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PURPOSE: To describe the utility of fundus autofluorescence (FAF) for detection and monitoring of acute regional outer retinopathy in punctate inner choroidopathy (PIC). DESIGN: Multimodal imaging case series METHODS: Patients with PIC and acute regional hyperautofluorescence were identified. Multimodal imaging, treatment, and clinical course were reviewed. RESULTS: Six eyes of five patients were included (5 women, mean age 39 years, range 28–69). All endorsed new symptoms. Short-wave blue FAF revealed regional hyperautofluorescence in the symptomatic eye, corresponding to ellipsoid zone (EZ) loss on optical coherence tomography (OCT). All patients were treated with local or systemic corticosteroids or immunosuppression, with resolution of symptoms and acute imaging abnormalities. CONCLUSIONS: Symptomatic acute regional outer retinopathy in PIC, manifesting as hyperautofluorescence and EZ loss, is easily identifiable using widefield FAF imaging. Treatment resulted in resolution of symptoms and imaging findings in our cohort, and should be considered in this patient population.

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Chemical Methods

Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than hydroxychloroquine (HCQ). Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR/Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives.Significance:This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in cancer.This article is highlighted in the In This Issue feature, p. 151

Purpose To determine the utility of routine screening ophthalmic exam in patients with systemic sarcoidosis and no history of uveitis. Methods Prospective, single-center, observational study conducted at Northwestern University from October 11, 2012 to October 1, 2020 of new patients with biopsy-proven systemic sarcoidosis and no history of uveitis, referred by medical subspecialists for screening ophthalmic exam. Results Forty-nine patients, with mean age of 51 ± 8.7 years, 59% female, 47% African American, 43% Caucasian, were enrolled. The majority (55%) had no ocular symptoms. The most common location of ocular involvement was the adnexa, in the form of conjunctival nodules (62%) and aqueous tear deficiency (23%). Intraocular inflammation was detected in 6 patients (13%); only 2 had active disease requiring treatment (4%). No asymptomatic patient had ocular involvement necessitating treatment. Conclusion Screening exams are indicated in sarcoidosis patients with ocular symptoms. No benefit of screening was demonstrated in asymptomatic patients.

Purpose Service providers often recommend unnecessary and expensive services to unsuspecting consumers, such as recommending a new part when a simple fix to the old will do, a phenomenon known as overprovisioning. The purpose of this paper is to examine to what extent consumers tend to defer their decisions should they suspect that sellers are overproviding services to them and they cannot prevent the sellers from doing so (they lack personal control); and how proper market signals can mitigate such suspicions, restore personal control and reduce deferrals. Design/methodology/approach The paper conducts three laboratory experiments. The experiments expose the participants to hypothetical repair scenarios and measure to what extent they suspect that sellers might be overproviding services to them and they feel that they lack the personal control to prevent the sellers from doing so. Thereafter, the experiments expose them to two different market signals, one conveying that the seller is providing quality services (a repair warranty; quality signal) and the other conveying that the seller is taking away any incentives their agents (technicians) may have to overprovide services (the technicians are paid a flat salary; quantity signal). The paper examines how these quality/quantity signals are able to reduce overprovisioning suspicions, restore personal control and reduce decision deferrals. Findings The paper has two main findings. First, the paper shows a mediation process at work i.e. suspecting potential overprovisioning by sellers leads consumers to defer their decisions indirectly because they feel that they lack personal control to prevent the sellers from doing so. Second, the paper shows that the quantity signal (flat salary disclosure), but not the quality signal (warranty), is able to mitigate suspicions of overprovisioning, restore personal control and reduce decision deferrals. Practical implications The paper suggests that although buyers may rely on quality signals to assure them of superior service, these signals do not guarantee that the quantity of service they are receiving is appropriate. Therefore, sellers will have to send a credible quality signal and a credible quantity signal to the consumers if they wish to tackle suspicions about service overprovision and service quality. Originality/value The paper is original in two ways. First, the paper theorizes and tests a mediation process model whereby quality/quantity signals differentially mitigate overprovisioning suspicions, restore personal control and reduce decision deferrals. Second, the paper speaks to the necessity of expanding the traditional signaling literature, designed primarily to detect poor quality hidden in the products/services of lower-quality sellers, to include detecting/solving overprovisioning often hidden in the services provided by higher-quality sellers.

