Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity.

Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.

Transcription Factor IRF8 Orchestrates the Adaptive Natural Killer Cell Response.

Natural killer (NK) cells are innate lymphocytes that display features of adaptive immunity during viral infection. Biallelic mutations in IRF8 have been reported to cause familial NK cell deficiency and susceptibility to severe viral infection in humans; however, the precise role of this transcription factor in regulating NK cell function remains unknown. Here, we show that cell-intrinsic IRF8 was required for NK-cell-mediated protection against mouse cytomegalovirus infection. During viral exposure, NK cells upregulated IRF8 through interleukin-12 (IL-12) signaling and the transcription factor STAT4, which promoted epigenetic remodeling of the Irf8 locus. Moreover, IRF8 facilitated the proliferative burst of virus-specific NK cells by promoting expression of cell-cycle genes and directly controlling Zbtb32, a master regulator of virus-driven NK cell proliferation. These findings identify the function and cell-type-specific regulation of IRF8 in NK-cell-mediated antiviral immunity and provide a mechanistic understanding of viral susceptibility in patients with IRF8 mutations.

Ebola virus VP35 interacts non-covalently with ubiquitin chains to promote viral replication.

Ebolavirus (EBOV) belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans. EBOV replication requires the activity of the viral polymerase complex, which includes the cofactor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface, and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity. Treatment with the compounds reduced replication of infectious EBOV in cells and in vivo in a mouse model. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.

Surface-based morphometry of the corpus callosum in young children of ages 1-5.

The corpus callosum (CC) is a large white matter fiber bundle in the brain and is involved in various cognitive, sensory, and motor processes. While implicated in various developmental and psychiatric disorders, much is yet to be uncovered about the normal development of this structure, especially in young children. Additionally, while sexual dimorphism has been reported in prior literature, observations have not necessarily been consistent. In this study, we use morphometric measures including surface tensor-based morphometry (TBM) to investigate local changes in the shape of the CC in children between the ages of 12 and 60 months, in intervals of 12 months. We also analyze sex differences in each of these age groups. We observed larger significant clusters in the earlier ages between 12 v 24 m and between 48 v 60 m and localized differences in the anterior region of the body of the CC. Sex differences were most pronounced in the 12 m group. This study adds to the growing literature of work aiming to understand the developing brain and emphasizes the utility of surface TBM as a useful tool for analyzing regional differences in neuroanatomical morphometry.

Evaluation of adherence to antipsychotics: A real-world data study using four different dosing assumptions.

AIMS: This study aimed to assess the frequency of dosing inconsistencies in prescription data and the effect of four dosing assumption strategies on adherence estimates for antipsychotic treatment. METHODS: A retrospective cohort, which linked prescription and dispensing data of adult patients with ≥1 antipsychotic prescription between 2015-2016 and followed up until 2019, in Catalonia (Spain). Four strategies were proposed for selecting the recommended dosing in overlapping prescription periods for the same patient and antipsychotic drug: (i) the minimum dosing prescribed; (ii) the dose corresponding to the latest prescription issued; (iii) the highest dosing prescribed; and (iv) all doses included in the overlapped period. For each strategy, one treatment episode per patient was selected, and the Continuous Medication Availability measure was used to assess adherence. Descriptive statistics were used to describe results by strategy. RESULTS: Of the 277 324 prescriptions included, 76% overlapped with other prescriptions (40% with different recommended dosing instructions). The number and characteristics of patients and treatment episodes (18 292, 18 303, 18 339 and 18 536, respectively per strategy) were similar across strategies. Mean adherence was similar between strategies, ranging from 57 to 60%. However, the proportion of patients with adherence ≥90% was lower when selecting all doses (28%) compared with the other strategies (35%). CONCLUSION: Despite the high prevalence of overlapping prescriptions, the strategies proposed did not show a major effect on the adherence estimates for antipsychotic treatment. Taking into consideration the particularities of antipsychotic prescription practices, selecting the highest dose in the overlapped period seemed to provide a more accurate adherence estimate.

