Search

Importance: Metformin and glyburide monotherapy are used as alternatives to insulin in managing gestational diabetes. Whether a sequential strategy of these oral agents results in noninferior perinatal outcomes compared with insulin alone is unknown., Objective: To test whether a treatment strategy of oral glucose-lowering agents is noninferior to insulin for prevention of large-for-gestational-age infants., Design, Setting, and Participants: Randomized, open-label noninferiority trial conducted at 25 Dutch centers from June 2016 to November 2022 with follow-up completed in May 2023. The study enrolled 820 individuals with gestational diabetes and singleton pregnancies between 16 and 34 weeks of gestation who had insufficient glycemic control after 2 weeks of dietary changes (defined as fasting glucose >95 mg/dL [>5.3 mmol/L], 1-hour postprandial glucose >140 mg/dL [>7.8 mmol/L], or 2-hour postprandial glucose >120 mg/dL [>6.7 mmol/L], measured by capillary glucose self-testing)., Interventions: Participants were randomly assigned to receive metformin (initiated at a dose of 500 mg once daily and increased every 3 days to 1000 mg twice daily or highest level tolerated; n = 409) or insulin (prescribed according to local practice; n = 411). Glyburide was added to metformin, and then insulin substituted for glyburide, if needed, to achieve glucose targets., Main Outcomes and Measures: The primary outcome was the between-group difference in the percentage of infants born large for gestational age (birth weight >90th percentile based on gestational age and sex). Secondary outcomes included maternal hypoglycemia, cesarean delivery, pregnancy-induced hypertension, preeclampsia, maternal weight gain, preterm delivery, birth injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admission., Results: Among 820 participants, the mean age was 33.2 (SD, 4.7) years). In participants randomized to oral agents, 79% (n = 320) maintained glycemic control without insulin. With oral agents, 23.9% of infants (n = 97) were large for gestational age vs 19.9% (n = 79) with insulin (absolute risk difference, 4.0%; 95% CI, -1.7% to 9.8%; P = .09 for noninferiority), with the confidence interval of the risk difference exceeding the absolute noninferiority margin of 8%. Maternal hypoglycemia was reported in 20.9% with oral glucose-lowering agents and 10.9% with insulin (absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%). All other secondary outcomes did not differ between groups., Conclusions and Relevance: Treatment of gestational diabetes with metformin and additional glyburide, if needed, did not meet criteria for noninferiority compared with insulin with respect to the proportion of infants born large for gestational age., Trial Registration: Netherlands Trial Registry Identifier: NTR6134.

Background and Purpose: To diagnose Lyme neuroborreliosis (LNB), cerebrospinal fluid (CSF) is tested for pleocytosis and intrathecal antibody production. The Dutch guideline for Lyme borreliosis indicates a lumbar puncture in the case of positive Borrelia serology or a strong clinical suspicion of LNB. This suggests that LNB might be underdiagnosed in patients with negative Borrelia serology and/or a minor clinical suspicion. The objective was to assess how often negative Borrelia serology occurs in the case of LNB., Method: A retrospective study was performed among patients with LNB visiting Gelre Hospitals between January 2007 and December 2020. Electronic medical records of patients with pleocytosis were reviewed to identify patients with LNB. Data were collected from medical records., Results: Included were 127 patients with LNB, 58 of whom were children. In 67 patients Borrelia antibodies were present in both serum and CSF. In 53 of 67 patients there was intrathecal antibody production. In 28 patients there was intrathecal antibody production but serum antibodies were absent. Of patients with positive serology 77% had antibodies in CSF versus 83% of patients with negative serology (p = 0.435). Of patients with positive serology 61% had intrathecal antibody production versus 78% of patients with negative serology (p = 0.073)., Conclusions: Twenty-eight LNB patients had intrathecal antibody production but no antibodies in serum. In this specific patient population, positive serum serology was not associated with antibodies in CSF nor with intrathecal antibody production. In Lyme endemic areas, in patients with symptoms suggestive for LNB, there is a need to lower the threshold for a lumbar puncture., (© 2022 European Academy of Neurology.)

