Search

Background: Systemic inflammation accompanies HIV-1 infection, resulting in microbial translocation from different tissues. We investigated interactions between lentivirus infections, neuroinflammation and microbial molecule presence in the brain. Methods: Brain tissues from adult humans with (n = 22) and without HIV-1 (n = 11) infection as well as adult nonhuman primates (NHPs) with (n = 11) and without (n = 4) SIVmac251 infection were investigated by RT-PCR/ddPCR, immunofluorescence and western blotting. Studies of viral infectivity, host immune gene expression and viability were performed in primary human neural cells. Findings: Among NHPs, SIV DNA quantitation in brain showed increased levels among animals with SIV encephalitis (n = 5) that was associated with bacterial genomic copy number as well as CCR5 and CASP1 expression in brain. Microbial DnaK and peptidoglycan were immunodetected in brains from uninfected and SIV-infected animals, chiefly in glial cells. Human microglia infected by HIV-1 showed increased p24 production after exposure to peptidoglycan that was associated CCR5 induction. HIV-1 Vpr application to human neurons followed by peptidoglycan exposure resulted in reduced mitochondrial function and diminished beta-III tubulin expression. In human brains, bacterial genome copies (250–550 copies/gm of tissue), were correlated with increased bacterial rRNA and GroEL transcript levels in patients with HIV-associated neurocognitive disorders (HAND). Glial cells displayed microbial GroEL and peptidoglycan immunoreactivity accompanied by CCR5 induction in brains from patients with HAND. Interpretation: Increased microbial genomes and proteins were evident in brain tissues from lentivirus-infected humans and animals and associated with neurological disease. Microbial molecule translocation into the brain might exacerbate neuroinflammatory disease severity and represent a driver of lentivirus-associated brain disease.

BACKGROUND: Colon cancer affects a patient's ability to work. Many patients who have colon cancer are employed at the time of diagnosis.OBJECTIVE: We evaluated work ability during the first 2 years after colon cancer diagnosis.DESIGN: This study is a national prospective study, the Prospective Dutch ColoRectal Cancer cohort, including clinical data and patient-reported outcomes.SETTINGS: Data were collected in 59 medical centers in the Netherlands.PATIENTS: Patients MAIN OUTCOME MEASURES: Work ability was assessed at baseline, 3, 6, 12, 18, and 24 months. The Work Ability Index (range, 0 to 49) was evaluated using linear mixed models. Outcomes were matched to population controls without cancer.RESULTS: Of 390 patients, 84% had paid employment. Work ability of patients with stage I to IV colon cancer was significantly lower at the time of diagnosis than in matched population controls (31 ± 8.2 and 41 ± 5.6). Patients with stage I to III disease receiving surgery only regained Work Ability Index scores comparable to matched population controls at 18 months. Patients receiving adjuvant systemic treatment initially demonstrated a decrease in work ability with improvements from 6 months onward and normalization at 24 months. Patients with stage IV disease did not demonstrate improvements in work ability outcomes over time. Work ability scores were negatively influenced by the administration of systemic treatment and ≥1 comorbidities.LIMITATIONS: Only patients with patient-reported outcomes and work at baseline were included in this analysis. Also, questionnaire response rates decreased over time.CONCLUSIONS: Work ability in patients with colon cancer is decreased for a prolonged time. Recovery depends on disease stage, type of treatment, and comorbidities. Patients with stage I to III disease treated with curative surgery alone were the first to regain work ability, followed by patients who receive adjuvant chemotherapy. Patients with stage IV disease did not regain work ability. See Video Abstract at http://links.lww.com/DCR/B759 .CAPACIDAD LABORAL EN PACIENTES CON CNCER DE COLON EN ESTADIO IIV RESULTADOS PROSPECTIVOS DE CNCER COLORECTAL EN UNA COHORTE HOLANDESA: ANTECEDENTES:El cáncer de colon afecta la capacidad de trabajo en un paciente. Muchos pacientes con cáncer de colon están empleados en el momento del diagnóstico.OBJETIVO:Evaluamos la capacidad laboral durante los dos primeros años posteriores al diagnóstico de cáncer de colon.DISEÑO:Es un estudio prospectivo nacional, la cohorte de cáncer colorrectal holandés, incluye datos clínicos y resultados informados por los pacientes.ENTORNO CLINICO:Se recopilaron datos de 59 centros médicos en los Países Bajos.PACIENTES:Se seleccionaron pacientes < 67 años, con cáncer de colon en estadio I-IV, que completaron los cuestionarios de índice de capacidad para el trabajo.PRINCIPALES MEDIDAS DE VALORACIÓN:La capacidad para el trabajo se evaluó al inicio, a los 3, 6, 12, 18 y 24 meses. El índice de capacidad para el trabajo (que va de 0 a 49) se evaluó mediante modelos lineales mixtos. Los resultados fueron comparados con el grupo control sin cáncer.RESULTADOS:De 390 pacientes, el 84% tenía un empleo remunerado. La capacidad de trabajo de los pacientes en estadio I-IV fue significativamente menor en el momento del diagnóstico en comparación con el grupo control (31 ± 8,2 y 41 ± 5,6, respectivamente). Los pacientes con enfermedad en estadio I-III que recibieron cirugía lograron recuperar puntajes del índice de capacidad laboral comparables a los controles a los 18 meses. Los pacientes que recibieron tratamiento sistémico adyuvante inicialmente demostraron una disminución en la capacidad de trabajo con mejoras a partir de los 6 meses en adelante y una normalización a los 24 meses. Los pacientes en estadio IV no demostraron mejoras en los resultados de la capacidad laboral a lo largo del tiempo. Las puntuaciones de capacidad para el trabajo se vieron influidas negativamente por la administración del tratamiento sistémico y la existencia de ≥1 comorbilidades.LIMITACIONES:En este análisis solo se incluyeron los pacientes con resultados y trabajo desde el inicio del estudio. Además, las tasas de respuesta al cuestionario disminuyeron con el tiempo.CONCLUSIONES:La capacidad de trabajo en pacientes con cáncer de colon se reduce durante un tiempo prolongado. La recuperación depende del estadio de la enfermedad, el tipo de tratamiento y la comorbilidad. Los pacientes con enfermedad en estadio I-III tratados con cirugía curativa exclusivamente, son los primeros en recuperar la capacidad para trabajar, seguidos de los pacientes que reciben quimioterapia adyuvante. Los pacientes con enfermedad en estadio IV no recuperan la capacidad para trabajar. Consulte Video Resumen en http://links.lww.com/DCR/B759 . (Traducción- Dr. Ingrid Melo ).

Systemic immunosuppressive therapy (IS) renders patients with inflammatory bowel disease (IBD) vulnerable to fulminant hepatitis B virus (HBV) infection. Seroprotection against HBV through a full vaccination scheme is preferably obtained before IS is initiated, but often conflicts with the clinical need to initiate therapy rapidly. Consequently, the vast majority of patients will use IS during booster vaccinations. In this retrospective cohort study, we examined the serological response after a modified vaccination schedule which includes an initial double dose of Fendrix in patients with IBD and compared the results with the serological responses of patients with IBD who received the standard schedule. Seroprotection rates were 86.2 % and 88.9 % in the modified and standard schedule groups respectively. One-third of patients obtained seroprotection after only one double dose vaccine. A double dose may be considered in patients with IBD at high short-term risk of HBV infection when a rapid protective response is warranted.