A focused review of visible light therapies for vitiligo.

BACKGROUND: Vitiligo can be challenging to treat and exhibit an unpredictable clinical course. Phototherapy in the form of visible light can achieve both repigmentation and depigmentation outcomes in vitiligo, with minimal associated adverse events. This review focuses on the mechanistic understandings and clinical outcomes of visible light-based treatments for vitiligo. METHODS: Articles were retrieved from PubMed starting from May 1965 until August 2023, yielding 496 unique articles. We conducted title, abstract, and full-text screening to identify articles describing the use of visible light (380-750 nm), either as part of combination therapy or as monotherapy, for repigmentation or depigmentation treatment in vitiligo. RESULTS: Twenty-seven articles met inclusion criteria, offering preclinical and clinical data regarding the utilization of helium-neon laser (red light) and blue light-emitting diodes (LEDs) as methods of repigmentation therapy in vitiligo. Preclinical and clinical data on the utilization of Q-switched ruby laser (694 nm) and frequency-doubled (FD) Nd:YAG laser (532 nm) for vitiligo depigmentation therapy were also identified. CONCLUSION: While limited by small studies and a lack of standardized administration of phototherapy, the evidence for visible light's effectiveness in managing vitiligo is encouraging. Red light therapy using He-Ne lasers and blue light therapy via LEDs can stimulate repigmentation in patients with vitiligo with minimal adverse events. Q-switched ruby and FD Nd:YAG lasers provide viable, visible light depigmentation options, either alone or with topical agents. With limited clinical data, larger studies are needed to validate the efficacy of visible light therapy in treating vitiligo and to better understand its long-term outcomes.

Patient Satisfaction and Willingness to Continue with Telemental Health Care During and After the Early Period of SARS-CoV-2 Pandemic: A User Survey.

Objective: The SARS-CoV-2 pandemic and related lockdown periods generated an increase in the use of virtual care for mental health (MH). This study aimed to assess patient satisfaction with Telemental Health services (TMH) during first lockdown and factors related to their willingness to continue using this service. Methods: We conducted a cross-sectional survey of 364 MH outpatients from 9 centers in the Barcelona region (Spain), who received TMH between April 20 and May 22, 2020. We assessed sociodemographic and clinical characteristics, prior experience, and familiarity with technologies and satisfaction with TMH. Willingness to receive TMH after the lockdown was measured separately for telephone and videoconferencing. We performed descriptive statistics and bivariate and multivariate regression models to predict TMH willingness. Results: From 450 patients contacted, 364 were interviewed. Satisfaction with TMH was high (mean 9.24, standard deviation 0.07); 2.47% preferred only TMH visits after lockdown, 23.08% preferred mostly TMH visits, 50.82% accepted some TMH visits, and 23.63% would prefer in-person consultations. Female patients and those having received TMH during lockdown showed higher odds of willingness to receive TMH in the future, while patients unfamiliar with technologies showed lower odds. Concerning TMH through telephone, willingness was more likely in patients living with more persons. Videoconferencing willingness was more likely for people living with depression. Conclusions: TMH was well accepted during the first lockdown and patients were willing to maintain it after lockdown. Low familiarity with new technologies is an important barrier to TMH willingness, which needs to be addressed for appropriate implementation going forward.

Cutting Edge: Heterogeneity in Cell Age Contributes to Functional Diversity of NK Cells.

Heterogeneity among naive adaptive lymphocytes determines their individual functions and fate decisions during an immune response. NK cells are innate lymphocytes capable of generating "adaptive" responses during infectious challenges. However, the factors that govern various NK cell functions are not fully understood. In this study, we use a reporter mouse model to permanently "time stamp" NK cells and type 1 innate lymphoid cells (ILC1s) to characterize the dynamics of their homeostatic turnover. We found that the homeostatic turnover of tissue-resident ILC1s is much slower than that of circulating NK cells. NK cell homeostatic turnover is further accelerated without the transcription factor Eomes. Finally, heterogeneity in NK cell age diversifies NK cell function, with "older" NK cells exhibiting more potent IFN-γ production to activating stimuli and more robust adaptive responses during CMV infection. These results provide insight into how the functional response of an NK cell varies over its lifespan.