Patient with "very small" (2 cm) renal mass can be offered active surveillance, thermal ablation, or partial nephrectomy. The management strategy will consider patient preferences and prioritize potential harms associated with each of these options. To date, outcomes of robot-assisted partial nephrectomy (RAPN) in patients with "very small" renal masses have not been reported.To assess the outcomes of RAPN among patients with "very small" renal masses.This was a retrospective analysis of a multi-institutional database including RAPN cases performed at eight high-volume US and European centers between 2009 and 2019. Patients were stratified into two groups according to clinical tumor size:2 cm ("very small" renal mass, study group) and 2-4 cm (control group).RAPN for renal masses.Baseline characteristics and intraoperative, pathological, and postoperative data were compared between the study and the control group. A "trifecta" was used as surrogate of "surgical quality."Overall, a total of 1019 patients were included in the analysis. Of these, 352 had a renal mass of2 cm (34.5%) and 667 (65.5%) had a renal mass of 2-4 cm. At baseline, the study group presented a lower rate of chronic kidney disease ≥stage III (p0.001), a lower RENAL score (p = 0.001), and lower rates of hilar (p = 0.04) and endophytic (p = 0.02) masses. Warm ischemia time was shorter for the study group (median 14 vs 18 min, p0.001), which also showed a lower rate of overall postoperative complications (9.6% vs 14.7%, p0.001) and no major complications. In terms of oncological outcomes, three and ten patients developed a local recurrence in the study and the control group, respectively (p = 0.1). In the study group, higher estimated glomerular filtration rates were found at discharge (p = 0.001) and at the last follow-up (p = 0.007), which showed a "trifecta" achievement of 90.6%. The retrospective design may limit the generalizability of the findings.Whenever an active treatment is indicated or warranted, RAPN represents a minimally invasive management option for "very small" renal masses, as it carries minimal risk of complications and has minimal impact on renal function. While both active surveillance and kidney ablation remain valid management options in these cases, RAPN can be offered and discussed with patients as it provides excellent outcomes with low morbidity.In this report, we observed that robot-assisted partial nephrectomy represents a true minimally invasive active treatment for "very small" renal masses (2 cm), as it carries minimal risk of complications and has minimal impact on renal function.

Despite the many advantages of multichannel retail, this paper raises certain issues that may pose various pitfalls to the retailer. We focus on how varying the price and loyalty conditions may instigate complex emotional responses that can adversely affect the retailer. We adopt a multi-method approach across three studies, combining facial expression analysis (Study 1), scenario-based experiments, and a self-reported survey (Studies 2 & 3). Our findings show how inconsistent pricing in online and offline stores influences consumers’ regret and disappointment, which in turn impact their post-purchase behaviours of returning or retaining the product. The research contributes both theoretically and managerially by delving into the emotional responses of consumers to promotional discrepancies in multichannel retail.

Background: Adverse associations of low-and no-calorie sweetened beverages (LNCSBs) with cardiometabolic outcomes in observational studies may be explained by reverse causality and residual confounding. Purpose: To address these limitations we used change analyses of repeated measures of intake and substitution analyses to synthesize the association of LNCSBs with cardiometabolic outcomes. Study Selection: MEDLINE, EMBASE, and the Cochrane Library were searched up to 10 June 2021 for prospective cohort studies ≥1-year follow-up duration in adults. Outcomes included changes in clinical measures of adiposity, risk of overweight/obesity, metabolic syndrome, diabetes, cardiovascular disease, and total mortality. Data Extraction: Two independent reviewers extracted data, assessed study quality, and certainty of evidence using GRADE. Data was pooled using random-effects model and expressed as mean difference (MD) or risk ratio (RR) and 95% CI. Data Synthesis: Fourteen cohorts (416,830 participants) met the eligibility criteria. Change in LNCSB intake was associated with lower weight (5 cohorts, 136,206 participants; MD, -0.008 [95% CI: -0.014, -0.002] kg/y). Substitution of LNCSBs for sugar-sweetened beverages (SSBs) was associated with lower weight (3 cohorts, 165,579 participants; MD, -0.12 [95% CI: -0.14, -0.01] kg/y) and lower incidence of obesity (1 cohort, 15,765 participants; RR, 0.88 [0.88, 0.89]), coronary heart disease (6 cohorts, 233,676 participants; RR, 0.89 [95% CI: 0.81, 0.98]), CVD mortality (1 cohort, 118,363 participants; RR, 0.95 [95% CI: 0.90, 0.99]), and total mortality (1 cohort, 118,363 participants; RR, 0.96 [95% CI: 0.94, 0.98]) with no adverse associations across other outcomes. Substitution of water for SSBs showed lower weight (3 cohorts, 165,579 participants; MD, -0.10 [95% CI: -0.13, -0.06] kg/y), lower waist circumference (1 cohort, 173 participants; MD, -2.71[95% CI: -4.27, -1.15] cm/y) and percent body fat (1 cohort, 173 participants; MD, -1.51 [95% CI: -2.61, -0.42] %/y), and lower incidence of obesity (1 cohort, 15,765 participants; RR, 0.85 [95% CI: 0.75, 0.97]) and diabetes (3 cohorts, 281,855 participants; RR, 0.96 [95% CI: 95% CI: 0.94, 0.98]). Substitution of LNCSBs for water showed no adverse associations. Limitations: The evidence was low to very low certainty owing downgrades for imprecision, indirectness and/or inconsistency. Conclusions: LNCSBs were not associated with cardiometabolic harm in analyses that model the exposure as change or substitutions. The available evidence provides some indication that LNCSBs in their intended substitution for SSBs may be associated with cardiometabolic benefit, comparable to the standard of care, water.