INTRODUCTION: The oral fluoropyrimidine S-1 has shown comparable efficacy to capecitabine in Asian and some Western studies on metastatic colorectal cancer. S-1 is associated with a lower incidence of hand-foot syndrome (HFS) and cardiac toxicity. We assessed the long-term tolerability of S-1 in patients who discontinued capecitabine for reasons of HFS or cardiac toxicity.PATIENTS AND METHODS: Patients with metastatic colorectal cancer who switched from capecitabine to S-1, given as monotherapy or in combination with other agents, were identified in a Dutch prospective cohort study (2016-2021). The incidence and severity of HFS, cardiotoxicity and other toxicities were assessed.RESULTS: Forty-seven patients were identified. The median duration of capecitabine treatment was 81 days (range 4-454). In 19 patients (40%) a dose reduction was applied prior to switch to S-1. Reasons for discontinuation of capecitabine were HFS in 36 (77%) patients, coronary artery vasospasms in 10 (21%) patients, and gastrointestinal toxicities in 1 patient (2%). The median number of S-1 cycles was 6 (range 1-36). The median time between last dose of capecitabine and first dose of S-1 was 11 days (range 1-49). After switch to S-1, all patients with prior HFS developed a lower grade or complete resolution of symptoms, and in all other patients symptoms did not recur. Other S-1-related adverse events were limited to grade 1-2. Six patients (13%) discontinued S-1 due to either known fluoropyrimidine-related or bevacizumab-related toxicities. Switch to S-1 did not appear to compromise treatment efficacy.CONCLUSION: S-1 is a valid alternative to capecitabine in case HFS or cardiotoxicity occurs.

Purpose: Although A1 pulley release is an effective treatment to reduce pain and improve hand function, complications may occur. More insight into risk factors for complications is essential to improve patient counseling and potentially target modifiable risk factors. This study aimed to identify factors associated with complications following A1 pulley release. Methods: Patients completed baseline questionnaires, including patient characteristics, clinical characteristics, and the Michigan Hand outcomes Questionnaire. We retrospectively reviewed medical records to identify complications classified using the International Consortium for Health Outcome Measurement Complications in Hand and Wrist conditions tool. Grade 1 complications comprise treatment with additional hand therapy, splinting, or analgesics, grade 2 treatment with antibiotics or steroid injections, grade 3A minor surgical treatment, grade 3B major surgical treatment, and grade 3C complex regional pain syndrome. Logistic regression analyses were performed to examine the contribution of patient characteristics, clinical characteristics, and patient-reported outcome measurement scores to complications. Results: Of the included 3,428 patients, 16% incurred a complication. The majority comprised milder grades 1 (6%) and 2 (7%) complications, followed by more severe grades 3B (2%), 3C (0.1%), and 3A (0.1%) complications. A longer symptom duration (standardized odds ratio [SOR], 1.09), ≥3 preoperative steroid injections (SOR, 3.22), a steroid injection within 3 months before surgery (SOR, 2.02), and treatment of the dominant hand (SOR, 1.34), index finger (SOR, 1.65), and middle finger (SOR, 2.01) were associated with a higher complication rate. Conclusion: This study demonstrates that ≥3 preoperative steroid injections and a steroid injection within 3 months before surgery were the most influential factors contributing to complications. These findings can assist clinicians during patient counseling and may guide preoperative treatment. We recommend that clinicians should consider avoiding steroid injections within 3 months before surgery and to be reluctant to perform >2 steroid injections. Type of study/level of evidence: Prognostic II.

PURPOSE: Evidence shows the value of home blood pressure (BP) monitoring in hypertension management. Questions exist about how to effectively incorporate these readings into BP follow-up visits. We developed and implemented a tool that combines clinical and home BP readings into an electronic health record (EHR)-integrated visualization tool. We examined how this tool was used during primary care visits and its effect on physician-patient communication and decision making about hypertension management, comparing it with home BP readings on paper. METHODS: We video recorded the hypertension follow-up visits of 73 patients with 15 primary care physicians between July 2018 and April 2019. During visits, physicians reviewed home BP readings with patients, either directly from paper or as entered into the EHR visualization tool. We used conversation analysis to analyze the recordings. RESULTS: Home BP readings were viewed on paper for 26 patients and in the visualization tool for 47 patients. Access to home BP readings during hypertension management visits, regardless of viewing mode, positioned the physician and patient to assess BP management and make decisions about treatment modification, if needed. Length of BP discussion with the visualization tool was similar to or shorter than that with paper. Advantages of the visualization tool included ease of use, and enhanced and faster sense making and decision making. Successful use of the tool required patients’ ability to obtain their BP readings and enter them into the EHR via a portal, and an examination room configuration that allowed for screen sharing. CONCLUSIONS: Reviewing home BP readings using a visualization tool is feasible and enhances sense making and patient engagement in decision making. Practices and their patients need appropriate infrastructure to realize these benefits.

Surgical A1 pulley release can considerably reduce pain and improve hand function, but individual outcomes are highly variable. This study aimed to identify factors contributing to self-reported pain and hand function 3 months postoperatively. We included 2681 patients who had received surgical treatment for a trigger finger or thumb and who completed the Michigan Hand outcomes Questionnaire (MHQ). Hierarchical linear regression models were used to investigate patient and clinical characteristics associated with postoperative pain and hand function. For both pain and hand function, the most influential factors associated with worse outcomes were worse MHQ scores at baseline (β 0.38 and 0.33, respectively) and ≥3 preoperative steroid injections (β –0.36 and –0.35). These factors indicated that patients with severe preoperative symptoms represent a group with a more advanced disease that is more difficult to treat. These findings can assist clinicians in patient counselling, expectation management and decision-making about the timing of the intervention. Level of evidence: II

Primary-care providers, clinic staff, and nurses play an important role in reducing child obesity; yet time restraints and clinical demands compete with effective pediatric weight management and prevention.To investigate the potential impact of an electronic health record (EHR) enabled tool to assist primary care teams in addressing child obesity, we conducted a controlled effectiveness study of FitTastic compared with usual care on the BMI pattern of 291 children (2 to 17 years) up to 4 years later.Per χStudy findings suggest that EHR-enabled tools to assist primary care teams in managing child obesity may be useful for helping to address the weight in children with overweight/obesity, especially in younger children (2 to 5 years). Digital and EHR-enabled technologies may prove useful for partnering health care teams and families in the important tasks of setting positive, family-centered healthy lifestyle behavioral goals and managing child overweight and obesity.

The IDEA trial showed no clinical relevant differences in efficacy between 3 and 6 months of oxaliplatin-based adjuvant chemotherapy (ACT) in colon cancer (CC), while toxicity was substantially lower in the 3 months regimen. Therefore, in 2017 the Dutch colorectal cancer guideline was revised and currently recommends 3 months of oxaliplatin-based ACT. Furthermore, the definition of high-risk stage II CC was restricted to pT4 tumors. We analyzed changes in ACT between 2015 and 2019. From the Netherlands Cancer Registry all 16 721 patients ≥18 years with resected high-risk stage II and stage III CC during 2015 to 2019 were selected. Differences in patient and treatment characteristics were analyzed per calendar year according to stage and age. Mean duration of oxaliplatin-based ACT decreased from 18.6 (±8.0) to 9.5 (±3.8) weeks between 2015 and 2019. In patients receiving ACT (n = 8170), the proportion treated with oxaliplatin increased from 74% to 83%. The proportion of patients receiving ACT was stable, 61% to 69% in stage III and 26% to 29% in pT4 stage II. ACT in previous high-risk pT3N0 disease decreased from 15% to 3%. Use of oxaliplatin increased from 27% to 49% in patients aged ≥75 years. The revised guideline was rapidly implemented and led to an increase in oxaliplatin-based ACT in the elderly and increased guideline-adherence in high-risk stage II CC.