Spirituality, Religiosity and Mental Health: A Clinical-care Approach.

No abstract present.

Is epilepsy related to psychiatric disorders in people with intellectual disability? A systematic review.

The prevalence of psychiatric disorders in people with Intellectual Disability (ID) is statistically higher than in the general population. There is a lack of consensus on the role that epilepsy plays in psychiatric disorders in people with ID. We carried out a systematic review of articles published between 1960 and 2022, focusing on high-quality, case-control original research studies that only included adult populations. The primary outcome was the prevalence of psychiatric disorders in people with intellectual disability with and without epilepsy. Six articles were finally included. Results were varied; some reported a statistical increase, whereas others did not find any statistical difference. Due to the current controversy on the role of epilepsy in psychiatric disorders in people with ID and the small number of publications on the topic, we cannot affirm a relationship between epilepsy and psychiatric disorders in people with ID.

Revascularization of coronary chronic total occlusions in an infarct-related artery and recurrence of ventricular arrhythmias among patients with secondary prevention implantable cardioverter defibrillator.

OBJECTIVES: To evaluate whether the revascularization of a coronary chronic total occlusion in an infarct-related artery (IRACTO) may be associated with lower recurrence of ventricular arrhythmias (VA) among patients with a secondary prevention implantable cardioverter defibrillator (ICD). BACKGROUND: IRACTO is increasingly recognized as an independent predictor of VA. It is unknown whether IRACTO revascularization can reduce the burden of VA. METHODS: Multicenter observational cohort study that included consecutive patients with prior myocardial infarction and secondary prevention ICD. The primary endpoint was any appropriate ICD therapy. RESULTS: Among the 460 patients included, 269 (58%) had at least one IRACTO at the coronary angiogram performed before ICD implantation; of these, 20 (7%) had their IRACTO successfully revascularized (IRACTO-R) afterwards. During a median follow-up of 48 months, 229 patients (49%) had at least one appropriate ICD therapy. Patients with IRACTO not revascularized (IRACTO-NR) had the highest incidence of ICD therapies (65%) while patients with IRACTO-R had the lowest (10%, p < .001). In the entire cohort, IRACTO-NR was an independent predictor of appropriate ICD therapies (HR 2.85, p < .001) and appropriate ICD shocks (HR 2.94, p < .001). Among patients with IRACTO at baseline, IRACTO-R was independently associated with a marked reduction of appropriate ICD therapies (HR 0.12, p = .002) and appropriate ICD shocks (HR 0.21, p = .03). CONCLUSIONS: In patients with prior myocardial infarction and secondary prevention ICD, IRACTO revascularization was independently associated with a markedly lower incidence of appropriate ICD therapies and shocks. These results should be corroborated by larger prospective studies.

Dose-reducing fluoroscopic system decreases patient but not occupational radiation exposure in chronic total occlusion intervention.

AIMS: Several novel low-dose fluoroscopic systems (LDS) developed recently, but real practice information of the net benefit for the patient and professionals is scarce. We evaluated separately patient and operator radiation exposure during percutaneous interventions of chronic total occlusions (CTO). METHODS: A total of 116 consecutive CTOs were analyzed (60 in LDS and 56 in standard-dose fluoroscopic system [SDS]). Digital dosimetry of patient and occupational (operator and scatter dose) exposure was prospectively recorded. RESULTS: Biometrics, demographics, CTO variables, and operators were distributed evenly. Patient radiation exposure was effectively decreased in LDS (dose area product [DAP] by 36%, Air Kerma [AK] by 47%). However, occupational data showed no statistical differences between LDS and SDS. The LDS uses less radiation amount but with higher energy (due to additional filtration) compared to SDS, therefore increasing the scatter dose. When comparing the C-arm scatter dose to the DAP we found higher scatter dose with the LDS (0.0139 mSv/gray (Gy)*cm2 vs. 0.0082 mSv/Gy*cm2, p < .001). This was confirmed in a larger dataset comprising 5,221 coronary procedures. CONCLUSIONS: LDS was safer for patients reducing DAP and AK compared to SDS. However, occupational doses were not lower and scatter dose higher. Radiological protection measures must be kept maximized even in LDS.

