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Summary: Background: The outcome of patients with metastatic tumors who discontinued immune checkpoint inhibitors (ICIs) not for progressive disease (PD) has been poorly explored. We performed a meta-analysis of all studies reporting the clinical outcome of patients who discontinued ICIs for reasons other than PD. Methods: We searched PubMed, Embase and Scopus databases, from the inception of each database to December 2023, for clinical trials (randomized or not) and observational studies assessing PD-(L)1 and CTLA-4 inhibitors in patients with metastatic solid tumors who discontinued treatment for reasons other than PD. Each study had to provide swimmer plots or Kaplan–Meier survival curves enabling the reconstruction of individual patient-level data on progression-free survival (PFS) following the discontinuation of immunotherapy. The primary endpoint was PFS from the date of treatment discontinuation overall and according to tumor histotype, type of treatment and reason of discontinuation. The Combersure’s method was used to estimate meta-analytical non-parametric summary survival curves assuming random effects at study level. Findings: Thirty-six studies (2180 patients) were included. The pooled median PFS (mPFS) was 24.7 months (95% CI, 18.8–30.6) and the PFS-rate at 12, 24, and 36 months was respectively 69.8% (95% CI, 63.1–77.3), 51.0% (95% CI, 43.4–59.8) and 34.0% (95% CI, 27.0–42.9). Univariable analysis showed that the mPFS was significantly longer for patients with melanoma (43.0 months), as compared with non-small cell lung cancer (NSCLC, 13.5 months) and renal cell carcinoma (RCC, 10.0 months; between-strata comparison test p-value < 0.001); for patients treated with anti-PD-(L)1 + anti-CTLA-4 as compared with anti-PD-(L)1 monotherapy (44.6 versus 19.9 months; p-value

Background: Controversy exists regarding the optimal duration of the extended adjuvant endocrine treatment (ET) in patients with early-stage breast-cancer (eBC).We performed a systematic review and trial-level meta-analysis of all randomized clinical trials (RCTs) comparing a “limited-extended” adjuvant ET (defined as more than 5 but less than 7.5 years of treatment overall) versus a “full-extended” adjuvant ET (defined as more than 7.5 years of treatment overall) in eBC. Methods: To be eligible, RCTs had to i) compare a “limited-extended” adjuvant ET versus a “full-extended” adjuvant ET in patients with eBC; and ii) report disease-free survival (DFS) hazard ratio (HR) according to the disease nodal-status [i.e., nodal-negative (N-ve) versus nodal-positive (N + ve)].The primary endpoint was to assess the difference in efficacy of full-versus limited-extended ET, measured in terms of the difference in DFS log-HR, according to the disease nodal-status. Secondary endpoint was the difference in efficacy of full-versus limited-extended ET according to tumor size (i.e., pT1 vs pT2/3/4), histological grade (i.e., G1/G2 vs G3), patients’ age (i.e., ≤60 vs > 60 years) and previous type of ET (i.e., aromatase inhibitors vs tamoxifen vs switch strategy). Results: Three phase III RCTs fulfilled the inclusion criteria. A total of 6689 patients were included in the analysis, of which 3506 (53%) had N + ve disease.The full-extended ET provided no DFS-benefit as compared with the limited-extended ET in patients with N-ve disease (pooled DFS-HR = 1.04, 95%CI: 0.89 to 1.22; I2 = 18%).Conversely, in patients with N + ve disease the full-extended ET significantly improved DFS, with a pooled DFS-HR of 0.85 (95%CI: 0.74 to 0.97; I2 = 0%).There was a significant interaction between the disease nodal-status and the efficacy of the full-versus limited-extended ET (p-heterogeneity = 0.048).The full-extended ET provided no significant DFS-benefit as compared with the limited-extended ET in all the other subgroups analyzed. Conclusions: Patients with eBC and N + ve disease can obtain a significant DFS-benefit from the full-extended as compared with the limited-extended adjuvant ET.

