Non-genetic factors and breast cancer: an umbrella review of meta-analyses.

BACKGROUND: Previous research has found associations between various non-genetic factors and breast cancer (BrCa) risk. This study summarises and appraises the credibility of the available evidence on the association between non-genetic factors and BrCa risk. METHODS: We conducted an umbrella review of meta-analyses. Medline, Scopus, and the Cochrane databases were systematically searched for meta-analyses examining non-genetic factors and BrCa incidence or mortality. The strength of the evidence was graded in four categories (i.e., weak, suggestive, highly suggestive, convincing). RESULTS: A total of 781 meta-analyses from 280 publications were evaluated and graded. We included exposures related to anthropometric measurements, biomarkers, breast characteristics and diseases, diet and supplements, environment, exogenous hormones, lifestyle and social factors, medical history, medication, reproductive history, and pregnancy. The largest number of examined associations was found for the category of diet and supplements and for exposures such as aspirin use and active smoking. The statistically significant (P-value < 0.05) meta-analyses were 382 (49%), of which 204 (53.4%) reported factors associated with increased BrCa risk. Most of the statistically significant evidence (n = 224, 58.6%) was graded as weak. Convincing harmful associations with heightened BrCa risk were found for increased body mass index (BMI), BMI and weight gain in postmenopausal women, oral contraceptive use in premenopausal women, increased androstenedione, estradiol, estrone, and testosterone concentrations, high Breast Imaging Reporting and Data System (BIRADS) classification, and increased breast density. Convincing protective factors associated with lower BrCa risk included high fiber intake and high sex hormone binding globulin (SHBG) levels while highly suggestive protective factors included high 25 hydroxy vitamin D [25(OH)D] levels, adherence to healthy lifestyle, and moderate-vigorous physical activity. CONCLUSIONS: Our findings suggest some highly modifiable factors that protect from BrCa. Interestingly, while diet was the most studied exposure category, the related associations failed to reach higher levels of evidence, indicating the methodological limitations in the field. To improve the validity of these associations, future research should utilise more robust study designs and better exposure assessment techniques. Overall, our study provides knowledge that supports the development of evidence-based BrCa prevention recommendations and guidance, both at an individual level and for public health initiatives. TRIAL REGISTRATION: PROSPERO CRD42022370675.

Racial Disparities in Infliximab Efficacy for Ulcerative Colitis: Evidence Synthesis and Effect Modification Assessment.

An increasing amount of research explores the role of race in clinical phenotypes and outcomes in ulcerative colitis (UC). We aimed to investigate racial differences in infliximab (IFX) treatment efficacy in UC. We used aggregate data from IFX trials and evidence synthesis methods to generate race-specific efficacy estimates. Then, we tested the effect modification by race by comparing the race-specific estimates derived from independent evidence syntheses. We computed ratios of relative risks (RRRs) and performed tests of statistical interaction. We analyzed data from five randomized, placebo-controlled trials evaluating IFX as induction and maintenance therapy for adults with moderate-to-severe UC (875 participants; 45% Asians). We found no substantial evidence of racial differences concerning the efficacy of IFX in inducing clinical response (RRR = 0.89, 95% CI: 0.66-1.20; p = 0.44), clinical remission (RRR = 0.58, 95% CI: 0.24-1.44; p = 0.24), and mucosal healing (RRR = 0.99, 95% CI: 0.69-1.41; p = 0.95), or maintaining clinical remission (RRR = 0.81, 95% CI: 0.46-1.42; p = 0.45) and mucosal healing (RRR = 0.84, 95% CI: 0.48-1.46; p = 0.53), between Asian and Caucasian populations. Future clinical studies should expand the participation of racial minorities to comprehensively assess potential racial differences in the effectiveness of advanced therapies, including IFX, in the context of treating UC.

Candida auris Infection, a Rapidly Emerging Threat in the Neonatal Intensive Care Units: A Systematic Review.

(1) Background: In recent years, a global epidemiological shift in candidemia has been observed, marked by the emergence of resistant non-albicans Candida species. Candida auris, in particular, has become a significant global concern, causing infections in both pediatric and adult populations within healthcare settings. Despite its widespread impact, there is a limited understanding of the clinical course and transmission dynamics of neonatal systemic Candida auris infections, hindering effective prevention and management. This study focused on the epidemiologic data, the clinical presentation, risk factors, and outcome of C. auris infection in neonatal population. (2) Methods: A systematic review of the literature using PubMed and Scopus databases until December 2023 was conducted. (3) Results: A total of 24 relevant studies were identified, encompassing 476 documented cases of Candida auris infection in neonates. Prematurity emerged as a primary risk factor, alongside total parenteral nutrition, central line insertion, mechanical ventilation, and prior broad-spectrum antibiotic use. The mortality rate reached approximately 42%, with therapeutic details sparingly reported in 12% of cases. Treatment strategies varied, with amphotericin B predominantly used as monotherapy, while combination antifungal agents were used in 44% of cases. Notably, 97.4% of cases exhibited fluconazole resistance, and 67.1% showed resistance to amphotericin B. Limited data were available on resistance to other antifungal agents. (4) Conclusions: Despite the rarity of neonatal Candida auris infections, their global occurrence necessitates comprehensive preparedness in patient care. A deeper understanding of Candida auris pathogenesis is crucial for developing effective strategies to control and prevent neonatal infections caused by this pathogen.