Sarcopenia predicts worse postoperative outcomes and decreased survival rates in patients with colorectal cancer: a systematic review and meta-analysis.

PURPOSE: Previous studies have shown an association of sarcopenia with adverse short- and long-term outcomes in multiple gastrointestinal cancer types. We aimed to investigate the prognostic value of sarcopenia on the postoperative outcomes and survival rates of patients with colorectal cancer (CRC). METHODS: A systematic literature search was performed using the PubMed, Embase, Cochrane, Google Scholar, and Scopus databases. We included studies that compared postoperative outcomes or survival rates in sarcopenic and non-sarcopenic patients with CRC. RESULTS: A total of 44 observational studies, comprising 18,891 patients, were included. The pooled prevalence of sarcopenia was 37% (n = 7009). The pooled analysis revealed an association between sarcopenia and higher risk of total postoperative complications (23 studies, OR = 1.84; 95% CI 1.35-2.49), postoperative severe complications (OR = 1.72; 95% CI 1.10-2.68), postoperative mortality (OR = 3.21; 95% CI 2.01-5.11), postoperative infections (OR = 1.40; 95% CI 1.12-1.76), postoperative cardiopulmonary complications (OR = 2.92; 95% CI 1.96-4.37), and prolonged length of stay (MD = 0.77; 95% CI 0.44-1.11) after colorectal cancer surgery. However, anastomotic leakage showed comparable occurrence between sarcopenic and non-sarcopenic patients (OR = 0.99; 95% CI 0.72 to 1.36). Regarding survival outcomes, sarcopenic patients had significantly shorter overall survival (25 studies, HR = 1.83; 95% CI = 1.57-2.14), disease-free survival (HR = 1.55; 95% CI = 1.29-1.88), and cancer-specific survival (HR = 1.77; 95% CI 1.40-2.23) as compared with non-sarcopenic patients. CONCLUSION: Among patients with colorectal cancer, sarcopenia is a strong predictor of increased postoperative complications and worse survival outcomes.

Peroral endoscopic myotomy as treatment for Zenker's diverticulum (Z-POEM): a multi-center international study.

BACKGROUND: Peroral endoscopic myotomy for the treatment of Zenker's diverticulum (Z-POEM) is a novel technique that has been described in several recent reports. This method utilizes the third space (submucosal layer) to create a tunnel to facilitate complete visualization of the septum and hence cutting it entirely. Conventional endoscopic septotomy carries the risk of recurrence due to incomplete visualization of the septum. While surgical correction is a risky and lengthy procedure in old comorbid patients with Zenker's diverticulum. The aim of this study is to assess the efficacy and safety of Z-POEM. METHODS: The study enrolled 24 patients diagnosed with Zenker's diverticulum (ZD) who underwent Z-POEM at seven independent endoscopy centers in five different countries. RESULTS: Mean patient age ± standard deviation (SD) was 74.3 ± 11 years. Most of the patients were males (n = 20, 83.3%); four (16.7%) were females. More than 50% of the patients (n = 14, 58.3%) had associated comorbidities. The mean size of the diverticula was 4 cm (range 2-7 cm). The Kothari-Haber Score was used to assess clinical symptoms; values ranged from 6 to 14 (median = 9). We achieved 100% technical success with a median procedure time of 61 min and no adverse events. Median hospital stay was 1 day (range 1-5 days). There is a significant reduction in the Kothari-Haber Score after Z-POEM (P < 0.0001). Technical success was achieved in 100% of the patients. Clinical success was achieved in 23/24 (95.8%) of the patients with a median follow-up of 10 months (range 6-24 months). CONCLUSION: Z-POEM is a safe and effective modality for managing ZD.

