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Simple Summary: Patients with HER2-positive metastatic breast cancer develop brain metastases in up to 30% of cases. The aim of this systematic review and meta-analysis was to determine the effect of different systemic therapies in patients with HER2-positive metastatic breast cancer and brain metastases, acknowledging the heterogeneity and sometimes low quality of 51 included studies. Tucatinib (combined with trastuzumab and capecitabine) and trastuzumab-deruxtecan appear to constitute the most effective systemic therapy, while pyrotinib might be an option in Asian patients. Preferably, future research will comprise of randomized controlled trials, including patients with active and/or inactive brain metastases. Aim: Patients with HER2-positive (HER2+) metastatic breast cancer (mBC) develop brain metastases (BM) in up to 30% of cases. Treatment of patients with BM can consist of local treatment (surgery and/or radiotherapy) and/or systemic treatment. We undertook a systematic review and meta-analysis to determine the effect of different systemic therapies in patients with HER2+ mBC and BM. Methods: A systematic search was performed in the databases PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and the Wiley/Cochrane Library. Eligible articles included prospective or retrospective studies reporting on the effect of systemic therapy on objective response rate (ORR) and/or median progression free survival (mPFS) in patients with HER2+ mBC and BM. The timeframe within the databases was from inception to 19 January 2022. Fixed-effects meta-analyses were used. Quality appraisal was performed using the ROBINS-I tool. Results: Fifty-one studies were included, involving 3118 patients. Most studies, which contained the largest patient numbers, but also often carried a moderate-serious risk of bias, investigated lapatinib and capecitabine (LC), trastuzumab-emtansine (T-DM1) or pyrotinib. The best quality data and/or highest ORR were described with tucatinib (combined with trastuzumab and capecitabine, TTC) and trastuzumab-deruxtecan (T-DXd). TTC demonstrated an ORR of 47.3% in patients with asymptomatic and/or active BM. T-DXd achieved a pooled ORR of 64% (95% CI 43–85%, I2 0%) in a heavily pretreated population with asymptomatic BM (3 studies, n = 96). Conclusions: Though our meta-analysis should be interpreted with caution due to the heterogeneity of included studies and a related serious risk of bias, this review provides a comprehensive overview of all currently available systemic treatment options. T-Dxd and TTC that appear to constitute the most effective systemic therapy in patients with HER2+ mBC and BM, while pyrotinib might be an option in Asian patients. [ABSTRACT FROM AUTHOR]

We investigated the prospective associations of body composition with cardiac structure and function and explored effect modification by sex and whether inflammation was a mediator in these associations. Total body (BF), trunk (TF) and leg fat (LF), and total lean mass (LM) were measured at baseline by a whole body DXA scan. Inflammatory biomarkers and echocardiographic measures were determined both at baseline and follow-up in the Hoorn Study (n = 321). We performed linear regression analyses with body composition measures as determinant and left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) or left atrial volume index (LAVI) at follow-up as outcome. Additionally, we performed mediation analysis using inflammation at follow-up as mediator. The study population was 67.7 ± 5.2 years and 50% were female. After adjustment, BF, TF and LF, and LM were associated with LVMI with regression coefficients of 2.9 (0.8; 5.1)g/m2.7, 2.3 (0.6; 4.0)g/m2.7, 2.0 (0.04; 4.0)g/m2.7 and − 2.9 (− 5.1; − 0.7)g/m2.7. Body composition measures were not associated with LVEF or LAVI. These associations were not modified by sex or mediated by inflammation. Body composition could play a role in the pathophysiology of LV hypertrophy. Future research should focus on sex differences in regional adiposity in relation with diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Background: This study aimed to determine the within-person and between-persons associations of low-grade inflammation (LGI) and endothelial dysfunction (ED) with echocardiographic measures related to diastolic dysfunction (DD) in two general populations and whether these associations differed by sex. Methods: Biomarkers and echocardiographic measures were measured at both baseline and follow-up in the Hoorn Study (n = 383) and FLEMENGHO (n = 491). Individual biomarker levels were combined into either a Z-score of LGI (CRP, SAA, IL-6, IL-8, TNF-α and sICAM-1) or ED (sICAM-1, sVCAM-1, sE-selectin and sTM). Mixed models were used to determine within-person and between-persons associations of biomarker Z-scores with left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) and left atrial volume index (LAVI). These associations were adjusted for a-priori selected confounders. Results: Overall Z-scores for LGI or ED were not associated with echocardiographic measures. Effect modification by sex was apparent for ED with LVEF in both cohorts (P-for interaction = 0.08 and 0.06), but stratified results were not consistent. Effect modification by sex was apparent for TNF-α in the Hoorn Study and E-selectin in FLEMENGHO with LVEF (P-for interaction≤0.05). In the Hoorn Study, women whose TNF-α levels increased with 1-SD over time had a decrease in LVEF of 2.2 (-4.5;0.01) %. In FLEMENGHO, men whose E-selectin levels increased with 1-SD over time had a decrease in LVEF of 1.6 (-2.7;-0.5) %. Conclusion: Our study did not show consistent associations of LGI and ED with echocardiographic measures. Some evidence of effect modification by sex was present for ED and specific biomarkers. [ABSTRACT FROM AUTHOR]