Lyme neuroborreliosis (LNB) is a tick-borne infection caused by Borrelia burgdorferi which can affect the nervous system in adults and children. The clinical course of LNB in adults is often different than in children. Studies comparing these differences are scarce. The aim of this study was to compare the clinical characteristics and outcome of LNB between children and adults. We performed an observational retrospective study among patients with LNB who presented at Gelre Hospital from 2007 to 2020 and had cerebrospinal fluid pleocytosis. Data were collected from electronic medical records. A total of 127 patients with LNB were identified. Included were 58 children (median age 8 years) and 69 adults (median age 56 years). The incidence of LNB was 3.2 per 100,000 inhabitants per year. The most common neurological manifestation in adults and in children was facial nerve palsy (67%). Unilateral facial nerve palsy was more prevalent in children (85%) than in adults (42%) (P < 0.001). Headache was also more prevalent in children (59%) than in adults (32%) (P = 0.003). (Poly)radiculitis was more prevalent in adults (51%) than in children (3%) (P < 0.001), encephalitis was not reported in children. In children, the time between symptom onset and diagnosis was 10 days versus 28 days in adults (P < 0.001). Complete recovery was reported significantly more often in children (83%) compared to adults (40%) (P < 0.001).    Conclusion: In a Lyme-endemic area in the Netherlands, LNB commonly presents with facial nerve palsy. Facial nerve palsy and headache are more prevalent in children, while radiculitis and encephalitis are mostly reported in adults. What is Known: • The clinical course of Lyme neuroborreliosis in adults is often different from children. . • The aim of this study was to compare the clinical characteristics and outcome of LNB between children and adults. What is New: • Lyme neuroborreliosis in the Netherlands commonly presents with facial nerve palsy. • Facial nerve palsy and headache are more prevalent in children than in adults. Radiculitis and encephalitis are mostly reported in adults., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Few studies evaluated the performance of noninvasive diagnostic strategies for suspected acute pulmonary embolism (PE) in pregnant women., Objectives: The aim of this study was to establish the safety and efficiency of the Wells rule with fixed and adapted D-dimer threshold, and the YEARS algorithm, combined with compression ultrasonography (CUS), in pregnant women with suspected PE in an individual patient data meta-analysis., Methods: We performed a systematic review to identify prospective diagnostic management studies in pregnant women with suspected PE. Primary outcomes were safety, defined as the failure rate, ie, the 3-month venous thromboembolism (VTE) incidence after excluding PE without chest imaging, and efficiency, defined as the proportion of patients in whom chest imaging could be avoided., Results: We identified 2 relevant studies, of which individual patient-level data were analyzed in a fixed-effect meta-analysis, totaling 893 pregnant women. The Wells rule with fixed and adapted D-dimer threshold as well as the YEARS algorithm could safely rule out acute PE (failure rate, 0·37%-1·4%), but efficiency improved considerably when applying pretest probability-adapted D-dimer thresholds. The efficiency of bilateral CUS was limited (2·3% overall; number needed to test 43), especially in patients without symptoms of deep-vein thrombosis (efficiency 0·79%; number needed to test 127)., Conclusion: This study supports the latest guideline recommendations (European Society of Cardiology 2019) to apply pretest probability assessment and D-dimer tests to rule out PE in pregnant women. From an efficiency perspective, the use of a strategy with pretest probability-adapted D-dimer threshold is preferred. The yield of CUS was very limited in patients without concomitant symptoms of deep-vein thrombosis., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Introduction: Little is known on coping strategies in patients with chronic symptoms suspected of Lyme borreliosis (LB). Different coping strategies might influence quality of life (QoL). We assessed coping strategies and QoL in patients with chronic symptoms suspected of LB., Methods: Adult patients referred to the Lyme Center Apeldoorn were included (November 2019-April 2021). Participants completed the RAND-36 to assess QoL and the Utrecht Coping List to assess coping strategies. Patient data were extracted from medical records. Patients were categorized based on clinical LB and serology. Linear regression analyses were conducted to examine an association between coping strategies and QoL subscales., Results: Included were 201 patients. Patients suspected of LB had a different coping profile and lower QoL compared to the reference population. Patients with negative serology and no clinical LB scored lowest on all QoL subscales. In multivariate analyses, correcting for age, gender, comorbidity, and patient category, a negative association was found between passive coping and the QoL subscales physical functioning (β(SE) = - 1.1(0.5)), social functioning (β(SE) = - 3.3(0.5)), role limitations (emotional) (β(SE) = - 5.5(0.8)), mental health (β(SE) = - 3.7(0.3)), vitality (β(SE) = - 2.3(0.3)), pain (β(SE) = - 2.3(0.5)), and general health (β(SE) = - 2.7(0.3)). A negative association was also found between palliative coping and the QoL subscale role limitations (physical) (β(SE) = - 1.8(0.6)) and between expressing emotions and mental health (β(SE) = - 1.3(0.6)). A positive association was found between active coping and the QoL subscales mental health (β(SE) = 1.0(0.3)) and role limitations (emotional) (β(SE) = 1.9(0.8))., Conclusion: In patients suspected of LB, dysfunctional coping strategies were associated with worse quality of life. There is a need for interventions that can guide patients with chronic symptoms suspected of LB towards more active coping and increase QoL., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Venous thromboembolism constitutes substantial health care costs amounting to approximately 60 million euros per year in the Netherlands. Compared with initial hospitalization, home treatment of pulmonary embolism (PE) is associated with a cost reduction. An accurate estimation of cost savings per patient treated at home is currently lacking., Aim: The aim of this study was to compare health care utilization and costs during the first 3 months after a PE diagnosis in patients who are treated at home versus those who are initially hospitalized., Methods: Patient-level data of the YEARS cohort study, including 383 normotensive patients diagnosed with PE, were used to estimate the proportion of patients treated at home, mean hospitalization duration in those who were hospitalized, and rates of PE-related readmissions and complications. To correct for baseline differences within the two groups, regression analyses was performed. The primary outcome was the average total health care costs during a 3-month follow-up period for patients initially treated at home or in hospital., Results: Mean hospitalization duration for the initial treatment was 0.69 days for those treated initially at home ( n  = 181) and 4.3 days for those initially treated in hospital ( n  = 202). Total average costs per hospitalized patient were €3,209 and €1,512 per patient treated at home. The adjusted mean difference was €1,483 (95% confidence interval: €1,181-1,784)., Conclusion: Home treatment of hemodynamically stable patients with acute PE was associated with an estimated net cost reduction of €1,483 per patient. This difference underlines the advantage of triage-based home treatment of these patients., Competing Interests: F.K. reports research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo, MSD, Actelion, the Dutch Heart Foundation, and the Netherlands Thrombosis Foundation, outside the submitted work. M.H. reports grants from ZonMW Dutch Healthcare Fund, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Pfizer-BMS, grants and personal fees from Bayer Health Care, grants from Aspen, and grants and personal fees from Daiichi-Sankyo, outside the submitted work., (Thieme. All rights reserved.)