Rotational Thromboelastometry as a Diagnostic Tool for Persistent Infection in Two-Stage Exchange Arthroplasty.

Background/Objectives: There is a lack of reliable biomarkers for diagnosis of infection eradication prior to second-stage reimplantation in two-stage exchange arthroplasty for periprosthetic joint infections (PJIs). The aim of this study was to assess the diagnostic accuracy of rotational thromboelastometry (ROTEM) for persistent infection in two-stage exchange arthroplasties. Methods: A pilot, retrospective analysis was performed including 70 patients who underwent a two-stage exchange arthroplasty for PJI. They were categorized as patients without (n = 64) or patients with persistent infection (n = 6) prior to reimplantation. Definition of persistent infection prior to reimplantation was based on the 2018 ICM criteria. Conventional coagulation biomarkers and ROTEM parameters were compared between groups. Results: Higher FIBTEM MCF values were associated with persistent infection (odds ratio [OR], 1.30, 95% confidence interval [CI], 1.04-1.63; p = 0.020), and FIBTEM MCF had the highest diagnostic accuracy for persistent infection prior to second-stage reimplantation (AUC, 0.907; 95% CI, 0.812-1.000). A cut-off value ≥ 18 mm for FIBTEM MCF was found to have 100.0% sensitivity and 73.4% specificity for diagnosing persistent infection prior to second-stage reimplantation. Moreover, the diagnostic accuracy of FIBTEM MCF was higher than that of fibrinogen levels (p = 0.036) and D-dimer (p = 0.006). Conclusions: Our findings indicate that ROTEM parameters have the potential to identify persistent infections before reimplantation in two-stage exchange arthroplasties for PJI. Such coagulation biomarkers could provide guidance regarding the optimal timing for reimplantation. Further studies in larger populations are warranted to validate the diagnostic accuracy of ROTEM parameters for persistent PJI.

Cancer-Associated Thrombosis: Pathophysiology, Laboratory Assessment, and Current Guidelines.

Dysregulated hemostasis in cancer patients is associated with various clinical conditions, from thromboembolic complications to disseminated intravascular coagulation. Despite the well-established association between cancer and thromboembolic complications, the mechanisms involved are not completely elucidated. There are several predisposing factors in cancer for increased thrombus generation, such as immobilization and chemotherapy. The term cancer-associated thrombosis (CAT) has been introduced to describe the close bidirectional relationship between cancer and thromboembolic events. Conventional coagulation tests (PT/aPTT) are more accurate in detecting a hypocoagulable rather than a hypercoagulable state; thus, their contribution to CAT management is limited. Traditionally, D-dimer levels have been the most common laboratory study for the evaluation of thrombotic risk. However, D-dimer levels only display a snapshot of the coagulation cascade, and they cannot provide a dynamic evaluation of evolving clot formation. Non-conventional assays, such as viscoelastic methods and microparticle formation are promising tools for the identification of patients at risk for developing CAT. Recent guidelines from the American Society of Clinical Oncology counsel against the estimation of thrombotic risk through a single test and recommend the use of scoring systems that take into account several risk factors. The present review outlines the current insights into the pathophysiological mechanisms of CAT and provides a comprehensive review of the latest advances in the laboratory assessment of CAT and the recent guidelines for the management of patients at risk for developing thromboembolic complications.

Bowel movement alterations predict the severity of diverticular disease and the risk of acute diverticulitis: a prospective, international st.

Background/Aims: Patients with diverticular disease (DD) frequently have abnormal bowel movements. However, it is unknown whether the entity of these alterations is associated with the severity of DD. We aimed to assess bowel habits and their relationship with the severity of DD according to Diverticular Inflammation and Complication Assessment (DICA) classification, Combined Overview on Diverticular Assessment (CODA) score, and fecal calprotectin (FC). Methods: An international, multicenter, prospective cohort study was conducted in 43 centers. A 10-point visual analog scale (VAS) was used to assess the severity of constipation and diarrhea. The association of constipation and diarrhea with DICA classification, CODA score, and basal FC was tested using non-parametric tests. Survival methods for censored observations were applied to test the association of constipation and diarrhea with the incidence of acute diverticulitis over a 3-year follow-up. Results: Of 871 patients with DD were included in the study. Of these, 208 (23.9%) and 199 (22.9%) reported a VAS score for constipation and diarrhea at least 3 at baseline, respectively. Higher constipation and diarrhea scores were associated with increasing DICA classification, CODA score and basal FC (P< 0.001). Constipation and diarrhea scores were independently associated with an increased hazard of developing acute diverticulitis (hazard ratio [HR]constipation = 1.15 per 1-VAS point increase, 95% confidence interval [CI], 1.04-1.27; P=0.004; and HRdiarrhea =1.14; 95% CI, 1.03-1.26; P=0.014, respectively). Conclusions: In newly diagnosed patients with DD, higher endoscopic and combined scores of DD severity were associated with higher scores of constipation and diarrhea at baseline. Both constipation and diarrhea were independent prognostic factors of acute diverticulitis.