Overcoming cellular senescence that is induced by telomere shortening is critical in tumorigenesis. A majority of cancers achieve telomere maintenance through telomerase expression. However, a subset of cancers takes an alternate route for elongating telomeres: recombination-based alternative lengthening of telomeres (ALT). Current evidence suggests that break-induced replication (BIR), independent of RAD51, underlies ALT telomere synthesis. However, RAD51-dependent homologous recombination is required for homology search and inter-chromosomal telomere recombination in human ALT cancer cell maintenance. Accumulating evidence suggests that the breakdown of stalled replication forks, the replication stress, induces BIR at telomeres. Nevertheless, ALT research is still in its early stage and a comprehensive view is still unclear. Here, we review the current findings regarding the genesis of ALT, how this recombinant pathway is chosen, the epigenetic regulation of telomeres in ALT, and perspectives for clinical applications with the hope that this overview will generate new questions.

Multicenter retrospective analysis of robotic partial nephrectomy for completely endophytic renal tumors (i.e. 3 points for the 'E' domain of the R.E.N.A.L. nephrometry score) was performed.Patients' demographics, tumor characteristics, perioperative, functional, pathological and oncological data were analyzed and compared with those of patients with exophytic and mesophytic masses (i.e. 1 and 2 points for the 'E' domain, respectively). Multivariable logistic regression analysis was used to assess variables for trifecta achievement (negative margin, no postoperative complications, and 90% estimated glomerular filtration rate [eGFR] recovery).Overall, 147 patients were included in the study group. Patients with a completely endophytic mass had bigger tumors (mean 4.2 vs. 4.1 vs. 3.2 cm; p 0.001) on preoperative imaging and higher overall R.E.N.A.L. score. There was no difference in mean operative time. Estimated blood loss was higher in the endophytic group (mean 177.75 vs. 185.5 vs. 130 ml; p = 0.001). Warm ischemia time was shorter for the exophytic group (median 16 vs. 21 vs. 22 min; p 0.001). Postoperative complications were more frequent in patients with endophytic tumor (24.8% vs. 19.5% vs. 14.8%; p 0.001). Six (4.5%) patients had positive surgical margins, there was no difference between groups. Trifecta was achieved in 44 patients in endophytic group (45.4 vs. 68.8 and 50.9%, p 0.001). Multivariable analysis for trifecta revealed that clinical tumor size (odds ratio: 0.667, 95% confidence interval: 0.56-0.79, p 0.001) was only significant predictor for trifecta achievement.Our findings confirm that RAPN in case of completely endophytic renal masses can be performed with acceptable outcomes in centers with significant robotic expertise.