Background  Diagnostic strategies for suspected pulmonary embolism (PE) have not been prospectively evaluated in COVID-19 patients. Methods  Prospective, multicenter, outcome study in 707 patients with both (suspected) COVID-19 and suspected PE in 14 hospitals. Patients on chronic anticoagulant therapy were excluded. Informed consent was obtained by opt-out approach. Patients were managed by validated diagnostic strategies for suspected PE. We evaluated the safety (3-month failure rate) and efficiency (number of computed tomography pulmonary angiographies [CTPAs] avoided) of the applied strategies. Results  Overall PE prevalence was 28%. YEARS was applied in 36%, Wells rule in 4.2%, and "CTPA only" in 52%; 7.4% was not tested because of hemodynamic or respiratory instability. Within YEARS, PE was considered excluded without CTPA in 29%, of which one patient developed nonfatal PE during follow-up (failure rate 1.4%, 95% CI 0.04-7.8). One-hundred seventeen patients (46%) managed according to YEARS had a negative CTPA, of whom 10 were diagnosed with nonfatal venous thromboembolism (VTE) during follow-up (failure rate 8.8%, 95% CI 4.3-16). In patients managed by CTPA only, 66% had an initial negative CTPA, of whom eight patients were diagnosed with a nonfatal VTE during follow-up (failure rate 3.6%, 95% CI 1.6-7.0). Conclusion  Our results underline the applicability of YEARS in (suspected) COVID-19 patients with suspected PE. CTPA could be avoided in 29% of patients managed by YEARS, with a low failure rate. The failure rate after a negative CTPA, used as a sole test or within YEARS, was non-negligible and reflects the high thrombotic risk in these patients, warranting ongoing vigilance., Competing Interests: Conflict of Interest Frederikus Klok reports research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, Daiichi-Sankyo, Actelion, the Dutch thrombosis association, The Netherlands Organization for Health Research and Development and the Dutch Heart foundation. Menno Huisman reports receiving research grants from ZonMW, Boehringer Ingelheim, Bayer Health Care and Pfizer-Bristol-Myers Squibb. He has received consultancy and lecture fees from Pfizer-Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Health Care and Aspen. The other authors have nothing to disclose., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Nonspecific symptoms in children suspected of Lyme borreliosis (LB) are challenging for clinicians. We assessed whether nonspecific symptoms are more prevalent among children with positive immunoglobulin G (IgG) serology or a history of clinical LB., Methods: We included children (<18 years) suspected of LB who visited the Lyme Center Apeldoorn of Gelre Hospital between 2008 and 2017. Serum samples were taken, and questionnaires on nonspecific symptoms completed. Clinical data were collected from patients' medical records. The prevalence of nonspecific symptoms was compared between patients with positive versus negative IgG serology and between patients with versus without previous LB with the χ and Fisher exact tests with Bonferroni correction. A history of LB was anamnestically determined. Patients with active Lyme manifestations were excluded., Results: Included were 149 children (66% female; median age 13 years); 29 (19%) had positive IgG serology; 36 (24%) had previous LB; 12 (8%) had both. Common nonspecific symptoms were sleep disturbances (58%), severe fatigue (57%) and headache (42%). The prevalence of nonspecific symptoms was similar in children with positive versus negative IgG serology. None of the nonspecific symptoms occurred more frequently in children with previous LB compared with children without. More prevalent in children without previous LB were sleep disturbances (40 vs. 66%; P = 0.002) and tingling (6 vs. 34%; P < 0.001)., Conclusions: Nonspecific symptoms were not more prevalent in children with positive IgG serology nor in children with previous LB, where some were significantly less prevalent. Hence, questionnaires on nonspecific symptoms cannot be used to identify children for serologic testing in Lyme centers.