Purpose Albumin and C-reactive protein (CRP) are non-specific markers of inflammation, which could affect muscle tissue during acute hospitalization. We investigated the association between albumin and CRP during acute hospitalization with functional and body composition parameters in patients admitted to geriatric rehabilitation. Methods The REStORing Health of Acutely Unwell AdulTs (RESORT) cohort includes geriatric rehabilitation patients assessed for change in activities of daily living (ADL, using the Katz index) during acute hospitalization, and subsequently for Katz ADL, gait speed (GS), handgrip strength (HGS) and skeletal muscle mass index (SMI) at geriatric rehabilitation admission. Albumin and CRP average (median), variation (interquartile range), and maximum or minimum were collected from serum samples, and were examined for their association with functional and body composition parameters using multivariable linear regression analysis adjusted for age, sex and length of acute hospital stay. Results 1769 Inpatients were included for analyses (mean age 82.6 years ± 8.1, 56% female). Median length of acute hospitalization was 7 [IQR 4, 13] days and median number of albumin and CRP measurements was 5 [IQR 3, 12] times. ADL declined in 89% of patients (median − 3 points, IQR − 4, − 2). Lower average albumin, higher albumin variation and lower minimum albumin were associated with larger declines in ADL and with lower ADL, GS, HGS and SMI at geriatric rehabilitation admission. Higher average and maximum CRP were associated with lower GS. Conclusion Inflammation, especially lower albumin concentrations, during acute hospitalization is associated with lower physical function at geriatric rehabilitation admission.

INTRODUCTION: The RECOURSE trial demonstrated a modest benefit in overall survival (OS) for trifluridine/tipiracil (FTD/TPI) versus placebo in pretreated metastatic colorectal cancer (mCRC) patients. Unfortunately, quality of life (QoL) was not assessed. We evaluated QoL and survival of patients treated with FTD/TPI in daily practice.PATIENTS AND METHODS: QUALITAS is a substudy of the Prospective Dutch CRC cohort (PLCRC). From 150 mCRC patients treated with FTD/TPI, QoL (EORTC QLQ-C30 and QLQ-CR29) was assessed monthly from study entry, and linked to clinical data of the Netherlands Cancer Registry. Joint models were constructed combining mixed effects models with Cox PH models. Primary endpoint was difference in QoL over time (which was deemed clinically relevant if ≥10 points). Secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), and OS. We analyzed the association between QLQ-C30 Summary Score (QoL-SS) at FTD/TPI initiation (baseline) and survival.RESULTS: There was no clinically relevant change in QoL-SS from baseline to 10 months post-baseline (i.e. the cut-off point after which 90% of patients had discontinued FTD/TPI treatment): -5.3 [95% CI -8.7;-1.5]. Patients who were treated with FTD/TPI for ≥ 3 months (n = 85) reported 6.3 [1.6;11.1] points higher baseline QoL, compared to patients treated < 3 months (n = 65, "poor responders"). In the latter, time to a clinically relevant QoL deterioration was < 2 months. Median PFS, TTF and OS were 2.9 [2.7;3.1], 3.1 [2.9;3.2] and 7.7 [6.6;8.8] months, respectively. Worse baseline QoL-SS was independently associated with shorter OS (HR 0.45 [0.32;0.63]), PFS (0.63 [0.48;0.83]), and TTF (0.64 [0.47;0.86]).CONCLUSION: The maintenance of QoL during FTD/TPI treatment in daily practice supports its use. The QoL deterioration in "poor responders" is likely due to disease progression. The strong association between worse baseline QoL and shorter survival suggests that clinicians should take QoL into account when determining prognosis and treatment strategy for individual patients.

BackgroundA short acting spinal anesthetic facilitates smooth flow since quick recovery of motor function will facilitate unassisted ambulation. The aim of this study was to estimate the effective dose (ED90) of intrathecal 2-chloroprocaine 1% in outpatient knee arthroscopy.MethodsTwo cohorts were included in two different hospitals. In cohort I, a randomized biased-coin up-and-down design with 40 patients was used to find the ED90. Four dose-levels of plain 2-chloroprocaine 1% were used: 25, 30, 35 and 40 mg. The identified primary outcome, the ED90, was validated in 50 patients in cohort II with an open label design. Secondary outcomes included time to complete recovery from motor and sensory block with spinal injection as time zero, peak sensory block level, urine retention and time until hospital discharge.ResultsForty patients were included in the final analysis in cohort I. The ED90 was estimated at 27.8 mg, successful spinal anesthesia was obtained in 38 patients (95%). Fifty patients were included in the final analysis in cohort II, 49 patients had successful anesthesia with a fixed round dose of 28 mg. In this Cohort, peak sensory block was T10/T11 (range: (L4–T4)). The median time to full recovery of the motor block was 60 min (45–60) and 90 min (75–105) for the sensory block. The mean time to hospital discharge was 2.9 hours (0.7).ConclusionThe ED90 of 2-chloroprocaine 1% in knee arthroscopy was estimated to be 27.8 mg. In an external population, the ED90 resulted in successful anesthesia in 98% of the patients (95% CI 89% to 100%).Trial registration numberNetherlands Trial Registry (NL6769).

Protein aggregates are hallmarks of neurodegenerative diseases. The protein quality control (PQC) system normally prevents proteins from misfolding and accumulation; however, proteins somehow escape this control on disease. Here we review advances in the role of PQC in protein aggregation and neurodegeneration. We focus primarily on the protein Tau, which aggregates in Alzheimer's disease (AD) and other tauopathies. We also examine recent advances in amyloid fibril structures and the process of fibril formation via phase separation, which are shedding new light on the role of PQC in protein aggregation diseases. While specific components of the quality control system appear to be altered in disease, most chaperones and degradation factors are unchanged at the cellular end stage. Advancing the understanding of quality control factors in neurodegeneration, particularly in the early stages of disease, is among the key challenges for neurodegeneration research.

The PROMETCO study is collecting real-world data on metastatic colorectal cancer (mCRC) patients with two progressions. This international, prospective, longitudinal, observational cohort study is collecting data on mCRC patients with two disease progressions since diagnosis and receiving subsequent treatment. Objectives include overall survival, treatment patterns, effectiveness and safety and patient-reported outcomes using the EuroQol 5-level, 5-dimensional questionnaire, the Brief Fatigue Inventory and a modified version of the ACCEPTance by the Patients of their Treatment (ACCEPT©) questionnaire. Data are collected retrospectively and prospectively up to 18 months. As of 13 October 2021, 544 patients from 18 countries had been enrolled. To the authors' knowledge, PROMETCO is the first international, real-world study of the continuum of care of mCRC patients in this setting. Trial registration number: NCT03935763 ( ClinicalTrials.gov )

Aims We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected. Methods and results The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS. Conclusion The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families.

Background Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients.

Introduction: The Memorial Sloan Kettering Cancer Centre (MSKCC) nomogram has been developed to estimate five-year overall survival (OS) after curative-intent surgery of colon cancer based on age, sex, T stage, differentiation grade, number of positive and examined regional lymph nodes. This is the first evaluation of the performance of the MSKCC model in a European population regarding prediction of OS. Material and methods: Population-based data from patients with stage I–III colon cancer diagnosed between 2010 and 2016 were obtained from the Netherlands Cancer Registry (NCR) for external validation of the MSKCC prediction model. Five-year survival probabilities were estimated for all patients in our dataset by using the MSKCC prediction equation. Histogram density plots were created to depict the distribution of the estimated probability and prognostic index. The performance of the model was evaluated in terms of its overall performance, discrimination, and calibration. Results: A total of 39,805 patients were included. Five-year OS was 71.9% (95% CI 71.5; 72.3) (11,051 events) with a median follow up of 5.6 years (IQR 4.1; 7.7). The Brier score was 0.10 (95% CI 0.10; 0.10). The C-index was 0.75 (95% CI 0.75; 0.76). The calibration measures and plot indicated that the model slightly overestimated observed mortality (observed/expected ratio = 0.86 [95% CI 0.86; 0.87], calibration intercept = −0.14 [95% CI −0.16; −0.11], and slope 1.07 [95% CI 1.05; 1.09], ICI = 0.04, E50 = 0.04, and E90 = 0.05). Conclusions: The external validation of the MSKCC prediction nomogram in a large Dutch cohort supports the use of this practical tool in the European patient population. These personalised estimated survival probabilities may support clinicians when informing patients about prognosis. Adding potential relevant prognostic factors to the model, such as primary tumour location, might further improve the model.