Background The current American Society of Anesthesiologists fasting guideline for formula-fed infants in the periprocedural setting is 6 h. Prolonged fasting in very young infants is associated with an increased risk for hypoglycemia and dehydration as well as patient discomfort and patient/parental dissatisfaction. This study aimed to determine the time to gastric emptying in healthy neonates after formula feeding by serially evaluating the gastric antrum with ultrasound. The authors hypothesized that gastric emptying times in formula-fed neonates are significantly shorter than the current 6 h fasting recommendation. Methods After institutional review board approval and written informed parental consent, ultrasound examination was performed in healthy full-term neonates before and after formula feeding at 15-min intervals until return to baseline. Ultrasound images of the gastric antrum were measured to obtain cross-sectional areas, which were then used to estimate gastric antral volumes. Results Forty-six of 48 recruited neonates were included in the final analysis. Gastric emptying times ranged from 45 to 150 min and averaged 92.9 min (95% CI, 80.2 to 105.7 min; 99% CI, 76.0 to 109.8 min) in the overall study group. No significant differences were found in times to gastric emptying between male and female neonates (male: mean, 93.3 [95% CI, 82.4 to 104.2 min]; female: mean, 92.6 [95% CI, 82.0 to 103.2 min]; P = 0.930) or those delivered by vaginal versus cesarean routes (vaginal: mean, 93.9 [95% CI, 81.7 to 106.1 min]; cesarean: mean, 92.2 [95% CI, 82.5 to 101.9 min]; P = 0.819). Conclusions These results demonstrate that gastric emptying times are substantially less than the current fasting guideline of 6 h for formula-fed, healthy term neonates. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Context:People with CHD are at increased risk for executive functioning deficits. Meta-analyses of these measures in CHD patients compared to healthy controls have not been reported.Objective:To examine differences in executive functions in individuals with CHD compared to healthy controls.Data sources:We performed a systematic review of publications from 1 January, 1986 to 15 June, 2020 indexed in PubMed, CINAHL, EMBASE, PsycInfo, Web of Science, and the Cochrane Library.Study selection:Inclusion criteria were (1) studies containing at least one executive function measure; (2) participants were over the age of three.Data extraction:Data extraction and quality assessment were performed independently by two authors. We used a shifting unit-of-analysis approach and pooled data using a random effects model.Results:The search yielded 61,217 results. Twenty-eight studies met criteria. A total of 7789 people with CHD were compared with 8187 healthy controls. We found the following standardised mean differences: −0.628 (−0.726, −0.531) for cognitive flexibility and set shifting, −0.469 (−0.606, −0.333) for inhibition, −0.369 (−0.466, −0.273) for working memory, −0.334 (−0.546, −0.121) for planning/problem solving, −0.361 (−0.576, −0.147) for summary measures, and −0.444 (−0.614, −0.274) for reporter-based measures (p < 0.001).Limitations:Our analysis consisted of cross-sectional and observational studies. We could not quantify the effect of collinearity.Conclusions:Individuals with CHD appear to have at least moderate deficits in executive functions. Given the growing population of people with CHD, more attention should be devoted to identifying executive dysfunction in this vulnerable group.

Canada recently mandated front-of-pack (FOP) labelling regulations, where foods meeting and/or exceeding recommended thresholds for nutrients-of-concern (i.e., saturated fat, sodium, and sugars) must display a ‘high-in’ FOP nutrition symbol. However, there is limited research on the amounts and sources of foods consumed by Canadians that would require a FOP symbol. The objective was to examine the intakes of nutrients-of-concern from foods that would display a FOP symbol and to identify the top food categories contributing to intakes for each nutrient-of-concern. Using the first day 24-hour dietary recall from the nationally representative 2015 Canadian Community Health Survey-Nutrition (CCHS), Canadian adults’ intakes of nutrients-of-concern from foods that would display a FOP symbol was examined. Foods were assigned to 1 of 62 categories to identify the top food categories contributing to intakes of energy and nutrient-of-concern that would display a FOP symbol for each nutrient-of-concern. Canadian adults (n = 13,495) consumed approximately 24% of total calories from foods that would display a FOP symbol. Foods that would display a FOP symbol for exceeding thresholds for nutrients-of-concern accounted for 16% of saturated fat, 30% of sodium, 25% of total sugar, and 39% of free sugar intakes among Canadian adults. The top food category contributing intakes of each nutrient-of-concern that would display a FOP symbol were nutrient-specific: Processed meat and meat substitutes for saturated fat; Breads for sodium; and Fruit juices & drinks for total and free sugars. Our findings show that Canadian FOP labelling regulations have the potential to influence the intakes of nutrients-of-concern for Canadian adults. Using the findings as baseline data, future studies are warranted to evaluate the impact of FOP labelling regulations.

