Timing of primary three-dose hepatitis B vaccination and postvaccination serologic testing among a large cohort of healthy adults.

This study evaluated the optimal timing of a primary three-dose hepatitis B vaccination and postvaccination serologic testing (PVST) among a large group of healthy naïve adults in the Netherlands. Data were collected from the Ease Travel Clinic hepatitis B vaccination database. The study population consisted of 22,997 adults who received three hepatitis B vaccinations. Seroprotection was attained in 97.3% individuals. When compared with PVST performed at 1-2 months (98.2%) after the final dose, lower seroprotection rates were observed with <1 (97.3%, p = 0.128), 3-6 (90.6%, p < 0.001), and ≥7 (88.4%, p < 0.001) months after vaccination. Among the subpopulation with a PVST 1-2 months, no statistically significant difference was observed for the various intervals between the first and second vaccination (<1, 1-2, 3-4, or ≥5 months). When compared with 4-5 months between the second and third vaccine dose, lower seroprotection rates were observed with <4 (odds ratio [OR]: 0.29, p = 0.020) and ≥12 (OR: 0.22, p < 0.001) months, although comparable rates were observed with 6-11 months interval (OR: 0.85, p = 0.262). Our data indicate that PVST should be obtained 1-2 months after the last vaccination and a delayed PVST was the major determinant of a lower seroprotection rate after primary three-dose hepatitis B vaccination schedule. Based on our data, the hepatitis B vaccination also leaves room for flexibility for the second dose and the third dose without the necessity of restarting the vaccination series or confirmation of the immune response to the vaccine.

The Clinical Frailty Scale as a triage tool for ICU admission of dialysis patients with COVID-19: an ERACODA analysis.

BACKGROUND: Several guidelines recommend using the Clinical Frailty Scale (CFS) for triage of critically ill coronavirus disease 2019 (COVID-19) patients. This study evaluates the impact of CFS on intensive care unit (ICU) admission rate and hospital and ICU mortality rates in hospitalized dialysis patients with COVID-19. METHODS: We analysed data of dialysis patients diagnosed with COVID-19 from the European Renal Association COVID-19 Database. The primary outcome was ICU admission rate and secondary outcomes were hospital and ICU mortality until 3 months after COVID-19 diagnosis. Cox regression analyses were performed to assess associations between CFS and outcomes. RESULTS: A total of 1501 dialysis patients were hospitalized due to COVID-19, of whom 219 (15%) were admitted to an ICU. The ICU admission rate was lowest (5%) in patients >75 years of age with a CFS of 7-9 and highest (27%) in patients 65-75 years of age with a CFS of 5. A CFS of 7-9 was associated with a lower ICU admission rate than a CFS of 1-3 [relative risk 0.49 (95% confidence interval 0.27-0.87)]. Overall, mortality at 3 months was 34% in hospitalized patients, 65% in ICU-admitted patients and highest in patients >75 years of age with a CFS of 7-9 (69%). Only 9% of patients with a CFS ≥6 survived after ICU admission. After adjustment for age and sex, each CFS category ≥4 was associated with higher hospital and ICU mortality compared with a CFS of 1-3. CONCLUSIONS: Frail dialysis patients with COVID-19 were less frequently admitted to the ICU. Large differences in mortality rates between fit and frail patients suggest that the CFS may be a useful complementary triage tool for ICU admission in dialysis patients with COVID-19.

The association between anti-acetylcholine receptor antibody level and clinical improvement in myasthenia gravis.

