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Background: The benefit of levothyroxine treatment of subclinical hypothyroidism (SCH) is subject to debate. This study compared treatment satisfaction between older adults with SCH using levothyroxine or placebo. Methods: We analyzed pooled individual participant data from two randomized, double-blind, placebo-controlled trials investigating the effects of levothyroxine treatment in older adults with SCH. Community-dwelling participants aged ≥65 years, with SCH (persistent thyrotropin levels 4.60-19.99 mIU/L for >3 months and normal free T4 level), were included. Intervention dose titration until thyrotropin levels normalized, with a mock dose adjustment of placebo. Treatment satisfaction was determined during the final study visit using the Treatment Satisfaction Questionnaire for Medication (TSQM), encompassing perceived effectiveness, side effects, convenience, and global satisfaction, along with the participants' desire to continue study medication after the trial. Results: We included 536 participants. At baseline, the median (interquartile range [IQR]) age was 74.9 (69.7-81.4) years, and 292 (55%) were women. The median (IQR) thyrotropin levels were 5.80 (5.10-7.00) mIU/L at baseline in both groups; at final visit, 4.97 (3.90-6.35) mIU/L in the placebo and 3.24 (2.49-4.41) mIU/L in the levothyroxine group. After treatment, the groups did not differ significantly in global satisfaction (mean difference [CI] -1.1 [-4.5 to 2.1], p = 0.48), nor in any other domain of treatment satisfaction. These results held true regardless of baseline thyrotropin levels or symptom burden. No major differences were found in the numbers of participants who wished to continue medication after the trial (levothyroxine 35% vs. placebo 27%), did not wish to continue (levothyroxine 27% vs. placebo 30%), or did not know (levothyroxine 37% vs. placebo 42%) ( p = 0.14). In a subpopulation with high symptom burden from hypothyroid symptoms at baseline, those using levothyroxine more often desired to continue the medication after the trial than those using placebo (mean difference [CI]: -21.1% [-35.6% to -6.5%]). Conclusion: These pooled data from two RCTs showed no major differences in treatment satisfaction between older adults receiving levothyroxine or placebo. This finding has important implications for decision-making regarding initiating levothyroxine treatment for SCH. Our findings generally support refraining from routinely prescribing levothyroxine in older adults with SCH.

The rationale of performing surgery for acute subdural hematoma (ASDH) to reduce mortality is often compared with the self-evident effectiveness of a parachute when skydiving. Nevertheless, it is of clinical relevance to estimate the magnitude of the effectiveness of surgery. The aim of this study is to determine whether surgery reduces mortality in traumatic ASDH compared with initial conservative treatment. A systematic search was performed in the databases IndexCAT, PubMed, Embase, Web of Science, Cochrane library, CENTRAL, Academic Search Premier, Google Scholar, ScienceDirect, and CINAHL for studies investigating ASDH treated conservatively and surgically, without restriction to publication date, describing the mortality. Cohort studies or trials with at least five patients with ASDH, clearly describing surgical, conservative treatment, or both, with the mortality at discharge, reported in English or Dutch, were eligible. The search yielded 2025 reports of which 282 were considered for full-text review. After risk of bias assessment, we included 102 studies comprising 12,287 patients. The data were synthesized using meta-analysis of absolute risks; this was conducted in random-effects models, with dramatic effect estimation in subgroups. Overall mortality in surgically treated ASDH is 48% (95% confidence interval [CI] 44-53%). Mortality after surgery for comatose patients (Glasgow Coma Scale ≤8) is 41% (95% CI 31-51%) in contemporary series (after 2000). Mortality after surgery for non-comatose ASDH is 12% (95% CI 4-23%). Conservative treatment is associated with an overall mortality of 35% (95% CI 22-48%) and 81% (95% CI 56-98%) when restricting to comatose patients. The absolute risk reduction is 40% (95% CI 35-45%), with a number needed to treat of 2.5 (95% CI 2.2-2.9) to prevent one death in comatose ASDH. Thus, surgery is effective to reduce mortality among comatose patients with ASDH. The magnitude of the effect is large, although the effect size may not be sufficient to overcome any bias.