Background: Studies have shown the safety of home treatment of patients with pulmonary embolism (PE) at low risk of adverse events. Management studies focusing on home treatment have suggested that 30% to 55% of acute PE patients could be treated at home, based on the HESTIA criteria, but data from day-to-day clinical practice are largely unavailable., Aim: To determine current practice patterns of home treatment of acute PE in the Netherlands., Method: We performed a post-hoc analysis of the YEARS study. The main outcomes were the proportion of patients who were discharged <24 h and reasons for admission if treated in hospital. Further, we compared the 3-month incidence of PE-related unscheduled readmissions between patients treated at home and in hospital., Results: Of the 404 outpatients with PE included in this post-hoc analysis of the YEARS study, 184 (46%) were treated at home. The median duration of admission of the hospitalized patients was 3.0 days. The rate of PE-related readmissions of patients treated at home was 9.7% versus 8.6% for hospitalized patients (crude hazard ratio 1.1 (95% CI 0.57-2.1)). The 3-month incidence of any adverse event was 3.8% in those treated at home (2 recurrent VTE, 3 major bleedings and two deaths) compared to 10% in the hospitalized patients (3 recurrent VTE, 6 major bleedings and fourteen deaths)., Conclusions: In the YEARS study, 46% of patients with PE were treated at home with low incidence of adverse events. PE-related readmission rates were not different between patients treated at home or in hospital., Competing Interests: Disclosures Frederikus Klok reports research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo, MSD and Actelion, the Dutch Heart foundation and the Netherlands Thrombosis Foundation, outside the submitted work. Menno Huisman reports grants from ZonMW Dutch Healthcare Fund, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Pfizer-BMS, grants and personal fees from Bayer Health Care, grants from Aspen, grants and personal fees from Daiichi-Sankyo, outside the submitted work. Marieke Kruip reports research grants from ZonMW Dutch Healthcare Fund, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Pfizer and personal fees from Bayer, outside the submitted work. Dr. Middeldorp reports grants and personal fees from Aspen, grants and personal fees from Daiichi Sankyo, grants and personal fees from Bayer, personal fees from BMS-Pfizer, personal fees from Boehringer-Ingelheim, personal fees from Portola, personal fees from Sanofi, outside the submitted work. All other authors have no disclosures., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM., Methods: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle., Ethics and Dissemination: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NTR6134; Pre-results., Competing Interests: Competing interests: JHD sits on advisory boards for Novo Nordisk A/S. BWM is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). BWM reports consultancy for ObsEva, Merck KGaA and Guerbet., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pulmonary embolism is one of the leading causes of maternal death in the Western world. Because of the low specificity and sensitivity of the d-dimer test, all pregnant women with suspected pulmonary embolism undergo computed tomographic (CT) pulmonary angiography or ventilation-perfusion scanning, both of which involve radiation exposure to the mother and fetus. Whether a pregnancy-adapted algorithm could be used to safely avoid diagnostic imaging in pregnant women with suspected pulmonary embolism is unknown., Methods: In a prospective study involving pregnant women with suspected pulmonary embolism, we assessed three criteria from the YEARS algorithm (clinical signs of deep-vein thrombosis, hemoptysis, and pulmonary embolism as the most likely diagnosis) and measured the d-dimer level. Pulmonary embolism was ruled out if none of the three criteria were met and the d-dimer level was less than 1000 ng per milliliter or if one or more of the three criteria were met and the d-dimer level was less than 500 ng per milliliter. Adaptation of the YEARS algorithm for pregnant women involved compression ultrasonography for women with symptoms of deep-vein thrombosis; if the results were positive (i.e., a clot was present), CT pulmonary angiography was not performed. All patients in whom pulmonary embolism had not been ruled out underwent CT pulmonary angiography. The primary outcome was the incidence of venous thromboembolism at 3 months. The secondary outcome was the proportion of patients in whom CT pulmonary angiography was not indicated to safely rule out pulmonary embolism., Results: A total of 510 women were screened, of whom 12 (2.4%) were excluded. Pulmonary embolism was diagnosed in 20 patients (4.0%) at baseline. During follow-up, popliteal deep-vein thrombosis was diagnosed in 1 patient (0.21%; 95% confidence interval [CI], 0.04 to 1.2); no patient had pulmonary embolism. CT pulmonary angiography was not indicated, and thus was avoided, in 195 patients (39%; 95% CI, 35 to 44). The efficiency of the algorithm was highest during the first trimester of pregnancy and lowest during the third trimester; CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester and in 32% who began the study in the third trimester., Conclusions: Pulmonary embolism was safely ruled out by the pregnancy-adapted YEARS diagnostic algorithm across all trimesters of pregnancy. CT pulmonary angiography was avoided in 32 to 65% of patients. (Funded by Leiden University Medical Center and 17 other participating hospitals; Artemis Netherlands Trial Register number, NL5726.)., (Copyright © 2019 Massachusetts Medical Society.)