BACKGROUND AND PURPOSE: Anti-acetylcholine receptor (AChR) antibodies (ab) in the serum are detected in most patients with generalized myasthenia gravis (MG) and used as a diagnostic tool. The aim of this study was to analyse a possible association between anti-AChR-ab serum levels and clinical improvement of MG. METHODS: The Maastricht University Medical Center is a centre of expertise for the treatment of MG. Between 1997 and 2020, more than 4000 anti-AChR-ab blood samples were measured for clinical care using a quantitative radioimmunoassay technique. These results, in combination with clinical status obtained from the patients' electronic patient files, were retrospectively analysed by a single blinded clinician. Symptoms of MG were classified using the Myasthenia Gravis Foundation of America (MGFA) scale. RESULTS: In total, 90 anti-AChR-ab-positive MG patients with 837 blood samples were included. The median follow-up time was 72 months. The majority of the included patients were women (61.1%), were on immunosuppressive drug therapy (88.9%), and underwent a thymectomy (54.4%). Multilevel logistic regression analysis showed a significantly inverse association between change in anti-AChR-ab level and the odds of MGFA improvement (per 10% decrease of anti-AChR-ab level: odds ratio 1.21, 95% confidence interval 1.12-1.31; p < 0.001). CONCLUSIONS: A change in anti-AChR-ab serum level is associated with clinical status in patients with MG. Analyses of anti-AChR-ab are not only useful for diagnostics but also in follow-up of adult symptomatic patients with MG. The use of repetitive anti-AChR-ab serum levels might be valuable in long-term monitoring for clinical improvement in patients with MG, however, further research is required for specific recommendations.

The estimation of a preference-based single index for the IBS-QoL by mapping to the EQ-5D-5L in patients with irritable bowel syndrome.

PURPOSE: The Irritable Bowel Syndrome Quality of Life (IBS-QoL) questionnaire is a commonly used and validated IBS-specific QoL instrument. However, this questionnaire is in contrast to the EQ-5D-5L, not preference-based and as such does not allow calculation of QALYs. The objective of this study was to describe the convergent- and known-group validity of both questionnaires and to develop a mapping algorithm from EQ-5D-5L which enable IBS-QoL scores to be transformed into utility scores for use in economic evaluations. METHODS: We used data from two multicenter randomized clinical trials, which represented the estimation and external validation dataset. The convergent validity was investigated by examining correlations between the EQ-5D-5L and IBS-QoL and the known-group validity by calculating effect sizes. Ordinary least squares (OLS), censored least absolute deviations (CLAD), and mixture models were used in this mapping approach. RESULTS: 283 IBS patients were included (n = 189 vs. n = 84). Mean IBS-QoL score was 71.13 (SD 15.66) and mean EQ-5D-5L utility score was 0.73 (SD 0.19). The overall sensitivity of the IBS-QoL and EQ-5D-5L to discriminate between patient and disease characteristics was similar. CLAD model 4, containing the total IBS-QoL score and squared IBS-SSS (IBS severity scoring system), was chosen as the most appropriate model to transform IBS-QoL scores into EQ-5D-5L utility scores. CONCLUSION: This study reports the development of an algorithm where the condition-specific questionnaire IBS-QoL can be used to calculate utility values for use in economic evaluations. Including a clinical measure, IBS-SSS, in the model improved the performance of the algorithm.

Patients with hereditary hemochromatosis reach safe range of transferrin saturation sooner with erythrocytaphereses than with phlebotomies.

INTRODUCTION: For the maintenance treatment of patients with hereditary hemochromatosis (HH), it is advised to keep the transferrin saturation (TSAT) <70% to prevent formation of non-transferrin-bound iron and labile plasma iron. The period of the initial iron depletion may last up to 1 year or longer and during this period, the patient is exposed to elevated TSAT levels. Therapeutic erythrocytapheresis (TE) is a modality which has proven to reduce treatment duration of patients with iron overload from HH. In this study, we investigated the time to reach TSAT <70% for both treatment modalities. METHODS: From a previous randomized controlled trial comparing erythrocytaphereses with phlebotomies (PBMs), we performed an analysis in a subgroup of patients who presented with TSAT >70%. Mann-Whitney U tests were performed to compare the number of treatments and the number of weeks to reach the interim goal of a persistent level of <70% for TSAT between TE and PBM. RESULTS: The period to reach TSAT levels of <70% was statistically significant shorter for the TE group compared to the PBM treatment group (median treatment procedures [IQR] 2.0 (5) vs 16.0 (23), P-value: <.001, and median treatment duration [IQR]: 5.5 (11) vs 19.0 (29) weeks, P-value: .007). CONCLUSION: Patients with HH reach a safe TSAT <70% significantly sooner and with less treatment procedures with TE compared to PBM.