Almost 40 years ago, scholars identified a “chilly climate” for women in college classrooms. To examine whether contemporary college classrooms remain “chilly,” we conducted quantitative and qualitative observations in nine classrooms across multiple disciplines at one elite institution. Based on these 95 hours of observation, we discuss three gendered classroom participation patterns. First, on average, men students occupy classroom sonic space 1.6 times as often as women. Men also speak out without raising hands, interrupt, and engage in prolonged conversations during class more than women students. Second, style and tone also differ. Men’s language is assertive, whereas women’s is hesitant and apologetic. Third, professors’ interventions and different structures of classrooms can alter existing gender status hierarchies. Extending Ridgeway’s gender system framework to college classrooms, we discuss how these gendered classroom participation patterns perpetuate gender status hierarchies. We thus argue that the chilly climate is an underexplored mechanism for the stalled gender revolution.

The goal of this study was to investigate the effect of transplantation of an adipose-derived stem cell (ASC) spheroid sheet on the regeneration of ulcerated oral mucosa. The ASC spheroid sheet was constructed by seeding three-dimensional (3D) spheroidal ASCs on a temperature-responsive hydrogel, where cell adhesion and spreading were improved by incorporating fibronectin. The 3D culture of ASCs enhanced their inherent paracrine properties for up to 1 week after transferring to two-dimensional (2D) culture conditions. Expansion of the hydrogel through temperature change promoted effective delivery of ASCs to the site of injury, and viability was maintained after transferring ASCs to the target substrate. Treatment with the ASC spheroid sheet accelerated wound closure and regeneration of the stratified multi-layered epithelium. The regenerated epithelium not only had structural integrity, but also displayed phenotypic polarization across the mucosa; basal epithelial cells expressed cytokeratin 5, whereas cytokeratin 13-positive cells were located in the supra-basal layers. In addition, by day 7 after treatment, the mucosa that received the ASC spheroid sheet had significantly decreased inflammation, similar to that of the normal mucosa. These results demonstrate that the ASC spheroid sheet is an effective treatment for ulcers in the oral cavity.

Detention facilities are no place for children who are irregular migrants. Yet both the United States (US) and Mexico have struggled with how to respond to the arrival of Central American children who are primarily fleeing violence. In these neighbouring countries, the detention of children reflects both an ineffective and misguided strategy to deter people from moving across their southern borders. This focus on border control is further reinforced by the US outsourcing of enforcement controls to Mexico. In the US, a preoccupation with border control can quickly undermine the purported interest of protecting migrant children because they lack the fundamental right to be free from detention. In Mexico, its role as a buffer State causes it to overlook its human rights, constitutional, and federal law commitments to the fundamental rights of children, while allowing practical obstacles to stand in the way of these legal obligations. This article examines how the political imperative of border control in the US influences the various approaches taken by the US and Mexico towards the detention of migrant children. It analyses the shortcomings and best practices of each system and concludes with recommended reforms that actualize the right of migrant children to be free from detention.

To assess the cross-sectional association between dietary indexes (DI) that underlie, respectively, the Nutri-score (NS), the proposed Canadian 'High In' Symbol (CHIL) and the Diabetes Canada Clinical Practice Guidelines (DCCP) with food consumption, nutrient intakes and metabolic markers.1836 adults (18-74 years) participating in the representative ESTEBAN study, conducted in mainland France in 2014-2016, were included in the analysis. Food consumption was assessed with three repeated 24 h dietary recalls. Anthropometric measurements and biomarkers of metabolic risk (cholesterol-total, LDL (Low Density Lipoprotein), HDL (High Density Lipoprotein)-triglycerides, glucose) were obtained through a clinical examination and fasting blood draw. The DI were assessed for their association with food consumption, dietary intakes and metabolic biomarkers as quintiles and continuous variables using multi-adjusted linear regression. Heathier diets were assigned to lower scores.Correlations between scores ranged from + 0.62 between CHIL-DI and NS-DI to + 0.75 between NS-DI and DCCP-DI. All DIs discriminated individuals according to the nutritional quality of their diets through food consumption and nutrient intakes (healthier diets were associated with lower intakes of energy, added sugars and saturated fat; and with higher intakes of fiber, vitamins and minerals). NS-DI was associated with blood glucose (adjusted mean in Q1 = 5 vs. Q5 = 5.46 mmol/dl, pThis study provides elements supporting the validity of the nutrient profiling systems underlying front-of-package nutrition labellings (FOPLs) to characterize the healthiness of diets.