Non-contrast computed tomography (CT) scanning allows for reliable coronary calcium score (CCS) calculation at a low radiation dose and has been well established as marker to assess the future risk of coronary artery disease (CAD) events in asymptomatic individuals. However, the diagnostic and prognostic value in symptomatic patients remains a matter of debate. This narrative review focuses on the available evidence for CCS in patients with stable chest pain complaints.PubMed, Embase, and Web of Science were searched for literature using search terms related to three overarching categories: CT, symptomatic chest pain patients, and coronary calcium. The search resulted in 42 articles fulfilling the inclusion and exclusion criteria: 27 articles (n = 38 137 patients) focused on diagnostic value and 23 articles (n = 44 683 patients) on prognostic value of CCS. Of these, 10 articles (n = 21 208 patients) focused on both the diagnostic and prognostic value of CCS.Between 22 and 10 037 patients were included in the studies on the diagnostic and prognostic value of CCS, including 43 % and 51 % patients with CCS 0. The most evidence is available for patients with a low and intermediate pre-test probability (PTP) of CAD. Overall, the prevalence of obstructive CAD (OCAD, defined as a luminal stenosis of ≥ 50 % in any of the coronary arteries) as determined with CT coronary angiography in CCS 0 patients, was 4.4 % (n = 703/16 074) with a range of 0-26 % in individual studies. The event rate for major adverse cardiac events (MACE) ranged from 0 % to 2.1 % during a follow-up of 1.6 to 6.8 years, resulting in a high negative predictive value for MACE between 98 % and 100 % in CCS 0 patients. At increasing CCS, the OCAD probability and MACE risk increased. OCAD was present in 58.3 % (n = 617/1058) of CCS 400 patients with percentages ranging from 20 % to 94 % and MACE occurred in 16.7 % (n = 175/1048) of these patients with percentages ranging from 6.9 % to 50 %.Accumulating evidence shows that OCAD is unlikely and the MACE risk is very low in symptomatic patients with CCS 0, especially in those with low and intermediate PTPs. This suggests a role of CCS as a gatekeeper for additional diagnostic testing. Increasing CCS is related to an increasing probability of OCAD and risk of cardiac events. Additional research is needed to assess the value of CCS in women and patient management in a primary healthcare setting.· A CCS of zero makes OCAD in patients at low-intermediate PTP unlikely. · A CCS of zero is related to a very low risk of MACE. · Categories of increasing CCS are related to increasing rates of OCAD and MACE. · Future studies should focus on the diagnostic and prognostic value of CCS in symptomatic women and the role in primary care.· Koopman MY, Willemsen RT, van der Harst P et al. The Diagnostic and Prognostic Value of Coronary Calcium Scoring in Stable Chest Pain Patients: A Narrative Review. Fortschr Röntgenstr 2022; 194: 257 - 265.Die kontrastfreie Computertomografie (CT) ermöglicht eine zuverlässige Berechnung des koronaren Kalziumscores (KKS) bei niedriger Strahlendosis und hat sich als Marker zur Beurteilung des Risikos für koronare Herzkrankheiten (KHK) bei asymptomatischen Personen bewährt. Der diagnostische und prognostische Wert bei symptomatischen Patienten bleibt jedoch umstritten. Die vorliegende Übersichtsarbeit befasst sich mit der verfügbaren Evidenz des KKS bei Patienten mit stabilen Brustschmerzbeschwerden.In PubMed, Embase und Web of Science wurde eine Literaturrecherche mit Suchbegriffen zu drei übergeordneten Kategorien durchgeführt: CT, Patienten mit symptomatischen Brustschmerzen und Koronarkalk. Die Suche ergab 42 Artikel, die die Ein- und Ausschlusskriterien erfüllten: 27 Artikel (n = 38 137 Patienten) konzentrierten sich auf den diagnostischen Wert und 23 Artikel (n = 44 683 Patienten) auf den prognostischen Wert des KKS. Davon befassten sich 10 Artikel (n = 21 208 Patienten) mit dem diagnostischen und dem prognostischen Wert des KKS.In die Studien zum diagnostischen und prognostischen Wert des KKS wurden zwischen 22 und 10 037 Patienten eingeschlossen, darunter 43 % bzw. 51 % Patienten mit KKS0. Die meisten Erkenntnisse liegen für Patienten mit einer niedrigen und mittleren Prätestwahrscheinlichkeit (PTP) für KHK vor. Insgesamt lag die Prävalenz der obstruktiven KHK (OKHK, definiert als luminale Stenose von ≥ 50 % in einer der Koronararterien), die mittels CT-Koronarangiografie bei KKS0-Patienten bestimmt wurde, bei 4,4 % (n = 703/16 074) mit einem Bereich von 0–26 % in einzelnen Studien. Die Ereignisrate für schwerwiegende unerwünschte kardiale Ereignisse („major adverse cardiac events“ MACE) reichte von 0 % bis 2,1 % während einer Nachbeobachtungszeit von 1,6 bis 6,8 Jahren, was bei KKS 0-Patienten zu einem hohen negativen Vorhersagewert für MACE zwischen 98 % und 100 % führte. Mit zunehmendem KKS stiegen die OKHK-Wahrscheinlichkeit und das MACE-Risiko. Bei 58,3 % (n = 617/1058) der Patienten mit einem KKS 400 lag eine OKHK vor, wobei die Spanne von 20 % bis 94 % reichte. Bei 16,7 % (n = 175/1048) dieser Patienten trat ein MACE auf, mit einer Spanne von 6,9 % bis 50 %.Es gibt zunehmend mehr Hinweise darauf, dass bei symptomatischen Patienten mit KKS0 eine OKHK unwahrscheinlich und das MACE-Risiko sehr gering ist, insbesondere bei den Patienten mit niedriger und mittlerer PTP. Dies weist auf eine „Torwächter“-Rolle des KKS hinsichtlich zusätzlicher diagnostischer Tests hin. Mit zunehmendem KKS steigt sowohl die Wahrscheinlichkeit einer OKHK als das Risiko für kardiale Ereignisse. Weitere Forschungsarbeiten sind erforderlich, um den Wert des KKS bei Frauen und beim Patientenmanagement im Rahmen der medizinischen Grundversorgung zu bewerten.