Alcohol consumption in later life and reaching longevity: the Netherlands Cohort Study.

BACKGROUND: whether light-to-moderate alcohol intake is related to reduced mortality remains a subject of intense research and controversy. There are very few studies available on alcohol and reaching longevity. METHODS: we investigated the relationship of alcohol drinking characteristics with the probability to reach 90 years of age. Analyses were conducted using data from the Netherlands Cohort Study. Participants born in 1916-1917 (n = 7,807) completed a questionnaire in 1986 (age 68-70 years) and were followed up for vital status until the age of 90 years (2006-07). Multivariable Cox regression analyses with fixed follow-up time were based on 5,479 participants with complete data to calculate risk ratios (RRs) of reaching longevity (age 90 years). RESULTS: we found statistically significant positive associations between baseline alcohol intake and the probability of reaching 90 years in both men and women. Overall, the highest probability of reaching 90 was found in those consuming 5- < 15 g/d alcohol, with RR = 1.36 (95% CI, 1.20-1.55) when compared with abstainers. The exposure-response relationship was significantly non-linear in women, but not in men. Wine intake was positively associated with longevity (notably in women), whereas liquor was positively associated with longevity in men and inversely in women. Binge drinking pointed towards an inverse relationship with longevity. Alcohol intake was associated with longevity in those without and with a history of selected diseases. CONCLUSIONS: the highest probability of reaching 90 years was found for those drinking 5- < 15 g alcohol/day. Although not significant, the risk estimates also indicate to avoid binge drinking.

Low socioeconomic status and perceptions of social inadequacy and shame: findings from the Dutch SMILE study.

BACKGROUND: Based on presumed negative social comparisons in lower socioeconomic status groups, we set out to examine whether notions of 'internalized inferiority' are more common in these groups. METHODS: Dutch Studie naar Medische Informatie en Leefwijzen in Eindhoven (SMILE) data on 1323 participants, aged 58-94 in 2008, were used to estimate odds ratios (ORs) of internalized inferiority by childhood and adulthood socioeconomic indicators. Questionnaires for social inadequacy and shame were used to measure internalized inferiority. RESULTS: Both adulthood low educational level [OR 1.58; 95% confidence interval (CI): 1.04-2.40] and low income level (OR 1.88; 95% CI: 1.23-2.88) had substantial associations with reports of social inadequacy. Recalled childhood poverty was strongly associated with reports of shame (OR 2.20; 95% CI: 1.39-3.48). CONCLUSIONS: The socioeconomic patterning of social inadequacy and shame suggests that notions of internalized inferiority in the individual, psychological makeup might be important in the generation and maintenance of socioeconomic inequalities in health.

In-depth Analysis of Lorlatinib-related neurocognitive Adverse Events in Patients With Non-small-cell Lung Cancer.

INTRODUCTION: Lorlatinib is a potent, brain penetrant, next-generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study. PATIENTS AND METHODS: This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of 2 weeks and 2 months after starting lorlatinib, in comparison to baseline. As a secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined. RESULTS: Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised parts b and c demonstrated a significant and clinically relevant decrease in scoring 2 weeks post initiation of lorlatinib (P = .036 and P = .003, respectively). However, these returned to baseline at the 2-month evaluation. The questionnaires did not result in significantly different outcomes over time. CONCLUSION: Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.

The efficacy of sensory nerve coaptation in DIEP flap breast reconstruction - Preliminary results of a double-blind randomized controlled trial.