Introduction: To provide evidence explaining the poor association between pCR and patients’ long-term outcome at trial-level in neoadjuvant RCTs for breast cancer (BC), we performed a systematic-review and meta-analysis of all RCTs testing neoadjuvant treatments for early-BC and reporting the hazard ratio of DFS (HRDFS) for the intervention versus control arm stratified by pathological response type (i.e., pCR yes versus no). Methods: The objective was to explore differences of treatment effects on DFS across patients with and without pCR.We calculated the pooled HRDFS in the two strata of pathological response (i.e., pCR yes versus no) using a random-effects model, and assessed the difference between these two estimates using an interaction test. Results: Ten RCTs and 8496 patients were included in the analysis.Patients obtaining pCR in the intervention-arm had a higher, although not statistically significant, risk of DFS-event as compared with patients obtaining pCR in the control-arm: the pooled HRDFS for the experimental versus control arm was 1.23 (95%CI, 0.91–1.65). On the opposite, the risk of DFS-event was higher for control as compared with the intervention-arm in the stratum of patients without pCR: the pooled HRDFS was 0.86 (95%CI, 0.78–0.95).Treatment effect on DFS was significantly different according to pathological response type (interaction test p: 0.014). Conclusion: We reported new evidence that contributes to explaining the poor surrogacy value of pCR at trial-level in neoadjuvant RCTs for early-BC.

Background: We report here for the first time, a comprehensive characterization of biological and clinical features of early-stage triple negative Invasive Lobular Carcinomas(TN-ILCs) Methods: We analyzed all consecutive patients with early-stage TN-ILC operated at two reference cancer-centers between 1994 and 2012.Primary objective was to assess the invasive disease-free survival(iDFS).Co-primary objective was to assess biological features of TN-ILCs, including molecular intrinsic subtypes based on PAM-50 assay, expression of androgen receptor (AR) and mutational status of ERBB2-gene.Additionally, DNA mutational status of an independent cohort of 45 TN-ILCs from three databases were analyzed, to confirm mutations in ERBB2-gene and to identify other recurrently mutated genes. Results: Among 4152 ILCs, 74(1.8%) were TN and were analyzed.The iDFS at 5 and 10 years of FUP were 50.4%(95%CI,38.0–61.6) and 37.2%(95%CI,25.5–48.8), respectively.The molecular subtype was defined through PAM50-classifier for 31 out of 74 TN-ILCs: 48% were Luminal-A(15/31), 3% luminal-B(1/31), 32% HER2-enriched (10/31), and only 16% basal-like(5/31).Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 94% of luminal tumors versus 53% in non-luminal tumors; p-value = 0.001).20% of TN-ILCs analyzed(7/35), harbored a pathogenetic and actionable mutation in the ERBB2-gene. Analysis of the independent cohort of 45 TN-ILCs from three different databases, confirmed similar percentage of pathogenetic and actionable mutations in ERBB2-gene(20%; 9/45).Among the top 10 molecular pathways significantly enriched for recurrently mutated genes in TN-ILCs(FDR

Renal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by ‘tuned’ malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury.

The interpretability of models has become a crucial issue in Machine Learning because of algorithmic decisions' growing impact on real-world applications. Tree ensemble methods, such as Random Forests or XgBoost, are powerful learning tools for classification tasks. However, while combining multiple trees may provide higher prediction quality than a single one, it sacrifices the interpretability property resulting in “black-box” models. In light of this, we aim to develop an interpretable representation of a tree-ensemble model that can provide valuable insights into its behavior. First, given a target tree-ensemble model, we develop a hierarchical visualization tool based on a heatmap representation of the forest's feature use, considering the frequency of a feature and the level at which it is selected as an indicator of importance. Next, we propose a mixed-integer linear programming (MILP) formulation for constructing a single optimal multivariate tree that accurately mimics the target model predictions. The goal is to provide an interpretable surrogate model based on oblique hyperplane splits, which uses only the most relevant features according to the defined forest's importance indicators. The MILP model includes a penalty on feature selection based on their frequency in the forest to further induce sparsity of the splits. The natural formulation has been strengthened to improve the computational performance of mixed-integer software. Computational experience is carried out on benchmark datasets from the UCI repository using a state-of-the-art off-the-shelf solver. Results show that the proposed model is effective in yielding a shallow interpretable tree approximating the tree-ensemble decision function.