Aim: Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non‐acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). Methods and results: A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS‐2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case‐control/two‐gated designs, exclusion of difficult‐to‐diagnose patients, absence of a pre‐specified cut‐off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta‐analysis was performed. Conclusion: The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well‐designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF. [ABSTRACT FROM AUTHOR]

Background: Joint replacement surgery of the lower extremities are common procedures in elderly persons who are at increased risk of postoperative falls. The use of mental state altering medications, such as opioids, antidepressants or benzodiazepines, can further contribute to impaired balance and risk of falls. The objective of the current systematic review was to evaluate the risk of the use of mental state altering medications on postoperative falls in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA). Methods: A comprehensive search of Medline, Embase and Cochrane Controlled Trials Register was conducted from 1 October 1975 to 1 September 2021. The search was repeated in may 2023 and conducted from 1 October 1975 to 1 June 2023. Clinical trials that evaluated the risk of medication on postoperative THA and TKA falls were eligible for inclusion. Articles were evaluated independently by two researchers for risk of bias using the Newcastle-Ottawa Scale. A meta-analysis was performed to determine the potential effect of postoperative use of mental state altering medications on the risk of falls. Lastly, a qualitative synthesis was conducted for preoperative mental state altering medications use. Results: Seven cohort studies were included, of which five studies focussed on the postoperative use of mental state altering medications and two investigated the preoperative use. Meta-analysis was performed for the postoperative mental state altering medications use. The postoperative use of mental state altering medications was associated with fall incidents (OR: 1.81; 95% CI: 1.04; 3.17) (p < 0.01) after THA and TKA. The preoperative use of opioids > 6 months was associated with a higher risk of fall incidents, whereas a preoperative opioid prescription up to 3 months before a major arthroplasty had a similar risk as opioid-naïve patients. Conclusions: The postoperative use of mental state altering medications increases the risk of postoperative falls after THA and TKA. Prior to surgery, orthopaedic surgeons and anaesthesiologists should be aware of the associated risks in order to prevent postoperative falls and associated injuries. [ABSTRACT FROM AUTHOR]

This study investigated the causal relation between circulating phylloquinone (vitamin K1) concentrations and type 2 diabetes by using a Mendelian randomization (MR) approach. We used data from three studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, Diabetes Genetics Replication and Meta-analysis (DIAGRAM), and the UK Biobank, resulting in 69,647 subjects with type 2 diabetes. We calculated a weighted genetic risk score including four genetic variants previously found to be associated with circulating phylloquinone concentrations. Inverse-variance weighted analysis was used to obtain a risk ratio (RR) for the causal relation between circulating phylloquinone concentrations and risk of type 2 diabetes. Presence of pleiotropy and the robustness of the results were assessed using MR-Egger and weighted-median analyses. Genetically predicted concentrations of circulating phylloquinone were associated with lower risk of type 2 diabetes with an RR of 0.93 (95% CI 0.89; 0.97) per every natural logarithm (Ln)-nmol/L-unit increase in circulating phylloquinone. The MR-Egger and weighted median analyses showed RRs of 0.94 (0.86; 1.02) and 0.93 (0.88; 0.98), respectively, indicating no pleiotropy. In conclusion, our study supports that higher circulating phylloquinone may be causally related with lower risk of type 2 diabetes, highlighting the importance of sufficient phylloquinone in the human diet. [ABSTRACT FROM AUTHOR]