BACKGROUND: Sensory nerve coaptation has great potential to restore sensation after autologous breast reconstruction. However, blinded and randomized studies are lacking. We therefore present the preliminary results of our ongoing double-blinded randomized controlled trial that compares sensory recovery of innervated versus non-innervated DIEP flaps. METHODS: Patients who underwent DIEP flap breast reconstruction between July 2019 and February 2022 were included and randomized. The anterior cutaneous branch of the second or third intercostal nerve was coapted. Pre- and postoperative sensory testing was performed with Semmes-Weinstein Monofilaments, Pressure Specified Sensory Device, and a thermostimulator, for tactile and temperature thresholds. RESULTS: This interim analysis comprised 41 patients contributing 29 innervated and 38 non-innervated breasts. At 24 months of follow-up, the mean monofilament value of the flap skin was lower in innervated than in non-innervated flaps (4.48 vs. 5.20, p = 0.003). Touch thresholds were lower the center of the innervated flaps (47.8 vs. 71.2 g/mm2, p = 0.036), and heat pain was more often imperceptible in non-innervated flaps (42.1% vs. 10.3%, p = 0.004). No adverse events were associated with sensory nerve coaptation. CONCLUSIONS: These preliminary results indicate superior sensibility and recovery of protective sensation in innervated compared with non-innervated DIEP flaps. Although the results of the completed trial must be awaited to establish the full clinical impact, including highly anticipated quality of life outcomes, we encourage continuation of scientific and clinical efforts in this promising technique.

Cost of illness of patients with small fiber neuropathy in the Netherlands.

ABSTRACT: Neuropathic pain is associated with substantial healthcare costs. However, cost-of-illness studies of small fiber neuropathy (SFN) are scarce. Our aim was to estimate the healthcare, patient and family, and productivity costs of patients with SFN in the Netherlands from a healthcare and societal perspective. In addition, the association of costs with age, pain impact on daily life, anxiety, depression, and quality of life (Qol) were examined. Cost questionnaires were completed by 156 patients with confirmed SFN. The average annual total health care and societal cost (€, 2020) was calculated at patient, SFN adult population, and societal level. The average annual healthcare, patient and family, and productivity costs per patient with a Pain Impact Numerical Rating Scale of 0 to 3 (mild), 4 to 6 (moderate), and 7 to 10 (severe) were calculated by using the cost questionnaire data. Quality of life was determined by the EuroQol 5D utility scores. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Associations of all costs were analyzed using linear regression analyses. At the patient level, the average annual SFN healthcare and societal cost of SFN was €3614 (95% confidence interval [CI] €3171-€4072) and €17,871 (95% CI €14,395-€21,480). At the SFN population level, the average healthcare costs were €29.8 (CI €26.4-€34.2) million, and on a societal level, these were €147.7 (CI 120.5-176.3) million. Severe pain was associated with significant lower Qol and higher depression scores, higher healthcare, patient and family, and productivity costs ( P < 0.001).

Pericardial Fat Is Associated With Less Severe Multiorgan Failure Over Time in Patients With Coronavirus Disease-19: The Maastricht Intensive Care COVID Cohort.

PURPOSE: Pericardial fat (PF) and epicardial adipose tissue (EAT) may enhance the proinflammatory response in corona virus-19 (COVID-19) patients. Higher PF and EAT volumes might result in multiorgan failure and explain unfavorable trajectories.The aim of this study was to examine the association between the volume of PF and EAT and multiorgan failure over time. MATERIALS AND METHODS: All mechanically ventilated COVID-19 patients with an available chest computed tomography were prospectively included (March-June 2020). PF and EAT volumes were quantified using chest computed tomography scans. Patients were categorized into sex-specific PF and EAT tertiles. Variables to calculate Sequential Organ Failure Assessment (SOFA) scores were collected daily to indicate multiorgan failure. Linear mixed-effects regression was used to investigate the association between tertiles for PF and EAT volumes separately and serial SOFA scores over time. All models were adjusted. RESULTS: Sixty-three patients were divided into PF and EAT tertiles, with median PF volumes of 131.4 mL (IQR [interquartile range]: 115.7, 143.2 mL), 199.8 mL (IQR: 175.9, 221.6 mL), and 318.8 mL (IQR: 281.9, 376.8 mL) and median EAT volumes of 69.6 mL (IQR: 57.0, 79.4 mL), 107.9 mL (IQR: 104.6, 115.1 mL), and 163.8 mL (IQR: 146.5, 203.1 mL). Patients in the highest PF tertile had a statistically significantly lower SOFA score over time (1.3 [-2.5, -0.1], P =0.033) compared with the lowest PF tertile. EAT tertiles were not significantly associated with SOFA scores over time. CONCLUSION: A higher PF volume is associated with less multiorgan failure in mechanically ventilated COVID-19 patients. EAT volumes were not associated with multiorgan failure.