Contains fulltext : 248202.pdf (Publisher’s version ) (Open Access) BACKGROUND: Within the field of peripheral nerve surgery, the use of fibrin glue as an alternative to conventional microsurgical suture repair is becoming increasingly popular. Advantages of fibrin glue for nerve reconstruction include technical ease of use, less tissue manipulation, and shorter operation times. Although fibrin glue seems a promising alternative to conventional microsurgical repair, further insight into the outcomes of nerve recovery is essential. OBJECTIVE: To summarize the current literature on the use of fibrin glue for peripheral nerve repair and compare these results with outcomes following conventional suture repair. METHODS: A systematic search in Embase, MEDLINE, Web of Science, Cochrane, and Google Scholar databases was performed. The search included animal, cadaveric, and human studies assessing outcomes following peripheral nerve repair using fibrin glue. Data on outcomes were subdivided into functional outcomes, electrophysiology, histopathology, biomechanical outcomes, and operation times. We calculated standardized mean differences and combined these in a random effects model to estimate the overall effect. RESULTS: From a total of 2057 references, 37 animal, two cadaveric, and four human studies were included. Fibrin glue repairs resulted in similar functional and electrophysiology outcomes and shorter operation times than suture repairs. However, fibrin glue alone resulted in lower strength and more dehiscence. No dehiscence was reported when fibrin glue was combined with one or two sutures. Yet, we also found that methodological details were poorly reported in animal studies, resulting in an unclear risk of bias. This should be taken into consideration when interpreting the results. CONCLUSION: The results indicate that nerve regeneration may be similar in fibrin glue repairs and suture repairs. Combining fibrin glue with one or two positional sutures allows for a precise realignment of the nerve fibers and seems to provide sufficient strength to prevent dehiscence.

The genetic regulation of ovarian development remains largely unclear. Indeed, in most cases of impaired ovarian development—such as 46,XX disorders of sex development (DSD) without SRY, and premature ovarian insufficiency (POI)—the genetic causes have not been identified, and the vast majority of disease-associated sequence variants could lie within non-coding regulatory sequences. In this study, we aimed to identify enhancers of five ovarian genes known to play key roles in early ovarian development, basing our analysis on the expression of enhancer derived transcripts (eRNAs), which are considered to characterize active enhancers. Temporal expression profile changes in mouse WT1-positive ovarian cells were obtained from cap analysis of gene expression at E13.5, E16.5 and P0. We compared the chronological expression profiles of ovarian-specific eRNA with expression profiles for each of the ovarian-specific genes, yielding two candidate sequences for enhancers of Wnt4 and Rspo1. Both sequences are conserved between mouse and human, and we confirmed their enhancer activities using transient expression assays in murine granulosa cells. Furthermore, by sequencing the region in patients with impaired ovarian development in 24 patients, such as POI, gonadal dysgenesis and 46,XX DSD, we identified rare single nucleotide variants in both sequences. Our results demonstrate that combined analysis of the temporal expression profiles of eRNA and mRNA of target genes presents a powerful tool for locating cis-element enhancers, and a means of identifying disease-associated sequence variants that lie within non-coding regulatory sequences, thus advancing an important unmet need in forward human genetics.

Introduction Evidence on physical and psychological well-being of in-hospital cardiac arrest (IHCA) survivors is scarce. The aim of this study is to describe long-term health-related quality of life (HRQoL), functional independence and psychological distress 3 and 12 months post-IHCA. Methods A multicenter prospective cohort study in 25 hospitals between January 2017 – May 2018. Adult IHCA survivors were included. HRQoL (EQ-5D-5L, SF-12), psychological distress (HADS, CSI) and functional independence (mRS) were assessed at 3 and 12 months post-IHCA. Results At 3-month follow-up 136 of 212 survivors responded to the questionnaire and at 12 months 110 of 198 responded. The median (IQR) EQ-utility Index score was 0.77 (0.65–0.87) at 3 months and 0.81 (0.70–0.91) at 12 months. At 3 months, patients reported a median SF-12 (IQR) physical component scale (PCS) of 38.9 (32.8–46.5) and mental component scale (MCS) of 43.5 (34.0–39.7) and at 12 months a PCS of 43.1 (34.6–52.3) and MCS 46.9 (38.5–54.5). Discussion Using various tools most IHCA survivors report an acceptable HRQoL and a substantial part experiences lower HRQoL compared to population norms. Our data suggest that younger (male) patients and those with poor functional status prior to admission are at highest risk of impaired HRQoL.

Purpose Mokken scale analysis (MSA) is an attractive scaling procedure for ordinal data. MSA is frequently used in health-related quality of life research. Two of MSA's prime features are the scalability coefficients and the automated item selection procedure (AISP). The AISP partitions a (large) set of items into scales based on the observed item scores; the resulting scales can be used as measurement instruments. There exist two issues in MSA: First, point estimates, standard errors, and test statistics for scalability coefficients are inappropriate for clustered item scores, which are omnipresent in quality of life research data. Second, the AISP insufficiently takes sampling fluctuation of Mokken’s scalability coefficients into account. Methods We solved both issues by providing point estimates and standard errors for the scalability coefficients for clustered data and by implementing a Wald-based significance test in the AISP algorithm, resulting in a test-guided AISP (T-AISP), that is available for both nonclustered and clustered test scores. Results We integrated the T-AISP into a two-step, test-guided MSA for scale construction, to guide the analysis for nonclustered and clustered data. The first step is performing a T-AISP and select the final scale( s ). For clustered data, within-group dependency is investigated on the final scale(s). In the second step, the strength of the scale(s) is determined and further analyses are performed. The procedure was demonstrated on clustered item scores obtained from administering a questionnaire on quality of life in schools to 639 students nested in 30 classrooms. Conclusions We developed a two-step, test-guided MSA for scale construction that takes into account sample fluctuation of all scalability coefficients and that can be applied to item scores obtained by a nonclustered or clustered sampling design.

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA 1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA 1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA 1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA 1c per serine, p=6·0 × 10 −5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10 −8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA 1c reduction per methionine, p=5·2 × 10 −6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA 1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.

BACKGROUND: Hemostasis during burn surgery is difficult to achieve, and high blood loss commonly occurs. Bleeding control measures are limited, and many patients require allogeneic blood transfusions. Cell salvage is a well-known method used to reduce transfusions. However, its evidence in burns is limited. Therefore, this study aimed to examine the feasibility of cell salvage during burn surgery.STUDY DESIGN AND METHODS: A prospective, observational study was conducted with 16 patients (20 measurements) scheduled for major burn surgery. Blood was recovered by washing saturated gauze pads with heparinized saline, which was then processed using the Cell Saver. Erythrocyte concentrate quality was analyzed by measuring hemoglobin, hematocrit, potassium, and free hemoglobin concentration. Microbial contamination was assessed based on cultures at every step of the process. Differences in blood samples were tested using the Student's t-test.RESULTS: The red blood cell mass recovered was 29 ± 11% of the mass lost. Patients' preoperative hemoglobin and hematocrit levels were 10.5 ± 1.8 g/dL and 0.33 ± 0.05 L/L, respectively. The erythrocyte concentrate showed hemoglobin and hematocrit levels of 13.2 ± 3.9 g/dL and 0.40 ± 0.11 L/L thus showing a concentration effect. The potassium level was lower in the erythrocyte concentrate (2.5 ± 1.5 vs. 4.1 ± 0.4 mmol/L, p CONCLUSION: Recovering erythrocytes during burn excisional surgery using cell salvage is possible. Despite strict sterile handling, erythrocyte concentrates of all patients showed bacterial contamination. The consequence of this contamination remains unclear and should be investigated in future studies.

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p 2 decrease), that was most notable in patients with eGFR 2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m 2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF.

PURPOSE Addressing financial toxicity among cancer patients is a complex process that requires a multifaceted approach, particularly for rural patients who may face additional cost-related barriers to care. In this study, we examined interventions being implemented by financial navigation staff at various cancer centers that help address financial toxicity experienced by oncology patients. METHODS We conducted semistructured interviews with a convenience sample of financial navigation staff across 29 cancer centers in both rural and urban areas in 7 states. Interviews were audio-recorded and transcribed. Descriptive coding and thematic analysis techniques were used to analyze the data. FINDINGS Thirty-five participants were interviewed, the majority of whom worked in cancer centers located in rural counties. Participants identified the use of screening tools, patient education, and access to tailored financial assistance resources as best practices. Immediate resource needs included additional financial navigation staff, including lay navigators and community health workers, to promote linkages to local resources. Suggested clinical areas for intervention included proactive and early implementation of financial assessments and discussions between providers and patients, along with training and access to regularly updated resources for those in financial navigator/counselor roles. Participants also discussed the need for policy-level interventions to reform health systems (including employment protections) and health insurance programs. CONCLUSIONS Implementing proactive methods to screen for and address financial needs of patients is essential to improving cancer-related outcomes. Additional programs and research are needed to help establish systematic and standardized methods to enhance financial navigation services, especially for underserved rural communities.