Rationale and Objective: Latinx individuals are at a higher risk for kidney failure than non-Latinx White individuals; however, they are less likely to receive pre-kidney failure medical care. The objective of this study was to determine the feasibility and acceptability of a community health worker (CHW) intervention that facilitated access to medical care for Latinx individuals. Study Design: Single-arm prospective study. Setting and Participants: Latinx adults were found to have albuminuria or risk factors for kidney disease at community screening events in Austin, Texas. Intervention: A 6-month CHW intervention that facilitated the following: (1) obtaining medical insurance; (2) medical care coordination with primary and nephrology care; (3) kidney disease education; and (4) connection with local resources to address health-related social needs. Outcomes: Recruitment, retention, medical care linkage, and participant and CHW-reported satisfaction with the intervention. Results: Of the 173 individuals who attended the 2 community screening events, 49 agreed to participate in the study, of whom, 51% were men with a mean ± standard deviation (SD) age of 45 ± 14 years, and all self-identified as Mexican or Chicano. The mean ± SD estimated glomerular filtration rate (eGFR) was 110 ± 21 mL/min/1.73 m2 and 41% of the participants reported a urine albumin-creatinine ratio of ≥30 mg/g. Among those enrolled, 28 of the 49 (57%) completed at least 1 CHW visit, and 20 of 49 (41%) completed the intervention. 7 individuals who needed assistance with insurance obtained insurance, and 15 of 20 (75%) scheduled an appointment with a primary care physician within 180 days. Participants reported that the US health care previously seemed inaccessible but gained insurance, the ability to navigate the system, and the ability to help others in their community to access medical care because of the program. Limitations: Small sample size and a single community may limit generalizability. Conclusions: We reported the acceptability of a CHW intervention. We encountered challenges with feasibility and identified strategies to overcome them. Studies are needed to test the effect of CHW interventions on outcomes and kidney health disparities. Funding: National Kidney Foundation young investigator research grant to Dr Novick. Plain Language Summary: Latinx individuals are at a higher risk for kidney failure than non-Latinx White individuals; however, they are less likely to receive pre-kidney failure medical care. We piloted a community health worker intervention that connected people with risk factors or showed evidence of kidney dysfunction at community screening events with medical care. Our findings indicate the acceptability of the intervention. We encountered challenges with feasibility and identified strategies to overcome them.

Background: To review the phenomenology, nosology, and treatment of postpartum psychosis. Methods: Using the keywords postpartum, puerperal, psychosis, bipolar, mania, depression, classification, nosology, phenomenology, diagnosis, suicide, infanticide, and treatment, four electronic databases, MEDLINE/PubMed (1966–2020), PsycINFO (1806–2020), EMBASE (1980–2020), and the Cochrane Database of Systematic Reviews were searched. We also searched the reference lists of articles identified to find articles of interest. Results: There is a lack of consensus about the diagnostic criteria. Although it is usually considered a rare entity, as many as 16% of women with bipolar I disorder have mood or psychotic episodes that meet the contemporary definition of postpartum psychosis. There is a paucity of data on the identification of women at risk of having postpartum psychosis. Atypical antipsychotics and lithium are commonly recommended for acute treatment of postpartum psychosis, however, there are no randomised trials of drugs in the acute treatment of manic/mixed or depressive episodes with psychosis in the postpartum period. Limitations: This is not a systematic review but rather a selective appraisal of the literature. Conclusions: Controversies surrounding its phenomenology and nosology have probably prevented consensus about its management. Accurate diagnosis of postpartum psychosis is crucial for suicide risk assessment and prediction, and treatment planning. As much as possible clinicians should consider applying the DSM-5 nomenclature to characterize disorders subsumed under the umbrella of postpartum psychosis. A nuanced approach that takes into consideration the predisposing, precipitating, perpetuating, and protective factors could potentially improve the short- and long-term prognosis of postpartum psychosis.