Background: An overview of the diagnostic performance of natriuretic peptides (NPs) for the detection of diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF), in a non-acute setting, is currently lacking.Methods: We performed a systematic literature search in PubMed and Embase.com (May 13, 2019). Studies were included when they (1) reported diagnostic performance measures, (2) are for the detection of DD or HFpEF in a non-acute setting, (3) are compared with a control group without DD or HFpEF or with patients with heart failure with reduced ejection fraction, (4) are in a cross-sectional design. Two investigators independently assessed risk of bias of the included studies according to the QUADAS-2 checklist. Results were meta-analysed when three or more studies reported a similar diagnostic measure.Results: From 11,728 titles/abstracts, we included 51 studies. The meta-analysis indicated a reasonable diagnostic performance for both NPs for the detection of DD and HFpEF based on AUC values of approximately 0.80 (0.73-0.87; I2 = 86%). For both NPs, sensitivity was lower than specificity for the detection of DD and HFpEF: approximately 65% (51-85%; I2 = 95%) versus 80% (70-90%; I2 = 97%), respectively. Both NPs have adequate ability to rule out DD: negative predictive value of approximately 85% (78-93%; I2 = 95%). The ability of both NPs to prove DD is lower: positive predictive value of approximately 60% (30-90%; I2 = 99%).Conclusion: The diagnostic performance of NPs for the detection of DD and HFpEF is reasonable. However, they may be used to rule out DD or HFpEF, and not for the diagnosis of DD or HFpEF. [ABSTRACT FROM AUTHOR]

Carriers of multidrug-resistant bacteria are at risk of infections with these bacteria; the precise size of this risk is unclear. We aimed to quantify the effect of gut colonisation on subsequent risk of infection with multidrug-resistant bacteria. We performed a systematic review and meta-regression analysis. We searched PubMed, Embase, Web of Science Core Collection, and Google Scholar for follow-up studies published from Jan 1, 1995, to March 17, 2022, that measured the incidence of infections with multidrug-resistant Gram-negative bacteria (MDR-GNB) and from Jan 1, 1995, to March 15, 2022, that measured the incidence of infections with vancomycin-resistant enterococci (VRE). We included original cohort studies and case-control studies that used incidence-density sampling, included 50 or more patients with enteric colonisation or positive urinary samples as a surrogate marker of colonisation, or both, and analysed infections clearly preceded by colonisation. We did not use any language restrictions. We excluded studies not reporting length of follow-up. Summary data were extracted and independently cross-verified by two authors. Carriage was defined as MDR-GNB or VRE, detected in faecal or urinary cultures. Our primary outcomes were cumulative incidence and incidence density of infection in patients colonised by multidrug-resistant bacteria. To estimate pooled incidences, general linearised mixed-effects meta-regressions were used, adjusting for varying follow-up durations. This study is registered with PROSPERO, CRD42020222415. Of the 301 studies identified, 44 studies (26 on MDR-GNB, 14 on VRE, and four on both MDR-GNB and VRE) from 14 countries were retained for qualitative synthesis, 40 of which were analysed with meta-regression, comprising data for 14 049 patients colonised with multidrug-resistant bacteria. The pooled cumulative incidence of infection was 14% (95% CI 10–18; p<0·0001) at a median follow-up time of 30 days for MDR-GNB (845 cases of infection in 9034 patients colonised) and 8% (5–13; p<0·0001) at 30 days for VRE (229 cases of infection in 4747 patients colonised). Infection incidence density (4·26 infections per 1000 patient-days; 95% CI 1·69–6·82) and cumulative incidence of infection (19%, 95% CI 15–25; p<0·0001; 602 cases of infection in 4547 patients colonised) were highest for carbapenem-resistant Gram-negative bacteria at 30 days. Risk of bias was rated low to moderate. The risk of infection was substantial, with the highest risk for patients colonised with carbapenem-resistant Gram-negative bacteria and the lowest in patients with VRE. These data might help to guide prophylactic and treatment decisions and form a valuable resource for planning clinical trials on targeted prevention. The Netherlands Organization for Health Research and Development [ABSTRACT FROM AUTHOR]

Summary: This study aims to determine the association between social jetlag and parameters of metabolic syndrome and type 2 diabetes (T2D) in a systematic review and meta‐analysis. A systematic literature search was conducted in PubMed/Embase/Scopus until May 2022. Included studies described an association between social jetlag and parameters of the metabolic syndrome and/or T2D, were available full text and written in English or Dutch. Data extraction and quality assessment were performed on pre‐piloted forms independently by two reviewers. Results were meta‐analysed using random‐effects analysis. A total of 6,290 titles/abstracts were screened, 176 papers were read full‐text, 68 studies were included. Three studies were rated as low quality, 27 were moderate, and 38 were high quality. High quality studies showed that having social jetlag compared to no social jetlag was significantly associated with higher body mass index in 20 studies (0.49 kg/m2, 95% confidence interval [CI] 0.21–0.77; I2 = 100%), higher waist circumference in seven studies (1.11 cm, 95% CI 0.42–1.80; I2 = 25%), higher systolic blood pressure in 10 studies (0.37 mmHg, 95% CI 0.00–0.74; I2 = 94%) and higher glycated haemoglobin in 12 studies (0.42%, 95% CI 0.12– 0.72; I2 = 100%). No statistically significant associations were found for obesity, abdominal obesity, high‐ and low‐density lipoprotein levels, cholesterol, triglycerides, diastolic blood pressure, hypertension, fasting glucose, homeostatic model assessment for insulin resistance, metabolic syndrome or T2D. Sensitivity analyses did not reduce heterogeneity. Despite substantial heterogeneity, social jetlag is associated with certain parameters of the metabolic syndrome and T2D, but not with prevalent metabolic syndrome or T2D. These findings should be interpreted with caution as the level of evidence is low and mostly based on cross‐sectional data. Longitudinal studies are needed to further assess the direction of causality. [ABSTRACT FROM AUTHOR]