ObjectivesTo conduct a scoping review of sedation clinical trials in the paediatric intensive care setting and summarise key methodological elements.DesignScoping review.Data sourcesPubMed, Embase, Cumulative Index to Nursing and Allied Health Literature and grey references including ClinicalTrials.gov from database inception to 3 August 2021.Study selectionAll human trials in the English language related to sedation in paediatric critically ill patients were included. After title and abstract screening, full-text review was performed. 29 trials were eligible for final analysis.Data extractionA coding manual was developed and pretested. Trial characteristics were double extracted.ResultsThe majority of trials were single centre (22/29, 75.9%), parallel group superiority (17/29, 58.6%), double-blinded (18/29, 62.1%) and conducted in an academic setting (29/29, 100.0%). Trial enrolment (≥90% planned sample size) was achieved in 65.5% of trials (19/29), and retention (≥90% enrolled subjects) in 72.4% of trials (21/29). Protocol violations were reported in nine trials (31.0%). The most commonly studied cohorts were mechanically ventilated patients (28/29, 96.6%) and postsurgical patients (11/29, 37.9%) with inclusion criteria for age ranging from 0±0.5 to 15.0±7.3 years (median±IQR). The median age of enrolled patients was 1.7 years (IQR=4.4 years). Patients excluded from trials were those with neurological impairment (21/29, 72.4%), complex disease (20/29, 69.0%) or receipt of neuromuscular blockade (10/29, 34.5%). Trials evaluated drugs/protocols for sedation management (20/29, 69.0%), weaning (3/29, 10.3%), daily interruption (3/29, 10.3%) or protocolisation (3/29, 10.3%). Primary outcome measures were heterogeneous, as were assessment instruments and follow-up durations.ConclusionsThere is substantial heterogeneity in methodological approach in clinical trials evaluating sedation in critically ill paediatric patients. These results provide a basis for the design of future clinical trials to improve the quality of trial data and aid in the development of sedation-related clinical guidelines.

BACKGROUND Adverse associations of low- and no-calorie sweetened beverages (LNCSB) with cardiometabolic outcomes in observational studies may be explained by reverse causality and residual confounding. PURPOSE To address these limitations we used change analyses of repeated measures of intake and substitution analyses to synthesize the association of LNCSB with cardiometabolic outcomes. DATA SOURCES MEDLINE, Embase, and the Cochrane Library were searched up to 10 June 2021 for prospective cohort studies with ≥1 year of follow-up duration in adults. STUDY SELECTION Outcomes included changes in clinical measures of adiposity, risk of overweight/obesity, metabolic syndrome, type 2 diabetes (T2D), cardiovascular disease, and total mortality. DATA EXTRACTION Two independent reviewers extracted data, assessed study quality, and assessed certainty of evidence using GRADE. Data were pooled with a random-effects model and expressed as mean difference (MD) or risk ratio (RR) and 95% CI. DATA SYNTHESIS A total of 14 cohorts (416,830 participants) met the eligibility criteria. Increase in LNCSB intake was associated with lower weight (5 cohorts, 130,020 participants; MD −0.008 kg/year [95% CI −0.014, −0.002]). Substitution of LNCSB for sugar-sweetened beverages (SSB) was associated with lower weight (three cohorts, 165,579 participants; MD, −0.12 [−0.14, −0.10,] kg/y) and lower incidence of obesity (OB) (one cohort, 15,765 participants; RR 0.88 [95% CI 0.88, 0.89]), coronary heart disease (six cohorts, 233,676 participants; 0.89 [0.81, 0.98]), cardiovascular disease mortality (one cohort, 118,363 participants; 0.95 [0.90, 0.99]), and total mortality (one cohort, 118,363 participants; 0.96 [0.94, 0.98]) with no adverse associations across other outcomes. Substitution of water for SSB showed lower weight (three cohorts, 165,579 participants; MD −0.10 kg/year [−0.13, −0.06]), lower waist circumference (one cohort, 173 participants; −2.71 cm/year [−4.27, −1.15]) and percent body fat (one cohort, 173 participants; −1.51% per year [−2.61, −0.42]), and lower incidence of OB (one cohort, 15,765 participants; RR 0.85 [0.75, 0.97]) and T2D (three cohorts, 281,855 participants; 0.96 [0.94, 0.98]). Substitution of LNCSB for water showed no adverse associations. LIMITATIONS The evidence was low to very low certainty owing to downgrades for imprecision, indirectness, and/or inconsistency. CONCLUSIONS LNCSB were not associated with cardiometabolic harm in analyses that model the exposure as change or substitutions. The available evidence provides some indication that LNCSB in their intended substitution for SSB may be associated with cardiometabolic benefit, comparable with the standard of care, water.