Laparoscopic Versus Open Hemihepatectomy: The ORANGE II PLUS Multicenter Randomized Controlled Trial.

PURPOSE: To compare outcomes after laparoscopic versus open major liver resection (hemihepatectomy) mainly for primary or metastatic cancer. The primary outcome measure was time to functional recovery. Secondary outcomes included morbidity, quality of life (QoL), and for those with cancer, resection margin status and time to adjuvant systemic therapy. PATIENTS AND METHODS: This was a multicenter, randomized controlled, patient-blinded, superiority trial on adult patients undergoing hemihepatectomy. Patients were recruited from 16 hospitals in Europe between November 2013 and December 2018. RESULTS: Of the 352 randomly assigned patients, 332 patients (94.3%) underwent surgery (laparoscopic, n = 166 and open, n = 166) and comprised the analysis population. The median time to functional recovery was 4 days (IQR, 3-5; range, 1-30) for laparoscopic hemihepatectomy versus 5 days (IQR, 4-6; range, 1-33) for open hemihepatectomy (difference, -17.5% [96% CI, -25.6 to -8.4]; P < .001). There was no difference in major complications (laparoscopic 24/166 [14.5%] v open 28/166 [16.9%]; odds ratio [OR], 0.84; P = .58). Regarding QoL, both global health status (difference, 3.2 points; P < .001) and body image (difference, 0.9 points; P < .001) scored significantly higher in the laparoscopic group. For the 281 (84.6%) patients with cancer, R0 resection margin status was similar (laparoscopic 106 [77.9%] v open 122 patients [84.1%], OR, 0.60; P = .14) with a shorter time to adjuvant systemic therapy in the laparoscopic group (46.5 days v 62.8 days, hazard ratio, 2.20; P = .009). CONCLUSION: Among patients undergoing hemihepatectomy, the laparoscopic approach resulted in a shorter time to functional recovery compared with open surgery. In addition, it was associated with a better QoL, and in patients with cancer, a shorter time to adjuvant systemic therapy with no adverse impact on cancer outcomes observed.

Diagnostic Performance of Magnetic Resonance Imaging for Parathyroid Localization of Primary Hyperparathyroidism: A Systematic Review.

Accurate preoperative localization is crucial for successful minimally invasive parathyroidectomy in primary hyperparathyroidism (PHPT). Preoperative localization can be challenging in patients with recurrent and/or multigland disease (MGD). This has led clinicians to investigate multiple imaging techniques, most of which are associated with radiation exposure. Magnetic resonance imaging (MRI) offers ionizing radiation-free and accurate imaging, making it an attractive alternative imaging modality. The objective of this systematic review is to provide an overview of the diagnostic performance of MRI in the localization of PHPT. PubMed and Embase libraries were searched from 1 January 2000 to 31 March 2023. Studies were included that investigated MRI techniques for the localization of PHPT. The exclusion criteria were (1) secondary/tertiary hyperparathyroidism, (2) studies that provided no diagnostic performance values, (3) studies published before 2000, and (4) studies using 0.5 Tesla MRI scanners. Twenty-four articles were included in the systematic review, with a total of 1127 patients with PHPT. In 14 studies investigating conventional MRI for PHPT localization, sensitivities varied between 39.1% and 94.3%. When employing more advanced MRI protocols like 4D MRI for PHPT localization in 11 studies, sensitivities ranged from 55.6% to 100%. The combination of MR imaging with functional techniques such as 18F-FCH-PET/MRI yielded the highest diagnostic accuracy, with sensitivities ranging from 84.2% to 100% in five studies. Despite the limitations of the available evidence, the results of this review indicate that the combination of MR imaging with functional imaging techniques such as 18F-FCH-PET/MRI yielded the highest diagnostic accuracy. Further research on emerging MR imaging modalities, such as 4D MRI and PET/MRI, is warranted, as MRI exposes patients to minimal or no ionizing radiation compared to other imaging modalities.