An e-Delphi study generates expert consensus on the trends in future continuing medical education engagement by resident, practicing, and expert surgeons.

Background: The Delphi method is a demonstrated way to gather structured expert opinions to forecast, plan, and prioritize around a given topic. It builds consensus through iterative rounds.Aims: The goal of this study was to build consensus-based predictions for the year 2022 about: future trends in surgeon continuing medical education (CME); the role of technology in learning for surgeons of different experience levels (trainee/resident, practicing, expert); and CME funding models.Methods: A three round e-Delphi method was employed for this study. Panelist identities were anonymized, and controlled feedback and consensus rules were employed. Fifteen international expert panelists' input was collected via electronically distributed, open-ended questionnaire (Round 1) and 5-point Likert scale ranking surveys (Rounds 2 and 3), in a series of nine questions (Round 1) and 26 and 25 summary statements (Rounds 2 and 3, respectively). Summary statements were collated via key words and ideas collected from panelist's input. Mean, median, standard deviation, and 95% confidence intervals were calculated.Results: Response rate was 100% for each round. Consensus in Round 2 was 61% and 88% in Round 3. Seven key finding statements with supporting background information was the result.Discussion: Reliable, affordable internet access was identified as a likely barrier to education for certain regions, even in 5 years' time. The use of similar educational resources were identified for all levels of surgeon, what varied was the reliance on a particular resource by each level of surgeon.Conclusion: Institutes of employment were predicted to have ended CME funding for expert surgeons by 2022. Industry sponsored CME was predicted to have a continued role for trainee/residents and practicing surgeons.

Underdiagnosis of psychiatric disorders in people with intellectual disabilities: Differences between psychiatric disorders and challenging behaviour.

BACKGROUND AND PURPOSE: The purpose of this study was to assess the level of mental disorders and challenging behaviour in individuals with intellectual disability (ID) supported by specialized services, but without a prior psychiatric diagnosis, and to compare the levels of different disorders depending on the severity of ID. METHODS: This is a cross-sectional study (N = 142) of population with ID. Inclusion criteria were the following: adult patients with ID and with no previous psychiatric diagnosis prior to this survey. The Wechsler Adults Intelligence Scale-II, the Psychiatric Assessment Schedule for Adults with Developmental Disability checklist and clinical interview, the Diagnostic Assessment for the Severely Handicapped scale and the Inventory for Client and Agency Planning were the assessment tools. RESULTS: A previously undiagnosed mental disorder was found in 29.6% of the sample. The most prevalent mental disorders were major depressive and anxiety disorders. An association between psychiatric comorbidity and challenging behaviour was found only for mild/moderate ID, especially for affective disorders. CONCLUSIONS: The presence of a psychiatric as well as a medical comorbidity is associated with severe ID, unlike challenging behaviour. Clinical limitations of the study have been discussed.

Ambulatory versus conventional laparoscopic appendectomy: a systematic review and meta-analysis.