Objectives: There is controversy whether non-specific symptoms can be related to previous Lyme borreliosis (LB). Positive serology can be considered a proxy for previous or persistent LB. We assessed non-specific symptoms and serology in patients suspected of LB referred to a Lyme centre., Methods: Included were adult patients who visited a Lyme centre between 2008 and 2014. Before medical consultation, serum samples were taken and questionnaires on non-specific symptoms completed. The prevalence of non-specific symptoms was calculated for patients with positive and negative IgG serology. Logistic regression was used to obtain odds ratios (ORs) with 95% confidence interval (CI) for an association between positive serology and non-specific symptoms., Results: Of 1439 included patients, 31.6% (455/1439) had positive serology. The most common non-specific symptoms were severe fatigue (61.4%, 883/1439), sleep disturbances (54.8%, 789/1439) and stiffness of neck/back (52.6%, 757/1439). The prevalence of severe fatigue was 53.0% (241/455) in patients with positive serology vs. 65.2% (642/984) in patients with negative serology (OR = 0.74; 95% CI, 0.58-0.94). The prevalence of sleep disturbances was respectively 46.2% (210/455) vs. 58.8% (579/984) (OR = 0.73; 95% CI, 0.58-0.93). The prevalence of stiffness of neck/back was respectively 47.7% (217/455) vs. 54.9% (540/984) (OR = 0.85; 95% CI, 0.67-1.06)., Conclusions: In patients referred to a Lyme centre, non-specific symptoms did not occur more frequently in patients with positive serology compared to patients with negative serology. Hence, a questionnaire on non-specific symptoms cannot be used for identifying patients with possible post-LB symptoms in clinical practice., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Making a distinction between facial palsy due to Lyme neuroborreliosis (LNB) and idiopathic facial palsy (IFP) is of importance to ensure timely and adequate treatment. The study objective was to assess incidence and patient characteristics of facial palsy due to LNB. Hospital records were reviewed of adult patients with facial palsy visiting the departments of neurology and/or otorhinolaryngology of Gelre hospitals between June 2007 and December 2017. Gelre hospitals are located in an area endemic for Lyme borreliosis. Patients with LNB had pleocytosis and intrathecal antibody production or pleocytosis with positive IgG serology. Patients with IFP had negative serology. Clinical characteristics were compared between patients with LNB and patients with IFP. Five hundred and fifty-nine patients presented with facial palsy, 4.7% (26) had LNB and 39.4% (220) IFP. The incidence of facial palsy due to LNB was 0.9/100 000 inhabitants/year. Over 70% of patients with facial palsy due to LNB did not report a recent tick bite and/or erythema migrans (EM). Patients with facial palsy due to LNB presented more often in July to September (69.2% vs. 21.9%, P &lt; 0.001), and had more often headache (42.3% vs. 15.5%, P &lt; 0.01). To reduce the risk of underdiagnosing LNB in an endemic area, we recommend testing for LNB in patients with facial palsy in summer months especially when presenting with headache, irrespective of a recent tick bite and/or EM.

Objective: Here we describe a rare case of systemic sarcoidosis in a healthy young man with neuroborreliosis as a putative trigger., Case: A 21-year-old forestry worker was diagnosed with systemic sarcoidosis involving his lungs, kidneys and skin. Additional diagnostics revealed signs indicative of a recent infection with Borrelia burgdorferi . The patient was treated successfully with prednisolone and antibiotics., Conclusion: Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology. This case suggests that an infection with B. burgdorferi , the causal agent of Lyme disease, could act as a trigger for sarcoidosis., Learning Point: We should maintain a high index of suspicion for underlying infectious processes like neuroborreliosis in patients with new-onset sarcoidosis before starting immunosuppressive regimens., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests.

Background: People with severe mental illness (SMI) show significantly shorter life expectancy, mostly due to more prevalent cardiovascular disease. Although age is a prominent contributor to contemporary risk assessment and SMI usually affects younger people, these assessments still do not reveal the actual risk. By assessing advanced glycation end products (AGEs), cardiovascular risk can be assessed independent of age., Aims: To establish whether detection of AGEs with the AGE-reader will give a more accurate cardiovascular risk assessment in people with SMI., Method: We compared assessment with the AGE-reader with that of the Systematic Coronary Risk Evaluation (SCORE) table in a group of 120 patients with SMI., Results: The AGE-reader showed an increased cardiovascular risk more often than the SCORE table, especially in the youngest group., Conclusions: Because of its ease of use and substantiation by studies done on other chronic diseases, we advocate use of the AGE-reader in daily care for patients with SMI to detect cardiovascular risk as early as possible. However, the findings of the current study should be evaluated with caution and should be seen as preliminary findings that require confirmation by a prospective longitudinal cohort study with a substantial follow-up observation period., Declaration of Interest: None.