Treat-to-Target and Regular Surveillance of Inflammatory Bowel Disease Are Associated with Low Incidence and Early-Stage Detection of Malignancies: A Retrospective Cohort Study.

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), increase the risk of malignancies, particularly colorectal cancer (CRC). We aimed to assess the incidence of malignancies in IBD patients managed using a treat-to-target approach and recommended surveillance. We retrospectively searched the electronic databases of two tertiary IBD centers in Milan from 2010 to 2019 for new diagnoses of malignancy in patients with pre-existing IBD. A total of 5239 patients with a follow-up of 19,820 years were included. In total, 71 malignancies were diagnosed in 70 patients (38 CD, 32 UC) with a mean age of 52.9 years, of whom 64% were former or active smokers. The annual incidence of all malignancies was 358 per 100,000 patient years (95% CI 275-444), and the standardized incidence rate (SIR) was 0.93 (95% CI 0.73-1.16). Gastrointestinal cancers were the most frequent (n = 17, 23.9%), in particular, CRC (n = 9), with an incidence of 45 per 100,000 (95% CI 15-74) and an SIR of 1.18 (95% CI 0.54-2.09). CRC occurred mainly in UC patients (6/8), while small bowel cancer was seen in CD patients (5/9). Melanoma and breast cancer (n = 8 each) were the most common non-GI cancers. No significant difference in incidence was found between CD or UC. Death occurred in nine patients (11%) and was due to cancer in eight of these cases, two of which were IBD-related. Most malignancies included in the surveillance were diagnosed at early (I-II) stages (20 vs. 4, p < 0.05). In patients with IBD, treat-to-target and strict surveillance were associated with a low incidence of cancer, similar to that of the general population, and the detection of malignancies at an early stage.

Pitfalls and perils of survival analysis under incorrect assumptions: the case of COVID-19 data / Escollos y peligros del análisis de supervivencia: el caso de los datos de COVID-19

Abstract | Non-parametric survival analysis has become a very popular statistical method in current medical research. However, resorting to survival analysis when its fundamental assumptions are not fulfilled can severely bias the results. Currently, hundreds of clinical studies are using survival methods to investigate factors potentially associated with the prognosis of coronavirus disease 2019 (COVID-19) and test new preventive and therapeutic strategies. In the pandemic era, it is more critical than ever to base decision-making on evidence and rely on solid statistical methods, but this is not always the case. Serious methodological errors have been identified in recent seminal studies about COVID-19: One reporting outcomes of patients treated with remdesivir and another one on the epidemiology, clinical course, and outcomes of critically ill patients. High-quality evidence is essential to inform clinicians about optimal COVID-19 therapies and policymakers about the true effect of preventive measures aiming to tackle the pandemic. Though timely evidence is needed, we should encourage the appropriate application of survival analysis methods and careful peer-review to avoid publishing flawed results, which could affect decision-making. In this paper, we recapitulate the basic assumptions underlying non-parametric survival analysis and frequent errors in its application and discuss how to handle data on COVID-19.

Resumen | El análisis de supervivencia es un método estadístico muy popular en la investigación médica actual. Sin embargo, el recurrir al análisis de supervivencia cuando no se cumplen sus supuestos fundamentales puede sesgar gravemente los resultados. Actualmente, cientos de estudios clínicos están utilizando esta metodología para estudiar los factores potencialmente asociados con el pronóstico de la COVID-19 y probar nuevas estrategias preventivas y terapéuticas. En la pandemia actual es más importante que nunca que las decisiones se basen en pruebas y en métodos estadísticos sólidos. Sin embargo, este no es siempre el caso. Se han detectado errores metodológicos graves en estudios seminales recientes sobre COVID-19: uno que informa los resultados de los pacientes tratados con remdesivir y otro sobre la epidemiología, el curso clínico y los resultados de los pacientes críticamente enfermos. La evidencia de calidad es esencial para informar a los médicos sobre las terapias óptimas contra la enfermedad y, a los legisladores, sobre el verdadero efecto de las medidas preventivas destinadas a abordar la pandemia. Aunque se necesitan pruebas oportunas, debemos fomentar la aplicación adecuada de los métodos de análisis de supervivencia y una cuidadosa revisión por pares para evitar la publicación de resultados defectuosos que pueden afectar la adopción de decisiones. En este artículo, recapitulamos los supuestos básicos que subyacen al análisis de supervivencia y los errores frecuentes en su aplicación, y discutimos cómo manejar los datos sobre la COVID-19.