BACKGROUND Robotic partial nephrectomy (RPN) in patients ≥75 years is certainly underused with concerns regarding surgical quality and a negligible impact on renal function. The aim of this study was to identify predictors of progression of chronic kidney disease for purely off-clamp (ocRPN) and on-clamp RPN (onRPN) in elderly patients on a multi-institutional series. METHODS A collaborative minimally-invasive renal surgery dataset was queried for "RPN" performed between July 2007 and March 2021 and "age≥75 years". A total of 205 patients matched the inclusion criteria. Descriptive analyses were used. Frequencies and proportions were reported for categorical variables while medians and interquartile ranges (IQR) were reported for continuous variables. Baseline, perioperative and functional data were compared between groups. New-onset of stages 3b,4,5 CKD in onRPN and ocRPN cohorts was computed by Kaplan-Meier analysis. Univariable and multivariable Cox regression analyses were performed to identify predictors of progression to severe CKD (sCKD [stages ≥3b]). For all statistical analyses, a two-sided p < 0.05 was considered significant. RESULTS Mean age of the cohort considered was 78 years (IQR 76-80). At a median follow-up of 29 months (IQR 14.5-44.5), new onset CKD-3b and CKD-4,5 stages was observed in 16.6% and 2.4% of patients, respectively. At Kaplan-Meier analysis, onRPN was associated with a significantly higher risk of developing sCKD (p=0.002). On multivariable analysis, hypertension (HR 2.64; 95% CI 1.14-6.11; p=0.023), on-clamp approach (HR 3.41; 95% CI 1.50-7.74; p=0.003) non-achievement of trifecta (HR 0.36; 95% CI 0.17-0.78; p=0.01) were independent predictors of sCKD. CONCLUSIONS RPN in patients≥75 years is a safe surgical option. On-clamp approach, hypertension and non-achievement of trifecta were independent predictors of sCKD in the elderly after RPN.

Dietary carbohydrates have been shown to influence cognitive performance and satiety in children. However, it remains unclear whether the carbohydrate source is a primary determinant of cognitive performance and satiety. The objective was to compare the effects of white potatoes and other carbohydrate-containing foods on cognitive performance, glycemic response, and satiety in children. On 6 separate mornings, in random order, children (n = 22) consumed 50 g of available carbohydrates from microwaved mashed potatoes (prepared from fresh potatoes then frozen), deep-fried potato strips (French fries), hash browns, white rice, white beans, or skipped a meal. Cognitive performance, glycemic response, and satiety were measured over 180 min. Cognitive performance was measured using a battery of tests assessing verbal declarative memory, spatial memory, short-term memory, working memory, and information processing speed. Although cognitive performance after the treatment meals did not differ from meal skipping, children recalled more words after French fries (9.1 ± 0.4 words) compared with mashed potatoes (8.2 ± 0.3 words; p = 0.001) and white rice (8.4 ± 0.3 words; p = 0.04) on the verbal declarative memory test. Blood glucose concentrations were higher after white rice compared with white beans, mashed potatoes, and hash browns (p < 0.05). Change from baseline subjective average appetite (mm/kcal) was lower after mashed potatoes compared with all other treatment meals (p < 0.05). In conclusion, verbal declarative memory was higher after French fries and subjective average appetite was lower after mashed potatoes. Future longitudinal studies are needed to confirm these short-term findings and to elucidate the mechanism of action.