• Vaccination >16 weeks of gestation provides antibodies for both the mother and the neonate. • Antibodies in human milk after vaccination against SARS-CoV-2 during pregnancy. • High virus neutralization observed in mother-infant dyads. Preventive measures against COVID-19 are essential for pregnant women. Pregnant women are particularly vulnerable to emerging infectious pathogens due to alterations in their physiology. We aimed to determine the optimum timing of vaccination to protect pregnant women and their neonates from COVID-19. A prospective observational longitudinal cohort study in pregnant women who received COVID-19 vaccination. We collected blood samples to evaluate levels of antispike, receptor binding domain and nucleocapsid antibodies against SARS-CoV-2 before vaccination and 15 days after the first and second vaccination. We determined the neutralizing antibodies from mother-infant dyads in maternal and umbilical cord blood at birth. If available, immunoglobulin A was measured in human milk. We included 178 pregnant women. Median antispike immunoglobulin G levels increased significantly from 1.8 to 5431 binding antibody units/ml and receptor binding domain from 6 to 4466 binding antibody units/ml. Virus neutralization showed similar results between different weeks of gestation at vaccination (P >0.3). We advise vaccination in the early second trimester of pregnancy for the optimum balance between the maternal antibody response and placental antibody transfer to the neonate. [ABSTRACT FROM AUTHOR]

• 18F-afatinib PET/CT is a safe tool to quantify 18F-afatinib uptake in NSCLC tumors. • Tumor uptake of 18F-afatinib is higher in EGFR mutated NSCLC versus wild type EGFR. • There is no difference in tracer uptake between EGFR common and uncommon mutations. • A TBR_WB 60−90 value of ≥6 is predictive of response to treatment using afatinib. Non-small cell lung cancer (NSCLC) tumors harboring common (exon19del, L858R) and uncommon (e.g. G719X, L861Q) activating epidermal growth factor receptor (EGFR) mutations are best treated with EGFR tyrosine kinase inhibitors (TKI) such as the first-generation EGFR TKI erlotinib, second-generation afatinib or third-generation osimertinib. However, identifying these patients through biopsy is not always possible. Therefore, our aim was to evaluate whether 18F-afatinib PET/CT could identify patients with common and uncommon EGFR mutations. Furthermore, we evaluated the relation between tumor 18F-afatinib uptake and response to afatinib therapy. 18F-afatinib PET/CT was performed in 12 patients: 6 EGFR wild type (WT), 3 EGFR common and 3 EGFR uncommon mutations. Tumor uptake of 18F-afatinib was quantified using TBR_WB 60−90 (tumor-to-whole blood activity ratio 60−90 min post-injection) for each tumor. Response was quantified per lesion using percentage of change (PC): [(response measurement (RM)–baseline measurement (BM))/BM]×100. Statistical analyses were performed using t-tests, correlation plots and sensitivity/specificity analysis. Twenty-one tumors were identified. Injected dose was 348 ± 31 MBq. Group differences were significant between WT versus EGFR (common and uncommon) activating mutations (p = 0.03). There was no significant difference between EGFR common versus uncommon mutations (p = 0.94). A TBR_WB 60−90 cut-off value of 6 showed the best relationship with response with a sensitivity of 70 %, a specificity of 100 % and a positive predictive value of 100 %. 18F-afatinib uptake was higher in tumors with EGFR mutations (common and uncommon) compared to WT. Furthermore, a TBR_WB 60−90 cut-off of 6 was found to best predict response to therapy. 18F-afatinib PET/CT could provide a means to identify EGFR mutation positive patients who benefit from afatinib therapy. [ABSTRACT FROM AUTHOR]