Preimplantation genetic testing for Neurofibromatosis type 1: more than 20 years of clinical experience.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects the skin and the nervous system. The condition is completely penetrant with extreme clinical variability, resulting in unpredictable manifestations in affected offspring, complicating reproductive decision-making. One of the reproductive options to prevent the birth of affected offspring is preimplantation genetic testing (PGT). We performed a retrospective review of the medical files of all couples (n = 140) referred to the Dutch PGT expert center with the indication NF1 between January 1997 and January 2020. Of the couples considering PGT, 43 opted out and 15 were not eligible because of failure to identify the underlying genetic defect or unmet criteria for in vitro fertilization (IVF) treatment. The remaining 82 couples proceeded with PGT. Fertility assessment prior to IVF treatment showed a higher percentage of male infertility in males affected with NF1 compared to the partners of affected females. Cardiac evaluations in women with NF1 showed no contraindications for IVF treatment or pregnancy. For 67 couples, 143 PGT cycles were performed. Complications of IVF treatment were not more prevalent in affected females compared to partners of affected males. The transfer of 174 (out of 295) unaffected embryos led to 42 ongoing pregnancies with a pregnancy rate of 24.1% per embryo transfer. There are no documented cases of misdiagnosis following PGT in this cohort. With these results, we aim to provide an overview of PGT for NF1 with regard to success rate and safety, to optimize reproductive counseling and PGT treatment for NF1 patients.

The Association of Gross Tumor Volume and Its Radiomics Features with Brain Metastases Development in Patients with Radically Treated Stage III Non-Small Cell Lung Cancer.

PURPOSE: To identify clinical risk factors, including gross tumor volume (GTV) and radiomics features, for developing brain metastases (BM) in patients with radically treated stage III non-small cell lung cancer (NSCLC). METHODS: Clinical data and planning CT scans for thoracic radiotherapy were retrieved from patients with radically treated stage III NSCLC. Radiomics features were extracted from the GTV, primary lung tumor (GTVp), and involved lymph nodes (GTVn), separately. Competing risk analysis was used to develop models (clinical, radiomics, and combined model). LASSO regression was performed to select radiomics features and train models. Area under the receiver operating characteristic curves (AUC-ROC) and calibration were performed to assess the models' performance. RESULTS: Three-hundred-ten patients were eligible and 52 (16.8%) developed BM. Three clinical variables (age, NSCLC subtype, and GTVn) and five radiomics features from each radiomics model were significantly associated with BM. Radiomic features measuring tumor heterogeneity were the most relevant. The AUCs and calibration curves of the models showed that the GTVn radiomics model had the best performance (AUC: 0.74; 95% CI: 0.71-0.86; sensitivity: 84%; specificity: 61%; positive predictive value [PPV]: 29%; negative predictive value [NPV]: 95%; accuracy: 65%). CONCLUSION: Age, NSCLC subtype, and GTVn were significant risk factors for BM. GTVn radiomics features provided higher predictive value than GTVp and GTV for BM development. GTVp and GTVn should be separated in clinical and research practice.

Prevalence of chromosomal alterations in first-trimester spontaneous pregnancy loss.

Pregnancy loss is often caused by chromosomal abnormalities of the conceptus. The prevalence of these abnormalities and the allocation of (ab)normal cells in embryonic and placental lineages during intrauterine development remain elusive. In this study, we analyzed 1,745 spontaneous pregnancy losses and found that roughly half (50.4%) of the products of conception (POCs) were karyotypically abnormal, with maternal and paternal age independently contributing to the increased genomic aberration rate. We applied genome haplarithmisis to a subset of 94 pregnancy losses with normal parental and POC karyotypes. Genotyping of parental DNA as well as POC extra-embryonic mesoderm and chorionic villi DNA, representing embryonic and trophoblastic tissues, enabled characterization of the genomic landscape of both lineages. Of these pregnancy losses, 35.1% had chromosomal aberrations not previously detected by karyotyping, increasing the rate of aberrations of pregnancy losses to 67.8% by extrapolation. In contrast to viable pregnancies where mosaic chromosomal abnormalities are often restricted to chorionic villi, such as confined placental mosaicism, we found a higher degree of mosaic chromosomal imbalances in extra-embryonic mesoderm rather than chorionic villi. Our results stress the importance of scrutinizing the full allelic architecture of genomic abnormalities in pregnancy loss to improve clinical management and basic research of this devastating condition.