Importance: The role of primary tumor resection (PTR) in synchronous patients with metastatic colorectal cancer (mCRC) who had unresectable metastases and few or absent symptoms of their primary tumor is unclear. Studying subgroups with low postoperative mortality may identify patients who potentially benefit from PTR.Objective: To determine the difference in 60-day mortality between patients randomized to systemic treatment only vs PTR followed by systemic treatment, and to explore risk factors associated with 60-day mortality.Design, Setting, and Participants: CAIRO4 is a randomized phase 3 trial initiated in 2012 in which patients with mCRC were randomized to systemic treatment only or PTR followed by systemic treatment with palliative intent. This multicenter study was conducted by the Danish and Dutch Colorectal Cancer Group in general and academic hospitals in Denmark and the Netherlands. Patients included between August 2012 and December 2019 with histologically proven colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms were eligible.Interventions: Systemic treatment, consisting of fluoropyrimidine-based chemotherapy with bevacizumab vs PTR followed by fluoropyrimidine-based chemotherapy with bevacizumab.Main Outcomes and Measures: The aim of the current analysis was to compare 60-day mortality rates in both treatment arms. A secondary aim was the identification of risk factors for 60-day mortality in the treatment arms. These aims were not predefined in the study protocol.Results: A total of 196 patients were included in the intention-to-treat analysis (112 [57%] men; median [IQR] age, 65 [59-70] years). Sixty-day mortality was 3% (95% CI, 1%-9%) in the systemic treatment arm and 11% (95% CI, 6%-19%) in the PTR arm (P = .03). In a per-protocol analysis, 60-day mortality was 2% (95% CI, 1%-7%) vs 10% (95% CI, 5%-18%; P = .048). Patients with elevated serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and/or neutrophils who were randomized to PTR had a significantly higher 60-day mortality than patients without these characteristics.Conclusions and Relevance: Patients with mCRC who were randomized to PTR followed by systemic treatment had a higher 60-day mortality than patients randomized to systemic treatment. Especially patients randomized to the PTR arm with elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase were at high risk of postoperative mortality. Final study results on overall survival have to be awaited.Trial Registration: ClinicalTrials.gov Identifier: NCT01606098.

Objective: To evaluate the long-term outcomes of single-incision midurethral slings (SIMS) in real-life practice. Study Design: This retrospective, single-arm, patient cohort study was performed in a large Dutch teaching hospital, including 397 consecutive women who underwent a SIMS-procedure between 2009 and 2018. Data were obtained through questionnaires and patient record study. Subjective improvement was the primary outcome, defined as a Patient Global Impression of Improvement (PGI-I) of ‘(very) much better’. Secondary outcomes were subjective cure rate (defined as a negative Urogenital Distress Inventory - item 4 ‘Do you experience involuntary urine leakage related to physical activity, coughing or sneezing?’), complication rate and sling failure (defined as the need for additional research or treatment for persisting stress urinary incontinence (SUI)). All data was analysed with a statistical significance level of 5%. Results: The mean follow-up time was 54 months. All patients received SIMS (Ajust® or Altis®). Of all respondents, 75% reported a (very) much improved burden of disease. The subjective cure rate was 61%. In 93 patients a total of 120 complications were registered. In 10% of patients a sling failure was observed, 76% of these failures appeared in the first two years post-surgery. Conclusion: This study showed that, in real life practice, SIMS are both effective and safe over a long period of time.

Background In some acute care trials, immediate informed consent is not possible, but deferred consent is often considered problematic. We investigated the opinions of patients, proxies, and physicians about deferred consent in an acute stroke trial to gain insight into its acceptability and effects. Methods Paper-based surveys were sent to patients who were randomly assigned in the Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage (ULTRA) trial between 2015 and 2018 in two tertiary referral centers and to physicians of centers who agreed or declined to participate. The primary outcome measure was the proportion of respondents who agreed with deferral of consent in the ULTRA trial. Secondary outcomes included respondents’ preferred consent procedure for the ULTRA trial, the effect of deferred consent on trust in physicians and scientific research, and the willingness to participate in future research. Results Eighty-nine of 135 (66%) patients or proxies and 20 of 30 (67%) physicians completed the survey. Of these, 82 of 89 (92%) patients or proxies and 14 of 20 (70%) physicians agreed with deferral of consent in the ULTRA trial. When asked for their preferred consent procedure for the ULTRA trial, 31 of 89 (35%) patients or proxies indicated deferred consent, 15 of 89 (17%) preferred immediate informed consent, and 32 of 89 (36%) had no preference. None of the patients’ or proxies’ trust in physicians or scientific research had decreased because of the deferred consent procedure. Willingness to participate in future studies remained the same or increased in 84 of 89 (94%) patients or proxies. Conclusions A large majority of the surveyed patients and proxies and a somewhat smaller majority of the surveyed physicians agreed with deferred consent in the ULTRA trial. Deferred consent may enable acute care trials in an acceptable manner without decreasing trust in medicine. Future research should investigate factors facilitating the responsible use of deferred consent, such as in-depth interviews, to study the minority of participants who agreed with deferred consent but still preferred immediate informed consent.

Introduction: In-hospital cardiac arrest (IHCA) is an adverse event associated with high mortality. Because of the impact of IHCA more data is needed on incidence, outcomes and associated factors that are present prior to cardiac arrest. The aim was to assess one-year survival, patient-centred outcomes after IHCA and their associated pre-arrest factors. Methods: A multicentre prospective cohort study in 25 hospitals between January 1st 2017 and May 31st 2018. Patients ≥ 18 years receiving cardiopulmonary resuscitation (CPR) for IHCA were included. Data were collected using Utstein and COSCA-criteria, supplemented by pre-arrest Modified Rankin Scale (MRS, functional status) and morbidity through the Charlson Comorbidity Index (CCI). Main outcomes were survival, health-related quality of life (HRQoL, EuroQoL) and functional status (MRS) after one-year. Results: A total of 713 patients were included, 64.5% was male, median age was 63 years (IQR 52–72) and 72.8% had a non-shockable rhythm, 394 (55.3%) achieved ROSC, 231 (32.4%) survived to hospital discharge and 198 (27.8%) survived one year after cardiac arrest. Higher pre-arrest MRS, age and CCI were associated with mortality. At one year, patients rated HRQoL 72/100 points on the EQ-VAS and 69.7% was functionally independent. Conclusion: One-year survival after IHCA in this study is 27.8%, which is relatively high compared to previous studies. Survival is associated with a patient's pre-arrest functional status and morbidity. HRQoL appears acceptable, however functional rehabilitation warrants attention. These findings provide a comprehensive insight in in-hospital cardiac arrest prognosis.