Diets high in calories can be used to model metabolic diseases, including obesity and its associated comorbidities, in animals. Drosophila melanogaster fed high-sugar diets (HSDs) exhibit complications of human obesity including hyperglycemia, hyperlipidemia, insulin resistance, cardiomyopathy, increased susceptibility to infection, and reduced longevity. We hypothesize that lipid storage in the high-sugar-fed fly's fat body (FB) reaches a maximum capacity, resulting in the accumulation of toxic lipids in other tissues or lipotoxicity. We took two approaches to characterize tissue-specific lipotoxicity. Ultra-HPLC-MS/MS and MALDI-MS imaging enabled spatial and temporal localization of lipid species in the FB, heart, and hemolymph. Substituent chain length was diet dependent, with fewer odd chain esterified FAs on HSDs in all sample types. By contrast, dietary effects on double bond content differed among organs, consistent with a model where some substituent pools are shared and others are spatially restricted. Both di- and triglycerides increased on HSDs in all sample types, similar to observations in obese humans. Interestingly, there were dramatic effects of sugar feeding on lipid ethers, which have not been previously associated with lipotoxicity. Taken together, we have identified candidate endocrine mechanisms and molecular targets that may be involved in metabolic disease and lipotoxicity.

Purpose: To report a case of a sterile iris abscess associated with herpes zoster ophthalmicus (HZO). Observations: A 69-year-old African American female presented to SUNY Downstate Medical Center complaining of left-sided eye pain for two weeks. The patient had a best-corrected visual acuity of 20/30 OD and 20/200 OS. On external exam, vesicles were noted on the left upper lid and tip of the nose. Anterior segment exam was notable for decreased sensation without epithelial defects. The patient had 2+ stromal edema with 3+ cell and flare. The iris was flat with 1+ nuclear sclerosis OU. The intraocular pressure (IOP) was 14 mmHg OD and 40 mmHg OS. The patient was diagnosed with HZO with secondary uveitic glaucoma.At ten weeks, anterior segment inflammation resolved and IOP stabilized. However, an iris nodule was noted superior nasal which continued to enlarge by 16 weeks follow up. Iris ultrasound revealed a 3 × 3 mm elevated lesion with internal homogeneity suggestive of an abscess.At five months, a dense, mature cataract developed. The patient underwent cataract extraction with sector iridectomy. Gram staining and cultures were negative for organisms but positive for polymorphic neutrophils. Histopathology revealed fibrosis, surface necrosis, and stromal infiltration with chronic inflammatory cells consistent with chronic iritis and a sterile abscess secondary to HZO. Conclusions and Importance: HZO is associated with a range of ocular sequelae with acquired iris nodule only mentioned once in the literature. As the second documented case, our findings will add to the general fund of knowledge regarding iris lesions and HZO.

The World Health Organization estimates that around 7 million people die every year from exposure to fine particles (PM2.5) in polluted air. Here, the number of premature deaths in Europe from different diseases associated to the ambient exposure to PM2.5 have here been studied both for present (1991–2010) and future periods (2031–2050, RCP8.5 scenario). This contribution combines different state-of-the-art approaches (use of high-resolution climate/chemistry simulations over Europe for providing air quality data; use of different baseline mortality data for specific European regions; inclusion of future population projections and dynamical changes for 2050 obtained from the United Nations (UN) Population Projections or use of non-linear exposure–response functions) to estimate the premature mortality due to PM2.5. The mortality endpoints included in this study are Lung Cancer (LC), Chronic Obstructive Pulmonary Disease (COPD), Cerebrovascular Disease (CEV), Ischemic Heart Disease (IHD), Lower Respiratory Infection (LRI) and other Non-Communicable Diseases (other NCDs). Different risk ratio and baseline mortalities for each disease end each age range have been estimated individually. The results indicate that the annual excess mortality rate from fine particulate matter in Europe is 904,000 [95% confidence interval (95% CI) 733,100–1,067,800], increasing by 73% in 2050s (1,560,000; 95% CI 1,260,000–1,840,000); meanwhile population decreases from 808 to 806 million according to the UN estimations. The results show that IHD is the main cause of premature mortality in Europe associated to PM2.5 (around 48%) both for the present and future periods. Despite several marked regional differences, premature deaths associated to all the endpoints included in this study will increase in the future period due to the climate penalty but especially because of changes in the population projected and its aging.