A two-step testing strategy is recommended in serological testing for Lyme borreliosis; positive and indeterminate enzyme-linked immunosorbent assay (ELISA) results are confirmed with immunoblots. Several ELISAs quantify the concentration of antibodies tested, however, no recommendation exists for an upper cut-off value at which an IgG ELISA is sufficient and the immunoblot can be omitted. The study objective was to determine at which IgG antibody level an immunoblot does not have any additional predictive value compared to ELISA results. Data of adult patients who visited a tertiary Lyme centre between 2008 and 2014 were analysed. Both an ELISA (Enzygnost Lyme link VlsE IgG) and immunoblot (recomLine blot Borrelia) were performed. Clinical data were extracted from the patient's digital medical record. Positive predictive values (PPVs) for either previous or active infection with Borrelia burgdorferi s.l. were calculated for different cut-off ELISA IgG antibody levels where the immunoblot was regarded as reference test. In total, 1454 patients were included. According to the two-step test strategy, 486 (33%), 69 (5%) and 899 (62%) patients had positive, indeterminate and negative Borrelia IgG serology, respectively. At IgG levels of 500 IU/ml and higher, all immunoblots were positive, resulting in a 100% PPV (95% CI: 97.0-100). At IgG levels of 200 IU/ml and higher, the PPV was 99.3% (95% CI: 97.4-99.8). In conclusion, at IgG levels of 200 IU/ml and higher, an ELISA was sufficient to detect antibodies to Borrelia burgdorferi s.l. At those IgG levels, a confirmatory immunoblot may be omitted in patients referred to a tertiary Lyme centre. Before these results can be implemented in routine diagnosis of Lyme borreliosis, confirmation of the results is necessary in other patient populations and using other quantitative ELISAs and immunoblots., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background: Controversy exists whether mood disorders, such as depression, are associated with Lyme borreliosis (LB). The study objective was to assess prevalence of depressive symptoms in subgroups of patients referred to a tertiary Lyme center, to investigate whether depressive symptoms can be used in clinical practice to discriminate for LB., Methods: This cohort study included adult patients who visited a tertiary Lyme center between January 2008 and December 2014. Prior to medical consultation, serum samples were taken and the Beck Depression Inventory II was completed to assess depressive symptoms. Lyme diagnosis was retrospectively extracted from the patient's medical record. Patients were classified based on clinical LB and serology results. Prevalence of moderate/severe depressive symptoms was calculated. Using logistic regression, odds ratios with 95% confidence intervals (CIs) were calculated for moderate/severe depressive symptoms., Results: In total, 1454 patients were included. Prevalence of moderate/severe depressive symptoms was lowest in patients with no clinical LB and positive serology (15.3%), higher in patients with clinical LB with positive and negative serology (19.3% and 20.9% respectively), and highest in patients with no clinical LB and negative serology (29.3%). The odds ratio for moderate/severe depressive symptoms in patients with LB and positive serology was 0.71 (95% CI, .50-1.03) compared to patients with no LB and negative serology., Conclusions: The prevalence of depressive symptoms was similar in patients with LB compared to patients with no evidence of infection. This suggests that depressive symptoms cannot be used to discriminate for LB in a tertiary Lyme center., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Validated diagnostic algorithms in patients with suspected pulmonary embolism are often not used correctly or only benefit subgroups of patients, leading to overuse of computed tomography pulmonary angiography (CTPA). The YEARS clinical decision rule that incorporates differential D-dimer cutoff values at presentation, has been developed to be fast, to be compatible with clinical practice, and to reduce the number of CTPA investigations in all age groups. We aimed to prospectively evaluate this novel and simplified diagnostic algorithm for suspected acute pulmonary embolism., Methods: We did a prospective, multicentre, cohort study in 12 hospitals in the Netherlands, including consecutive patients with suspected pulmonary embolism between Oct 5, 2013, to July 9, 2015. Patients were managed by simultaneous assessment of the YEARS clinical decision rule, consisting of three items (clinical signs of deep vein thrombosis, haemoptysis, and whether pulmonary embolism is the most likely diagnosis), and D-dimer concentrations. In patients without YEARS items and D-dimer less than 1000 ng/mL, or in patients with one or more YEARS items and D-dimer less than 500 ng/mL, pulmonary embolism was considered excluded. All other patients had CTPA. The primary outcome was the number of independently adjudicated events of venous thromboembolism during 3 months of follow-up after pulmonary embolism was excluded, and the secondary outcome was the number of required CTPA compared with the Wells' diagnostic algorithm. For the primary outcome regarding the safety of the diagnostic strategy, we used a per-protocol approach. For the secondary outcome regarding the efficiency of the diagnostic strategy, we used an intention-to-diagnose approach. This trial is registered with the Netherlands Trial Registry, number NTR4193., Findings: 3616 consecutive patients with clinically suspected pulmonary embolism were screened, of whom 151 (4%) were excluded. The remaining 3465 patients were assessed of whom 456 (13%) were diagnosed with pulmonary embolism at baseline. Of the 2946 patients (85%) in whom pulmonary embolism was ruled out at baseline and remained untreated, 18 patients were diagnosed with symptomatic venous thromboembolism during 3-month follow-up (0·61%, 95% CI 0·36-0·96) of whom six had fatal pulmonary embolism (0·20%, 0·07-0·44). CTPA was not indicated in 1651 (48%) patients with the YEARS algorithm compared with 1174 (34%) patients, if Wells' rule and fixed D-dimer threshold of less than 500 ng/mL would have been applied, a difference of 14% (95% CI 12-16)., Interpretation: In our study pulmonary embolism was safely excluded by the YEARS diagnostic algorithm in patients with suspected pulmonary embolism. The main advantage of the YEARS algorithm in our patients is the absolute 14% decrease of CTPA examinations in all ages and across several relevant subgroups., Funding: This study was supported by unrestricted grants from the participating hospitals., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aims: Present-day screening of the diabetic foot involves the Semmes Weinstein Monofilament Test for evaluating loss of sensibility, while testing for intrinsic muscle weakness is not implied. Just as with the early detection of sensibility loss, early detection of intrinsic muscle weakness might have important implications for the prevention of both ulceration and deformity in patients with diabetes. The purpose of this study is to investigate the prevalence of patients with diabetes presenting intrinsic muscle weakness of the hallux, but with a normal sensibility of the sole of the foot., Methods: A cross-sectional study design was applied. Intrinsic muscle function of the hallux was measured with the Paper Grip Test, while sensibility of the sole of the foot was measured with the Semmes Weinstein Monofilament Test 5.07/10-g., Results: In a period of three months a total of 266 patients with diabetes (mean age 60, 134 females (50%), 177 type 2 diabetes mellitus (67%)) met the inclusion criteria and were examined for both intrinsic muscle weakness of the hallux and sensibility of the soles of the feet. The results showed that intrinsic muscle weakness was present more frequent in patients with impaired sensibility (P=0.001), also 20% of the population had intrinsic muscle weakness in the presence of normal sensibility. Multivariate regression analysis showed that only age is associated with patients with diabetes presenting normal sensibility but impaired intrinsic muscle function (P=0.017)., Conclusions: The Paper Grip Test could have added value to current physical examination of the feet in patients with diabetes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Data on the prevalence of valvular heart disease in very old individuals are scarce and based mostly on in-hospital series. In addition, the potential detrimental effect of valvular heart disease on the activities of daily living is unknown. The present study evaluated the prevalence of significant valvular heart disease and the impact of valvular heart disease on the activities of daily living in community dwelling nonagenarians. Nested within the Leiden 85-plus study, a population based follow-up study of the oldest old, a sample of 81 nonagenarians was recruited., Methods: The left ventricular (LV) dimensions, function and the presence and severity of heart valvular disease were evaluated by echocardiography. Significant valvular heart disease included any mitral or aortic stenosis severity, moderate or severe mitral regurgitation, moderate or severe aortic regurgitation and moderate or severe tricuspid regurgitation. Activities of daily living were assessed using the Groningen Activity Restriction Scale (GARS)., Results: LV cavity diameters (end-diastolic diameter 47 +/- 8 mm, end-systolic diameter 30 +/- 8 mm) and systolic LV function (LV ejection fraction 66 +/- 13%) were within normal for the majority of the participants. Significant valvular disease was present in 57 (70%) individuals, with mitral regurgitation and aortic regurgitation as the most frequent valve diseases (49% and 28% respectively). The GARS score between individuals with and without significant valvular heart disease was similar (36.2 +/- 9.2 vs. 34.4 +/- 13.2, p = 0.5)., Conclusions: Nonagenarian, outpatient individuals have a high prevalence of significant valvular heart disease. However, no relation was observed between the presence of significant valvular heart disease and the ability to perform activities of daily living.