Diagnostic Performance of Electronic Noses in Cancer Diagnoses Using Exhaled Breath: A Systematic Review and Meta-analysis.

Importance: There has been a growing interest in the use of electronic noses (e-noses) in detecting volatile organic compounds in exhaled breath for the diagnosis of cancer. However, no systematic evaluation has been performed of the overall diagnostic accuracy and methodologic challenges of using e-noses for cancer detection in exhaled breath. Objective: To provide an overview of the diagnostic accuracy and methodologic challenges of using e-noses for the detection of cancer. Data Sources: An electronic search was performed in the PubMed and Embase databases (January 1, 2000, to July 1, 2021). Study Selection: Inclusion criteria were the following: (1) use of e-nose technology, (2) detection of cancer, and (3) analysis of exhaled breath. Exclusion criteria were (1) studies published before 2000; (2) studies not performed in humans; (3) studies not performed in adults; (4) studies that only analyzed biofluids; and (5) studies that exclusively used gas chromatography-mass spectrometry to analyze exhaled breath samples. Data Extraction and Synthesis: PRISMA guidelines were used for the identification, screening, eligibility, and selection process. Quality assessment was performed using Quality Assessment of Diagnostic Accuracy Studies 2. Generalized mixed-effects bivariate meta-analysis was performed. Main Outcomes and Measures: Main outcomes were sensitivity, specificity, and mean area under the receiver operating characteristic curve. Results: This review identified 52 articles with a total of 3677 patients with cancer. All studies were feasibility studies. The sensitivity of e-noses ranged from 48.3% to 95.8% and the specificity from 10.0% to 100.0%. Pooled analysis resulted in a mean (SE) area under the receiver operating characteristic curve of 94% (95% CI, 92%-96%), a sensitivity of 90% (95% CI, 88%-92%), and a specificity of 87% (95% CI, 81%-92%). Considerable heterogeneity existed among the studies because of differences in the selection of patients, endogenous and exogenous factors, and collection of exhaled breath. Conclusions and Relevance: Results of this review indicate that e-noses have a high diagnostic accuracy for the detection of cancer in exhaled breath. However, most studies were feasibility studies with small sample sizes, a lack of standardization, and a high risk of bias. The lack of standardization and reproducibility of e-nose research should be addressed in future research.

Coronary Artery Calcifications Are Associated With More Severe Multiorgan Failure in Patients With Severe Coronavirus Disease 2019 Infection: Longitudinal Results of the Maastricht Intensive Care COVID Cohort.

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is regarded as a multisystemic disease. Patients with preexisting cardiovascular disease have an increased risk for a more severe disease course. This study aimed to investigate if a higher degree of coronary artery calcifications (CAC) on a standard chest computed tomography (CT) scan in mechanically ventilated patients was associated with a more severe multiorgan failure over time. MATERIALS AND METHODS: All mechanically ventilated intensive care unit patients with SARS-CoV-2 infection who underwent a chest CT were prospectively included. CT was used to establish the extent of CAC using a semiquantitative grading system. We categorized patients into 3 sex-specific tertiles of CAC: lowest, intermediate, and highest CAC score. Daily, the Sequential Organ Failure Assessment (SOFA) scores were collected to evaluate organ failure over time. Linear mixed-effects regression was used to investigate differences in SOFA scores between tertiles. The models were adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, cardiovascular risk factors, and chronic liver, lung, and renal disease. RESULTS: In all, 71 patients were included. Patients in the highest CAC tertile had, on average, over time, 1.8 (0.5-3.1) points higher SOFA score, compared with the lowest CAC tertile ( P =0.005). This association remained significant after adjustment for age, sex, and APACHE II score (1.4 [0.1-2.7], P =0.042) and clinically relevant after adjustment for cardiovascular risk factors (1.3 [0.0-2.7], P =0.06) and chronic diseases (1.3 [-0.2 to 2.7], P =0.085). CONCLUSION: A greater extent of CAC is associated with a more severe multiorgan failure in mechanically ventilated coronavirus disease 2019 patients.

