range of different technologies were used to deliver content, including websites (n=6), email (n=2), computer software (n=2), social media messaging (n=1), smartphone app (n=1), virtual reality (n=1), and videoconferencing (n=1). Interventions contained 15 different change techniques with an average of 4 per study. The techniques most frequently administered (>30% of intervention arms) were cognitive restructuring, relapse prevention, motivational enhancement, goal setting, and social support. Assessment of study quality indicated that 7 studies met the criteria for moderate or strong global ratings, but only 8 out of 12 studies evaluated change immediately following the treatment. Across included studies, two-thirds of participants completed after-treatment evaluation, and one-quarter completed follow-up evaluation. After-intervention evaluation indicated reduced severity (5/9, 56%), frequency (2/3, 67%), and duration (3/7, 43%). Follow-up evaluation indicated that 3 pre-post studies for gaming, gambling, and internet use demonstrated reduced severity, frequency, and duration of consumption. At 3-month evaluation, just 1 pre-post study indicated significant change to mental health symptoms. CONCLUSIONS: Web-based treatments for online behavioral addictions use an array of mechanisms to deliver cognitive and behavioral change techniques. Web-based treatments demonstrate promise for short-term reduction in symptoms, duration, or frequency of online addictive behaviors. However, there is limited evidence on the effectiveness of web-based treatments over the longer term due to the absence of controlled trials.

Circulating tumor and invasive cell expression profiling predicts effective therapy in pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy. METHODS: The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results. RESULTS: Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS. CONCLUSIONS: Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).