Objectives: To determine the prospective relationship between blood pressure (BP) and cognitive function across a wide age range., Design: Prospective population-based cohort study., Setting: The Rotterdam Study and the Leiden 85-plus Study., Participants: Three thousand seventy-eight men and women, initial age 55 to 84 from the Rotterdam Study and 276 men and women, initial age 85, from the Leiden 85-plus Study., Measurements: Systolic BP (SBP) and diastolic BP (DBP) were measured at baseline, cognitive function was assessed at the end of follow-up using a dedicated neuropsychological test battery. The association between baseline BP levels and cognitive function later in life was assessed in 10-year age groups in the Rotterdam Study and in 85-year-olds of the Leiden 85-plus Study., Results: In the youngest participants (<65), SBP and DBP were not associated with cognitive function 11 years later. For persons aged 65 to 74, higher baseline SBP and DBP were related to worse cognitive function 11 years later. In contrast, in older age (> or = 75), higher SBP and DBP seemed to be related to better cognitive function at the end of follow-up. This effect appeared strongest in the highest age group (aged 85)., Conclusion: High BP was associated with greater risk of cognitive impairment in persons younger than 75 but with better cognitive function in older persons. Age-specific guidelines for BP management are needed, because the current directive that "lower is better" may not apply to BP levels in the very old.

Low blood pressure in the very old has been associated with organ dysfunction and excess mortality but the underlying mechanism has yet to be elucidated. We hypothesized that cardiac dysfunction contributes to low blood pressure in the very old. We invited a convenience sample consisting of 82 participants all aged 90 years from a population-based cohort study in the very old. Blood pressure was measured twice, and all but one underwent echocardiography to assess cardiac dimensions and functional cardiac parameters. Some 47 participants were free from haemodynamically significant valvular disease and were included in the present analyses. There were low values for mean cardiac output (2.04 l(-1) min(-1) m(-2), s.e. 0.40) and mean stroke volume (31.4 ml m(-2), s.e. 7.7). For every 10-mm Hg decrease in systolic blood pressure, cardiac output was 0.09 l(-1) min(-1) m(-2) lower (s.e. 0.04, P=0.019), and stroke volume was 1.58 ml m(-2) lower (s.e. 0.68, P=0.024). Mean left ventricular ejection fraction was normal and 2.39% (s.e. 1.16, P=0.046) higher for each 10-mm Hg decrease in systolic blood pressure. Mean left ventricular dimensions were normal but the E/A ratio was reduced (0.68, s.d. 0.21), indicating diastolic dysfunction. In conclusion, among the oldest old, low systolic blood pressure correlates with low cardiac output. Systolic ventricular function is not impaired.

Background. Symptoms of mountain sickness are due to hypoxia of the brain. The pathogenesis is complex, but acid-base disturbances certainly play a role. When arterial oxygen levels drop, hyperventilation is induced, resulting in a respiratory alkalosis. However, this alkalosis inhibits the hyperventilation necessary for maintaining oxygen pressure. We present a case of a patient with symptoms of mountain sickness at relatively low altitudes, who appeared to have Conn's syndrome (primary hyperaldosteronism). Case. A 61-year-old male with hypokalaemic hypertension presented with symptoms of mountain sickness at relatively low altitudes. Hyperaldosteronism was suspected and laboratory results showed a non-suppressible aldosterone concentration and a mild metabolic alkalosis. A CT scan of the abdomen revealed an adenoma in the left adrenal gland. Treatment of aldosterone blockade by eplerone normalized blood pressure and the symptoms of mountain sickness at low altitudes disappeared completely. Discussion. We suggest that in our patient with hyperaldosteronism, the pre-existing metabolic alkalosis inhibited the central respiratory centre after relatively mild hyperventilation. Therefore, mountain sickness in our patient could occur at a relatively low altitude.