PURPOSE: Ambulatory laparoscopic appendectomy has gained popularity due to the improved understanding of patient selection criteria, the application of enhanced recovery pathways, and the potential for improving healthcare resource utilization. The aim of the review was to compare the morbidity and readmission rates between ambulatory and conventional laparoscopic appendectomy (LA). METHODS: A systematic search was undertaken using PubMed, Embase, Cochrane, and Web of Science. Studies from 2014 to 2018, on adult patients undergoing ambulatory LA, were considered. Meta-analyses were conducted to pool the total number of complications and readmission events in the ambulatory and conventional groups. RESULTS: A total of 5 studies met our inclusion criteria accounting for 7079 total of patients with acute appendicitis treated by ambulatory LA and 6370 patients treated by conventional LA. We included four observational studies (two prospective and two retrospective) and one randomized controlled trial. Length of stay was significantly lower in the ambulatory group (mean difference = - 15.63 h, 95% CI = - 21.78 to - 9.49, P = < 0.00001). The relative risk (RR) of reoperation was 0.49 (95% CI = 0.12-1.95, P = 0.31). The results demonstrated a pooled RR of overall morbidity of 0.79 (95% CI = 0.65-0.97, P = 0.02) and a pooled RR of readmission of 0.72 (95% CI = 0.59-0.88, P = 0.002), both results favoring the ambulatory LA group. CONCLUSION: There is a lack of high-quality comparative studies making conclusive recommendations not possible at this time. Based on current data, ambulatory LA may be safe and feasible as compared with conventional LA.

Enhanced recovery after surgery protocol allows ambulatory laparoscopic appendectomy in uncomplicated acute appendicitis: a prospective, randomized trial.

BACKGROUND: Previous observational studies have demonstrated the safety of discharging patients after laparoscopic appendectomy within the same day without hospitalization. The application of Enhanced Recovery After Surgery (ERAS) guidelines has resulted in shorter length of stay, fewer complications, and reduction in medical costs. The aim of this study was to investigate if ERAS protocol implementation in patients with acute uncomplicated appendicitis decreases the length of stay enough to allow for ambulatory laparoscopic appendectomy. METHODS: In this prospective, randomized controlled clinical trial, 108 patients were randomized into two groups: laparoscopic appendectomy with ERAS (LA-E) or laparoscopic appendectomy with conventional care (LA-C). The primary endpoint was postoperative length of stay. The secondary end points were time to resume diet, postoperative pain, postoperative complications, re-admission rate, and reoperation rate. RESULTS: From January 2016 through May 2017, 50 patients in the LA-E group and 58 in the LA-C were analyzed. There were no significant differences in preoperative data. Regarding the primary end point of the study, the ERAS protocol significantly reduced the postoperative length of stay with a mean of 9.7 h (SD: 3.1) versus 23.2 h (SD: 6.8) in the conventional group (p < 0.001). The ERAS protocol allowed ambulatory management in 90% of the patients included in this group. There was a significant reduction in time to resume diet (110 vs. 360 min, p < 0.001) and less moderate-severe postoperative pain (28 vs. 62.1%, p < 0.001) in the LA-E versus LA-C group. The rate of complications, readmissions, and reoperations were comparable in both groups (p = 0.772). CONCLUSIONS: ERAS implementation was associated with a significantly shorter length of stay, allowing for the ambulatory management of this group of patients. Ambulatory laparoscopic appendectomy is safe and feasible with similar rates of morbidity and readmissions compared with conventional care.

Ranolazine for stable angina pectoris.