Introduction: Insomnia symptoms are very common in Bipolar Disorder. Our aim was to assess the potential association between insomnia, emotion dysregulation and suicidality in subjects with Bipolar Disorder. Methods: Seventy-seven subjects with Bipolar Disorder type II with a depressive episode with mixed features were recruited. Patients were assessed with SCID-DSM-5, the Insomnia Severity Index (ISI), the Difficulties in Emotion Regulation Scale (DERS), the Scale for Suicide Ideation (SSI) while evaluating manic and depressive symptoms. Results: Subjects with insomnia symptoms compared to those without showed higher scores in the DERS scale and subscales, including impulsivity, and in the SSI scale. Insomnia symptoms significantly predicted the severity of depressive symptoms, emotion dysregulation, and suicidality in subjects with bipolar disorder. In particular, insomnia was related to difficulties in some areas of emotion regulation including impulsivity. Emotion dysregulation significantly mediated the association between insomnia and depressive symptoms (Z = 2.9, p = 0.004). Furthermore, emotional impulsivity mediated the association between insomnia symptoms and suicidality (Z = 2.2, p = 0.03). Conclusion: In our study, subjects with bipolar disorder suffering from insomnia experienced a greater severity of depressive symptoms and suicidality compared to subjects without insomnia. Insomnia was associated with emotion dysregulation, impulsivity and suicidality. Further research is necessary to investigate if these latter features may benefit from early insomnia treatment in subjects with bipolar disorder.

In this data article, we present a dataset made up of personal, social and clinical records related to patients undergoing a rehabilitation program. Data refers to records registered in the “Acceptance/Discharge Report for the rehabilitation area” (ADR) which implements the Italian law (DGR 731/2005) and refer to hospitalization at the rehabilitation hospital of Rome “San Raffaele” in the years from 2015 to 2018 of patients suffering from orthopedic and neurological pathologies. For each ADR report, the clinical status of the patient at the date of acceptance and discharge is reported using, among other, the Barthel index as a measure of the Activities Daily Living of the patient.These data can be used to understand the influence of many different factors in the rehabilitation progress of clinical patients.

Introduction: The epidemiology of Clostridium difficile infection (CDI) has changed in the last two decades. There is a lack of information regarding incidence and severity of CDI, especially in the developing world. Methods: This was a retrospective and observational study from four hospitals of three Mexican cities. Patients were diagnosed with CDI when presented with loose stools and had at least one of the following tests positive: toxins assay, real-time PCR, or an endoscopic image compatible with pseudomembranous colitis. CDI was classified according to international guidelines. Demographic and clinical data as well as information regarding total hospital admissions, total length-of-hospital stay, and other variables related to hospitalization were gathered from the epidemiology and administration departments of each hospital. Results: A total of 2050 hospital beds were analyzed with 288,171 patients hospitalized accumulating 1,576,446 days of hospitalization during the study period. The average rate of CDI per 1000 hospital-days was lower than the rates reported in the US and Europe, although in 2015 CDI rates were almost persistently above the mean rate for the study period. More than half of PCR positive patients were ribotype 027. Conclusion: Hospital rates of CDI are increasing in Mexican hospitals with a predominance of infections caused by ribotype 027. Keywords: Clostridium difficile, Hospital acquired infections, Hospital diarrhea, Infection rates

We developed a Drosophila model of T2D in which high sugar (HS) feeding leads to insulin resistance. In this model, adipose TG storage is protective against fatty acid toxicity and diabetes. Initial biochemical and gene expression studies suggested that deficiency in CoA might underlie reduced TG synthesis in animals during chronic HS feeding. Focusing on the Drosophila fat body (FB), which is specialized for TG storage and lipolysis, we undertook a series of experiments to test the hypothesis that CoA could protect against the deleterious effects of caloric overload. Quantitative metabolomics revealed a reduction in substrate availability for CoA synthesis in the face of an HS diet. Further reducing CoA synthetic capacity by expressing FB-specific RNAi targeting pantothenate kinase (PK orfumble) or phosphopantothenoylcysteine synthase (PPCS) exacerbated HS-diet-induced accumulation of FFAs. Dietary supplementation with pantothenic acid (vitamin B5, a precursor of CoA) was able to ameliorate HS-diet-induced FFA accumulation and hyperglycemia while increasing TG synthesis. Taken together, our data support a model where free CoA is required to support fatty acid esterification and to protect against the toxicity of HS diets.