High BP is associated with decline of renal function. Whether this is true for very old people largely is unknown. Therefore, this study assessed the effect of BP on creatinine clearance over time in very old participants. A total of 550 inhabitants (34% men) of Leiden, The Netherlands, were enrolled in a population-based study at their 85th birthday and followed until death or age 90. BP was measured twice at baseline and at age 90 yr. Creatinine clearance was estimated annually (Cockcroft-Gault formula). The mean creatinine clearance at baseline was 45.4 ml/min (SD 11.5). Systolic BP was not associated with changes in creatinine clearance during follow-up. Those with diastolic BP (DBP) <70 mmHg had an accelerated decline of creatinine clearance (1.63 ml/min per yr) compared with those with DBP between 70 and 79 mmHg (1.21 ml/min per yr; P = 0.01), 80 to 89 mmHg (1.26 ml/min per yr; P = 0.03), and >89 mmHg (1.38 ml/min per yr; P = 0.32). Participants with a decline in systolic BP during follow-up had an accelerated decline of creatinine clearance compared with those with stable BP (1.54 [SE 0.09] versus 0.98 ml/min per yr [SE 0.09]; P < 0.001). Similar results were found for a decline in DBP (1.54 [SE 0.10] versus 1.06 ml/min per yr [SE 0.08]; P < 0.001). In the oldest individual, high BP is not associated with renal function. In contrast, low DBP is associated with an accelerated decline of renal function. The clinical implications of these findings have to be studied.

Background: To investigate markers of autonomic tone on a standard electrocardiogram in relation to mortality in old age., Methods: A total of 599 inhabitants of Leiden, the Netherlands, were enrolled in a population-based follow-up study at their 85th birthday. Electrocardiograms (ECGs) were taken on entry and annually thereafter. ECGs were analysed automatically to determine four markers of autonomic tone, i.e. heart rate, the occurrence of ventricular extrasystoles and two time domain measures of heart rate variability. All participants were followed up for mortality., Results: Participants with a heart rate in the highest quartile had a 1.8-fold increased total mortality risk (95% confidence interval (CI) 1.0-3.4), but not an increased cardiovascular mortality risk. The occurrence of at least one ventricular extrasystole was related with a 2.3-fold increased total mortality risk (95% CI 1.3-3.9) and a 3.6-fold increased cardiovascular mortality (95% CI 1.6-8.2). In stratified analyses, the prognostic effect was confined to males. Both measures of heart rate variability were not related to mortality., Conclusion: High heart rate and the occurrence of a ventricular extrasystole, both markers of sympathetic dominance, were predictive of mortality in old age. Two short-term measures of heart rate variability as measured on a standard 10-s ECG were not related to mortality, and hence may not reflect autonomic tone in old age.

Objective: To study the impact of a history of hypertension and current blood pressure on mortality in the oldest old., Design: An observational population-based cohort study., Setting: Community city of Leiden, The Netherlands., Participants: Five hundred and ninety-nine inhabitants of the birth-cohort 1912-1914 were enrolled on their 85th birthday. There were no selection criteria related to health or demographic characteristics., Interventions: The mean follow-up was 4.2 years. Medical histories were obtained from general practitioners. Medication histories were obtained from the participant's pharmacist. Blood pressure was measured twice at baseline., Main Outcome Measures: All cause and cardiovascular mortality., Results: Five hundred and seventy-one participants were included, 39.2% had a history of hypertension. During follow-up 290 participants died, 119 due to cardiovascular causes. Compared to participants without a history of hypertension, those with a history of hypertension had increased mortality from cardiovascular causes [relative risk (RR) 1.60, confidence interval (CI) 1.06-2.40] but equal mortality from all causes (RR 1.19, CI 0.91-1.55). High blood pressure at baseline (age 85) was not a risk factor for mortality. Baseline blood pressure values below 140/70 mmHg (n = 48) were associated with excess mortality, predominantly in participants with a history of hypertension., Conclusion: In the oldest old, high blood pressure is not a risk factor for mortality, irrespective of a history of hypertension. Blood pressure values below 140/70 mmHg are associated with excess mortality.

Objective: The objective of this study was to explore the relationship between home hazards and the incidence of falls in the oldest old population., Study Design and Setting: The Leiden 85-plus Study is a population-based study of all 85-year-old inhabitants of Leiden in the birth-cohort 1912-1914. Participants and general practitioners were interviewed at baseline and annually there after. We analyzed the incidence of falling in the first year dependent on the presence of home hazards at baseline. There were no exclusion criteria other than the inability to walk alone., Results: During the 1-year follow-up, 44% of the participants experienced one or more falls. Participants without preceding falls (n=246) had a 4-fold risk for falls in the presence of six or seven home hazards (relative risk 3.58, 95% confidence interval 1.75-5.05) compared with those without home hazards. Participants with preceding falls (n=234) had no increased risk of falls with increasing numbers of home hazards, although they had a higher risk to fall. The data confirmed the known increased risk for falls in participants with physical impairments., Conclusion: We conclude that participants without a history of preceding falls have an increased risk of falling due to the presence of home hazards.