Purpose We investigated changes in ARDS severity and associations with outcome in COVID–19 ARDS patients. Methods We compared outcomes in patients with ARDS classified as ‘mild’, ‘moderate’ or ‘severe’ at calendar day 1, and after reclassification at calendar day 2. The primary endpoint was 28–day mortality. We also identified which ventilatory parameters had an association with presence of severe ARDS at day 2. We repeated the analysis for reclassification at calendar day 4. Results Of 895 patients, 8.5%, 60.1% and 31.4% had mild, moderate and severe ARDS at day 1. These proportions were 13.5%, 72.6% and 13.9% at day 2. 28–day mortality was 25.3%, 31.3% and 32.0% in patients with mild, moderate and severe ARDS at day 1 (p = 0.537), compared to 28.6%, 29.2% and 44.3% in patients reclassified at day 2 (p = 0.005). No ventilatory parameter had an independent association with presence of severe ARDS at day 2. Findings were not different reclassifying at day 4. Conclusions In this cohort of COVID–19 patients, ARDS severity and mortality between severity classes changed substantially over the first 4 days of ventilation. These findings are important, as reclassification could help identify target patients that may benefit from alternative approaches., Graphical abstract Unlabelled Image

Counterproductive work behavior (CWB) is a topic of considerable importance for organizational scholars and practitioners. Yet, despite a wide-ranging consensus that negative affect (NA) is a precursor to CWB, there is surprisingly little consensus as to whether CWB enactment will subsequently lead to lower or higher levels of NA. That is, scholars disagree as to whether CWB has a reparative (negative) or generative (positive) effect on subsequent NA. We submit that both perspectives have validity, and thus the question should not be whether CWB is associated with lower or higher subsequent levels of NA, but rather for whom. This article is dedicated to answering this question. Drawing from the behavioral concordance model, we position empathy as a moderator of this relationship, such that CWB will be reparative for those with lower levels of empathy and generative for those with higher levels of empathy. Findings across 3 experience-sampling studies support our hypotheses and highlight a number of interesting directions for future research. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Several studies have shown that the first encounter with influenza virus shapes the immune response to future infections or vaccinations. However, a detailed analysis of the primary antibody response is lacking as this is difficult to study in humans. It is therefore not known what the frequency and dynamics of the strain-specific hemagglutinin (HA) head- and stem-directed antibody responses are directly after primary influenza virus infection. Here, sera of twelve H1N1pdm2009 influenza virus-infected cynomolgus macaques were evaluated for HA-head and HA-stem domain antibody responses. We observed an early induction of HA-stem antibody responses, which was already decreased by day 56. In contrast, responses against the HA-head domain were low early after infection and increased at later timepoint. The HA-specific B cell repertoires in each animal showed diverse VH-gene usage with preferred VH-gene and JH-gene family usage for HA-head or HA-stem B cells but a highly diverse allelic variation within the VH-usage. HA-head B cells had shorter CDRH3s and higher VH-gene somatic hyper mutation levels relative to HA-stem B cells. In conclusion, our data suggest that HA-stem antibodies are the first to react to the infection while HA-head antibodies show a delayed response, but a greater propensity to enter the germinal center and undergo affinity maturation.

Background Unplanned or unintended pregnancies form a major public health concern because they are associated with unfavorable birth outcomes as well as social adversity, stress and depression among parents-to-be. Several risk factors for unplanned pregnancies in women have previously been identified, but studies usually take a unidimensional approach by focusing on only one or few factors, disregarding the possibility that predictors might cluster. Furthermore, data on predictors in men are largely overlooked. The purpose of this study is to determine predictors of unplanned versus planned pregnancy, to determine predictors of ambivalent feelings regarding pregnancy, and to investigate how characteristics of men and women with an unplanned pregnancy cluster together. Methods This study was embedded in Generation R, a multiethnic population-based prospective cohort from fetal life onwards. Pregnancy intention was reported by 7702 women and 5367 partners. Information on demographic, mental, physical, social, and sexual characteristics was obtained. Logistic regression, multinomial regression and cluster analyses were performed to determine characteristics that were associated with an unplanned pregnancy, with ambivalent feelings regarding the unplanned pregnancy and the co-occurrence of characteristics in women and men with unplanned pregnancy. Results Twenty nine percent of the pregnancies were unplanned. Logistic regression analyses showed that 42 of 44 studied predictors were significantly associated with unplanned pregnancy. The most important predictors were young age, migration background, lower educational level, lower household income, financial difficulties, being single, lower cognitive ability, drug use prior to pregnancy, having multiple sexual partners in the year prior to the pregnancy, younger age of first sexual contact and a history of abortion. Multinomial regression analyses showed that a Turkish or Moroccan background, Islamic religion, little financial opportunities, being married, having ≥3 children, high educational level, more mental health and social problems and older age of first sexual contact were associated with prolonged ambivalent feelings regarding pregnancy. Different combinations of characteristics were observed in the four clusters of women and men with unplanned pregnancy. Conclusions Many predictors are related with unplanned pregnancies, ambivalent feelings toward the pregnancy, and we identified very heterogeneous groups of women and men with unplanned pregnancies. This calls for heterogeneous measures to prevent unplanned pregnancies.

DNA‐sensing receptor Cyclic GMP–AMP Synthase (cGAS) and its downstream signaling effector STimulator of INterferon Genes (STING) have gained significant interest in the field of tumor immunology, as a dysfunctional cGAS‐STING pathway is associated with poor prognosis and worse response to immunotherapy. However, studies so far have not taken into account the polymorphic nature of the STING‐encoding STING1 gene. We hypothesized that the presence of allelic variance in STING1 would cause variation between individuals as to their susceptibility to cancer development, cancer progression, and potential response to (immuno)therapy. To start to address this, we defined the genetic landscapes of STING1 in cervical scrapings and investigated their corresponding clinical characteristics across a unique cohort of cervical cancer patients and compared them with independent control cohorts. Although we did not observe an enrichment of particular STING1 allelic variants in cervical cancer patients, we did find that the occurrence of homozygous variants HAQ/HAQ and R232H/R232H of STING1 were associated with both younger age of diagnosis and higher recurrence rate. These findings were accompanied by worse survival, despite comparable mRNA and protein levels of STING and numbers of infiltrated CD8+ T cells. Our findings suggest that patients with HAQ/HAQ and R232H/R232H genotypes may have a dysfunctional cGAS‐STING pathway that fails to promote efficient anticancer immunity. Interestingly, the occurrence of these genotypes coincided with homozygous presence of the V48V variant, which was found to be individually associated with worse outcome. Therefore, we propose V48V to be further evaluated as a novel prognostic marker for cervical cancer., Homozygous variants of the STING1 gene are associated with poor outcome in human cervical cancer. Moreover, patients with homozygous variants of STING1 are diagnosed at an earlier age and have a higher recurrence rate. Likely, these patients have a dysfunctional cGAS‐STING pathway that fails to promote efficient anticancer immunity.