Laparoscopic versus open resections in the posterosuperior liver segments within an enhanced recovery programme (ORANGE Segments): study protocol for a multicentre randomised controlled trial.

BACKGROUND: A shift towards parenchymal-sparing liver resections in open and laparoscopic surgery emerged in the last few years. Laparoscopic liver resection is technically feasible and safe, and consensus guidelines acknowledge the laparoscopic approach in the posterosuperior segments. Lesions situated in these segments are considered the most challenging for the laparoscopic approach. The aim of this trial is to compare the postoperative time to functional recovery, complications, oncological safety, quality of life, survival and costs after laparoscopic versus open parenchymal-sparing liver resections in the posterosuperior liver segments within an enhanced recovery setting. METHODS: The ORANGE Segments trial is an international multicentre randomised controlled superiority trial conducted in centres experienced in laparoscopic liver resection. Eligible patients for minor resections in the posterosuperior segments will be randomised in a 1:1 ratio to undergo laparoscopic or open resections in an enhanced recovery setting. Patients and ward personnel are blinded to the treatment allocation until postoperative day 4 using a large abdominal dressing. The primary endpoint is time to functional recovery. Secondary endpoints include intraoperative outcomes, length of stay, resection margin, postoperative complications, 90-day mortality, time to adjuvant chemotherapy initiation, quality of life and overall survival. Laparoscopic liver surgery of the posterosuperior segments is hypothesised to reduce time to functional recovery by 2 days in comparison with open surgery. With a power of 80% and alpha of 0.04 to adjust for interim analysis halfway the trial, a total of 250 patients are required to be randomised. DISCUSSION: The ORANGE Segments trial is the first multicentre international randomised controlled study to compare short- and long-term surgical and oncological outcomes of laparoscopic and open resections in the posterosuperior segments within an enhanced recovery programme. TRIAL REGISTRATION: ClinicalTrials.gov NCT03270917 . Registered on September 1, 2017. Before start of inclusion. PROTOCOL VERSION: version 12, May 9, 2017.

Parental lifespan and the likelihood of reaching the age of 90 years in the Netherlands Cohort Study.

AIM: Growing evidence suggests an association between parental longevity and lifespan of subsequent generations. We aimed to reproduce earlier findings, showing a positive association between parental longevity and offspring's longevity. Additionally, we investigated whether this is mainly driven by the maternal or paternal germline in male and female offspring. METHODS: For these analyses, data from the oldest birth cohort (1916-17) of the Netherlands Cohort Study was used. Participants filled in a baseline questionnaire in 1986 (at age 68-70 years). Follow up for vital status information until the age of 90 years (2006-07) was >99.9% complete. Multivariable-adjusted Cox regression analyses with a fixed follow-up time were based on 2368 men and 2657 women with complete parental survival data and relevant confounders to calculate risk ratios (RR) of reaching longevity. RESULTS: In age-adjusted models, paternal and maternal age at death were significantly positively associated with reaching 90 years in both male and female offspring. In male offspring, paternal age at death (≥90 years vs <80 years) showed the strongest association with survival to 90 years (RR 1.42, 95% CI 1.07-1.89), after confounder correction. In female offspring, maternal age at death (≥90 years vs <80 years) showed the strongest association with survival to 90 years (RR 1.20, 95% CI 1.04-1.40). DISCUSSION: After confounder adjustment, stronger and significant associations were observed between paternal lifespan and male offspring longevity, and maternal lifespan and female offspring longevity. Future research should investigate through which pathways a longer lifespan of parents is transmitted to their offspring. Geriatr Gerontol Int 2021; 21: 215-221.