BACKGROUND: Stable angina pectoris is a chronic medical condition with significant impact on mortality and quality of life; it can be macrovascular or microvascular in origin. Ranolazine is a second-line anti-anginal drug approved for use in people with stable angina. However, the effects of ranolazine for people with angina are considered to be modest, with uncertain clinical relevance. OBJECTIVES: To assess the effects of ranolazine on cardiovascular and non-cardiovascular mortality, all-cause mortality, quality of life, acute myocardial infarction incidence, angina episodes frequency and adverse events incidence in stable angina patients, used either as monotherapy or as add-on therapy, and compared to placebo or any other anti-anginal agent. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and the Conference Proceedings Citation Index - Science in February 2016, as well as regional databases and trials registers. We also screened reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) which directly compared the effects of ranolazine versus placebo or other anti-anginals in people with stable angina pectoris were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed risk of bias. Estimates of treatment effects were calculated using risk ratios (RR), mean differences (MD) and standardised mean differences (SMD) with 95% confidence intervals (CI) using a fixed-effect model. Where we found statistically significant heterogeneity (Chi² P < 0.10), we used a random-effects model for pooling estimates. Meta-analysis was not performed where we found considerable heterogeneity (I² ≥ 75%). We used GRADE criteria to assess evidence quality and the GRADE profiler (GRADEpro GDT) to import data from Review Manager 5.3 to create 'Summary of findings' tables. MAIN RESULTS: We included 17 RCTs (9975 participants, mean age 63.3 years). We found very limited (or no) data to inform most planned comparisons. Summary data were used to inform comparison of ranolazine versus placebo. Overall, risk of bias was assessed as unclear.For add-on ranolazine compared to placebo, no data were available to estimate cardiovascular and non-cardiovascular mortality. We found uncertainty about the effect of ranolazine on: all-cause mortality (1000 mg twice daily, RR 0.83, 95% CI 0.26 to 2.71; 3 studies, 2053 participants; low quality evidence); quality of life (any dose, SMD 0.25, 95% CI -0.01 to 0.52; 4 studies, 1563 participants; I² = 73%; moderate quality evidence); and incidence of non-fatal acute myocardial infarction (AMI) (1000mg twice daily, RR 0.40, 95% CI 0.08 to 2.07; 2 studies, 1509 participants; low quality evidence). Add-on ranolazine 1000 mg twice daily reduced the fervour of angina episodes (MD -0.66, 95% CI -0.97 to -0.35; 3 studies, 2004 participants; I² = 39%; moderate quality evidence) but increased the risk of non-serious adverse events (RR 1.22, 95% CI 1.06 to 1.40; 3 studies, 2053 participants; moderate quality evidence).For ranolazine as monotherapy compared to placebo, we found uncertain effect on cardiovascular mortality (1000 mg twice daily, RR 1.03, 95% CI 0.56 to 1.88; 1 study, 2604 participants; low quality evidence). No data were available to estimate non-cardiovascular mortality. We also found an uncertain effect on all-cause mortality for ranolazine (1000 mg twice daily, RR 1.00, 95% CI 0.81 to 1.25; 3 studies, 6249 participants; low quality evidence), quality of life (1000 mg twice daily, MD 0.28, 95% CI -1.57 to 2.13; 3 studies, 2254 participants; moderate quality evidence), non-fatal AMI incidence (any dose, RR 0.88, 95% CI 0.69 to 1.12; 3 studies, 2983 participants; I² = 50%; low quality evidence), and frequency of angina episodes (any dose, MD 0.08, 95% CI -0.85 to 1.01; 2 studies, 402 participants; low quality evidence). We found an increased risk for non-serious adverse events associated with ranolazine (any dose, RR 1.50, 95% CI 1.12 to 2.00; 3 studies, 947 participants; very low quality evidence). AUTHORS' CONCLUSIONS: We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.

Phosphorylation modulates rapid nucleocytoplasmic shuttling and cytoplasmic accumulation of Neurospora clock protein FRQ on a circadian time scale.

The Neurospora clock protein FREQUENCY (FRQ) is an essential regulator of the circadian transcription factor WHITE COLLAR COMPLEX (WCC). In the course of a circadian period, the subcellular distribution of FRQ shifts from mainly nuclear to mainly cytosolic. This shift is crucial for coordinating the negative and positive limbs of the clock. We show that the subcellular redistribution of FRQ on a circadian time scale is governed by rapid, noncircadian cycles of nuclear import and export. The rate of nuclear import of newly synthesized FRQ is progressively reduced in a phosphorylation-dependent manner, leading to an increase in the steady-state level of cytoplasmic FRQ. The long-period frq(7) mutant displays reduced kinetics of FRQ(7) protein phosphorylation and a prolonged accumulation in the nucleus. We present a mathematical model that describes the cytoplasmic accumulation of wild-type and mutant FRQ on a circadian time scale on the basis of frequency-modulated rapid nucleocytoplasmic shuttling cycles.