Aims Pulsed field ablation (PFA) is a novel atrial fibrillation (AF) ablation modality that has demonstrated preferential tissue ablation, including no oesophageal damage, in first-in-human clinical trials. In the MANIFEST-PF survey, we investigated the 'real world' performance of the only approved PFA catheter, including acute effectiveness and safety-in particular, rare oesophageal effects and other unforeseen PFA-related complications. Methods and results This retrospective survey included all 24 clinical centres using the pentaspline PFA catheter after regulatory approval. Institution-level data were obtained on patient characteristics, procedure parameters, acute efficacy, and adverse events. With an average of 73 patients treated per centre (range 7-291), full cohort included 1758 patients: mean age 61.6 years (range 19-92), female 34%, first-time ablation 94%, paroxysmal/persistent AF 58/35%. Most procedures employed deep sedation without intubation (82.1%), and 15.1% were discharged same day. Pulmonary vein isolation (PVI) was successful in 99.9% (range 98.9-100%). Procedure time was 65 min (38-215). There were no oesophageal complications or phrenic nerve injuries persisting past hospital discharge. Major complications (1.6%) were pericardial tamponade (0.97%) and stroke (0.4%); one stroke resulted in death (0.06%). Minor complications (3.9%) were primarily vascular (3.3%), but also included transient phrenic nerve paresis (0.46%), and TIA (0.11%). Rare complications included coronary artery spasm, haemoptysis, and dry cough persistent for 6 weeks (0.06% each). Conclusion In a large cohort of unselected patients, PFA was efficacious for PVI, and expressed a safety profile consistent with preferential tissue ablation. However, the frequency of 'generic' catheter complications (tamponade, stroke) underscores the need for improvement. There was no specific funding received to conduct this survey. Conflict of interest: V.Y.R. reports receiving consulting fees and equity (stock) from Farapulse Inc. and is a consultant for Boston Scientific Inc.; he also has additional disclosures unrelated to this manuscript that are listed in the Supplementary material online. B.S. reports receiving speaker’s fees and research grants from Boston Scientific/Farapulse, Medtronic, Biosense Webster, and Abbott. T.R. reports research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the sitem insel support fund. Speaker/consulting honoraria or travel support from Abbott/SJM, Bayer, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, Medtronic, and Pfizer-BMS. Support for his institution’s fellowship programme from Abbott/SJM, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. L.R. reports receiving speaker honoraria from Abbott/SJM and consulting honoraria from Medtronic. K.N. reports speaker’s Fees from Farapulse, Inc. A.M. reports research grant and fees from Farapulse. A.R. reports receiving research grant from Farapulse. J.H. reports receiving speaker fees and grant support from Biosense Webster and Medtronic. Y.B.: reports receiving Research grant from Medtronic and Atricure and consulting fees from Abbott, Biosense Webster, Boston Scientific. P.S. reports member of the advisory board for Abbott, Biosense Webster, Boston Scientific, and Medtronic. C.S. reports receiving modest honoraria from Medtronic. A.A. reports receiving consultant fees from Farapulse Inc., Boston Scientific Inc., Galaxy Medical Inc., Biosense Webster, and performs contracted research for Farapulse Inc., Boston Scientific Inc., Galaxy Medical Inc., Biosense Webster. F.A. reports receiving consulting fees from Boston Scientific, Medtronic and Microport CRM. S.B. reports receiving consulting fees for Medtronic, Boston Scientific, Microport, Zoll, and BMS. T.D. reports receiving speaker honoraria from Galaxy Medical, Abbott and Biotronik, being a consultant to Farapulse, and serving on a Clinical Events Committee for Boston Scientific. S.W. reports receiving grants and personal fees from Abbott, Boston Scientific, Medtronic, and personal fees from Boehringer Ingelheim, Brystol Myers Squibb, Bayer Vital, Accutus, Daiichi, Farapulse Inc. M.G. reports grant from Farapulse Inc. and Abbott. R.T. reports receiving consulting fees from Boston Scientific, Abbot Medical, Biotronik, and speakers honorarium from Boston Scientific, Abbot Medical, Biotronik, Biosense Webster. B.K. reports receiving Travel and Congress Sponsoring from Biotronik, Abbott, Impulse Dynamics, DGK AG EP, EHRA, Pfizer; she also received fellowship sponsoring from Johnson & Johnson, Boston Scientific and Lecture Honorary from Biotronik, Impulse Dynamics, C.T.I. GmbH, Doctrina Med. D.S. reports receiving an educational grant from Farapulse Inc., and is a consultant For Boston Scientific Inc. R.W. reports receiving consultant fees and travel expenses from Boston Scientific and Biotronik; investigator-initiated funding for research projects (initiated by him) from Bristol-Myers Squibb, Pfizer, and Boston Scientific; and speaking honoraria from Boston Scientific, Biotronik, and Medtronic. D.S. reports receiving speaking fees from Pfizer, Bayer, Abbott, Johnson & Johnson, and Medtronic; grant from Abbott, Johnson & Johnson, and Boston Scientific; and consulting fees from Boston Scientific and Johnson & Johnson. A.S. reports receiving lecture and consulting honoraria from Medtronic, Abbott, and Bayer. J.K. reports personal fees from Bayer, Biosense Webster, Boehringer Ingelheim, Medtronic, and Abbott for participation in scientific advisory boards, and has received speaker honoraria from Bayer, Biosense Webster, Biotronik, Boehringer Ingelheim, CathVision, Medtronic, Mylan, Pfizer, ProMed, and Abbott. P.J. reports receiving equity from Farapulse and consulting fees and grant from Boston Scientific. N.D. reports receiving consulting fees from Boston scientific. J.C. reports receiving speaker’s fees and research grants from Boston Scientific/Farapulse, Medtronic, Biosense Webster, and Abbott. P.N. reports receiving grant from the Ministry of Health, Czech Republic, DRO (NHH, 00023884). All the remaining authors have declared no conflict of interest.

Few genetically dominant mutations involved in human disease have been fully explained at the molecular level. In cases where the mutant gene encodes a transcription factor, the dominant-negative mode of action of the mutant protein is particularly poorly understood. Here, we studied the genome-wide mechanism underlying a dominant-negative form of the SOX18 transcription factor (SOX18RaOp) responsible for both the classical mouse mutant Ragged Opossum and the human genetic disorder Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome. Combining three single-molecule imaging assays in living cells together with genomics and proteomics analysis, we found that SOX18RaOp disrupts the system through an accumulation of molecular interferences which impair several functional properties of the wild-type SOX18 protein, including its target gene selection process. The dominant-negative effect is further amplified by poisoning the interactome of its wild-type counterpart, which perturbs regulatory nodes such as SOX7 and MEF2C. Our findings explain in unprecedented detail the multi-layered process that underpins the molecular aetiology of dominant-negative transcription factor function.

Background Home blood pressure measurements have equal or even greater predictive value than clinic blood pressure measurements regarding cardiovascular outcomes. With advances in home blood pressure monitors, we face an imminent flood of home measurements, but current electronic health record systems lack the functionality to allow us to use this data to its fullest. We designed a data visualization display for blood pressure measurements to be used for shared decision making around hypertension. Methods We used an iterative, rapid-prototyping, user-centred design approach to determine the most appropriate designs for this data display. We relied on visual cognition and human factors principles when designing our display. Feedback was provided by expert members of our multidisciplinary research team and through a series of end-user focus groups, comprised of either hypertensive patients or their healthcare providers required from eight academic, community-based practices in the Midwest of the United States. Results A total of 40 participants were recruited to participate in patient (N = 16) and provider (N = 24) focus groups. We describe the conceptualization and development of data display for shared decision making around hypertension. We designed and received feedback from both patients and healthcare providers on a number of design elements that were reported to be helpful in understanding blood pressure measurements. Conclusions We developed a data display for substantial amounts of blood pressure measurements that is both simple to understand for patients, but powerful enough to inform clinical decision making. The display used a line graph format for ease of understanding, a LOWESS function for smoothing data to reduce the weight users placed on outlier measurements, colored goal range bands to allow users to quickly determine if measurements were in range, a medication timeline to help link recorded blood pressure measurements with the medications a patient was taking. A data display such as this, specifically designed to encourage shared decision making between hypertensive patients and their healthcare providers, could help us overcome the clinical inertia that often results in a lack of treatment intensification, leading to better care for the 35 million Americans with uncontrolled hypertension.

Contains fulltext : 238268.pdf (Publisher’s version ) (Closed access) IMPORTANCE: To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM). OBJECTIVE: To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment. DESIGN, SETTING, AND PARTICIPANTS: An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment. INTERVENTIONS: Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles. MAIN OUTCOMES AND MEASURES: Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm). RESULTS: In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively. CONCLUSIONS AND RELEVANCE: In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02758951.