OBJECTIVE(S): To compare short-term treatment outcomes of opioid pharmacotherapy for neonatal opioid withdrawal syndrome (NOWS). STUDY DESIGN: PubMed/MEDLINE, Embase, PsycINFO, and The Cochrane Library were searched from inception through September 30, 2018. Primary outcome was treatment duration (LOT). Secondary outcomes included hospitalization duration (LOS) and rate of adjunct drug needed (RAD). RESULTS: Of 753 publications, 11 studies met inclusion criteria. There was no difference in LOT (WMD −1.39 [−5.79 to −3.01] days, I(2) 82%) or LOS (WMD −1.48 [−5.75 to −2.79] days, I(2) 92%) between morphine and methadone. RAD with morphine was higher (RR 1.51 [1.35–1.69], I(2) 0%). Buprenorphine was associated with shorter LOT (WMD 7.70 [0.88–14.53] days, I(2) 76%) and LOS (WMD 5.61 [−0.01 to −11.24] days, I(2) 60%) compared with morphine, in addition to methadone according to two cohort studies. CONCLUSIONS: Methadone had superior primary treatment success compared with morphine. Buprenorphine was associated with the shortest overall durations of treatment and hospitalization.

Objectives The canine trachea is considered to be an excellent preclinical model for tracheal research due to its similar mechanical and dimensional characteristics to the human trachea. However, normative biomechanical properties have yet to be defined and it is one of the main reasons tracheal reconstruction has not succeeded in animal models at large scale. Variation and inaccurate measurement due to a lack of proper apparatus for mechanical tests further prevent determination of normative mechanical data of the trachea. The goal of this study was to overcome these shortcomings by designing the measuring apparatus using 3D-printing technology. Using this apparatus, we determined the normative biomechanical properties of the canine trachea. Methods Whole tracheas were obtained from thirteen mongrel dogs. Biomechanical measurements were performed to determine the radial compressive strength and tensile strength of the intact trachea, and the elastic modulus of the tracheal cartilage. Results Structural parameter data indicated the canine trachea to have inner-diameters similar to those of the human trachea and other widely used animal models. The compressive strength was 4.24 N while the tensile strength was 29.96 N. The elastic modulus of the cartilage portion of the trachea was 1.58 N without showing a significant difference in value based on the location of the trachea. Conclusions This study delineates a comprehensive and foundational characterization of the biomechanical properties of both the intact and cartilage portion of the canine trachea. The parameters were in agreement with those of the human trachea, confirming the canine trachea to be an excellent preclinical model for tracheal research.

A subset of cancer cells maintains their telomeres without telomerase through the recombination-based alternative lengthening of telomeres (ALT) pathway. Currently, it is not yet clear in what context ALT is induced and how the pathway choice is made. Here, we show that abrogation of Brca2 reinforces break-induced replication (BIR) and engages with ALT pathway. Brca2 depletion in telomerase-null mouse cells alleviated the growth defect, accompanied by telomere elongation, suggesting the induction of ALT. We also found that Brca2-depleted telomerase-null cells exhibited dynamic clustering of telomeres from G2 phase in Promyelocytic Nuclear (PML) bodies. For Brca2-deficient ALT induction, Rad51 was dispensable but Mre11 and Rad52 were required. Congruently, conservative telomeric DNA synthesis was apparent in mitosis, indicating that the absence of Brca2 directed towards Rad52-mediated BIR. Collectively, we propose that Brca2 abrogation can instigate ALT tumourigenesis through the induction of BIR. This study implies that inhibitors of BIR may be useful for BRCA2-associated ALT-type cancers. Assessing ALT features may be considered for the tailored therapy of BRCA2-associated cancers.

Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than hydroxychloroquine (HCQ). Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR/Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives. Significance: This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in cancer. This article is highlighted in the In This Issue feature, p. 151

To assess the outcomes of retroperitoneal robot-assisted partial nephrectomy (r-RAPN) in a large cohort of patients with postero-lateral renal masses comparing to those of transperitoneal RAPN (t-RAPN). Patients with posterior (R.E.N.A.L. score grading P) or lateral (grading X) renal mass who underwent RAPN in six high-volume US and European centers were identified and stratified into two groups according to surgical approach: r-RAPN (“study group”) and t-RAPN (“control group”). Baseline characteristics, intraoperative, and postoperative data were collected and compared. Overall, 447 patients were identified for the analysis. 231 (51.7%) and 216 (48.3%) patients underwent r-RAPN and t-RAPN, respectively. Baseline characteristics were not statistically significantly different between the groups. r-RAPN group reported lower median operative time (140 vs. 170 min, p

We present a case of a 44-year-old man with biopsy-proven primary vitreoretinal lymphoma (PVRL), who developed multiple ocular recurrences over the course of six years. Recurrences were imaged with color fundus photography, fundus autofluorescence, and optical coherence tomography. This case demonstrates a single patient with a myriad of imaging findings of PVRL as well as response to a variety of therapeutic interventions.