Introduction: Lockdown measures have a profound effect on many aspects of daily life relevant for diabetes self-management. We assessed whether lockdown measures, in the context of the COVID-19 pandemic, differentially affect perceived stress, body weight, exercise and related this to glycemic control in people with type 1 and type 2 diabetes., Research Design and Methods: We performed a short-term observational cohort study at the Leiden University Medical Center. People with type 1 and type 2 diabetes ≥18 years were eligible to participate. Participants filled out online questionnaires, sent in blood for hemoglobin A1c (HbA1c) analysis and shared data of their flash or continuous glucose sensors. HbA1c during the lockdown was compared with the last known HbA1c before the lockdown., Results: In total, 435 people were included (type 1 diabetes n=280, type 2 diabetes n=155). An increase in perceived stress and anxiety, weight gain and less exercise was observed in both groups. There was improvement in glycemic control in the group with the highest HbA1c tertile (type 1 diabetes: -0.39% (-4.3 mmol/mol) (p<0.0001 and type 2 diabetes: -0.62% (-6.8 mmol/mol) (p=0.0036). Perceived stress was associated with difficulty with glycemic control (p<0.0001)., Conclusions: An increase in perceived stress and anxiety, weight gain and less exercise but no deterioration of glycemic control occurs in both people with relatively well-controlled type 1 and type 2 diabetes during short-term lockdown measures. As perceived stress showed to be associated with glycemic control, this provides opportunities for healthcare professionals to put more emphasis on psychological aspects during diabetes care consultations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pituitary adenohypophyseal tumors are considered as benign and termed "adenomas". However, many tumors are invasive and a proportion of these exhibit an "aggressive behavior" with premature death due to progressive growth. Only very rare (0.2%) tumors with metastases are considered malignant and termed "carcinomas". Taking into account this variability in behavior and the oncological definition, pathologists have proposed changing the term adenoma to tumor. Here we explain why use the term tumor instead of adenoma and identify tumor characteristics, associated with a high risk for poor prognosis. In a cohort of 125 tumors with aggressive behavior (APT) and 40 carcinomas with metastases (PC), clinical and pathological features were very similar. The comparison of this cohort (APT+PC) with a reference surgical cohort of 374 unselected patients clearly shows that the two cohorts differ greatly, especially the percentage of tumors with Ki67 ≥ 10% (35%vs3%; p < 0.001). A five-tiered prognostic classification, associating invasion and proliferation, identified grade 2b tumors (invasive and proliferative), with a high risk of recurrence/progression. Because half of the APT+ PC tumors have a Ki67 index ≥10%, and 80% of them show 2 or 3 positive markers of proliferation, we suggest that tumors that are clinically aggressive, invasive and highly proliferative with a Ki67 ≥ 10%, represent tumors with malignant potential. The percentage of grade 2b tumors, suspected of malignancy, which will become aggressive tumors or carcinomas is unknown. It is probably very low, but higher than 0.2% in surgical series. Early identification and active treatment of these aggressive tumors is needed to decrease morbidity and prolong survival.

Background: Sciatica is a condition that is characterised by radicular pain in the leg and primarily caused by a herniated lumbar intervertebral disk. In addition to leg pain, patients can experience back pain, leg numbness and leg weakness resulting in decreased productivity and social activity. The majority of sciatica cases recovers spontaneously and therefore patients are initially treated conservatively with oral pain medication. However, some patients experience intractable pain that severely impedes them and no consensus exists on the optimal conservative treatment to reduce this discomfort in the acute phase of sciatica. The aim of the TEIAS trial is to assess the effectiveness, cost-effectiveness and predictive capability on patient outcome of transforaminal epidural injection (TEI) compared to treatment with standard pain medication., Methods: This study is designed as a prospective, open-label, mono-centered, randomized controlled trial. Patients that visit their general practitioner with complaints of radicular leg pain and meet the selection criteria are asked to participate in this study. Eligible patients will be randomized to treatment with TEI or to treatment with standard oral pain medication. Treatment of TEI will comprise lidocaine with methylprednisolone acetate for L3 and below and lidocaine with dexamethasone above L3. A total of 142 patients will be recruited and follow-up will occur after 1, 2, 4, 10 and 21 weeks for assessment of pain, functionality, patient received recovery and cost-effectiveness. The primary outcome will be the average score for leg pain at 2 weeks. For this outcome we defined a clinically relevant difference as 1.5 on the 11-point NRS scale., Discussion: Adequate conservative treatment in the acute phase of sciatica is lacking, particularly for patients with severe symptoms. Focusing on effectiveness, cost-effectiveness and predictive capability on patient outcome of TEI will produce useful information allowing for more lucid decision making in the conservative treatment of sciatica in the acute phase., Trial Registration: This trial is registered in the ClinicalTrials.gov database under registry number NCT03924791 on April 23, 2019.

The European Society of Endocrinology (ESE) survey reported on the largest cohort of 125 aggressive pituitary tumours (APT) and 40 pituitary carcinomas (PC). Whilst the survey focused on treatment effectiveness, all pathological data were not explored in detail. Here, we comment on some interesting pathological findings, notably the difference between APT and PC., (© 2018 European Society of Endocrinology.)

Background: Systematic reviews and meta-analyses of observational studies are frequently performed, but no widely accepted guidance is available at present. We performed a systematic scoping review of published methodological recommendations on how to systematically review and meta-analyse observational studies., Methods: We searched online databases and websites and contacted experts in the field to locate potentially eligible articles. We included articles that provided any type of recommendation on how to conduct systematic reviews and meta-analyses of observational studies. We extracted and summarised recommendations on pre-defined key items: protocol development, research question, search strategy, study eligibility, data extraction, dealing with different study designs, risk of bias assessment, publication bias, heterogeneity, statistical analysis. We summarised recommendations by key item, identifying areas of agreement and disagreement as well as areas where recommendations were missing or scarce., Results: The searches identified 2461 articles of which 93 were eligible. Many recommendations for reviews and meta-analyses of observational studies were transferred from guidance developed for reviews and meta-analyses of RCTs. Although there was substantial agreement in some methodological areas there was also considerable disagreement on how evidence synthesis of observational studies should be conducted. Conflicting recommendations were seen on topics such as the inclusion of different study designs in systematic reviews and meta-analyses, the use of quality scales to assess the risk of bias, and the choice of model (e.g. fixed vs. random effects) for meta-analysis., Conclusion: There is a need for sound methodological guidance on how to conduct systematic reviews and meta-analyses of observational studies, which critically considers areas in which there are conflicting recommendations.

Background: Data are sparse on the range of BMI among patients acutely admitted to general hospitals. We investigated BMI values and associated patient characteristics, reasons for hospital admission, and mortality in Denmark., Methods: We identified all persons with an acute inpatient admission 2011-2014 in Central Denmark Region and assessed BMI measurements recorded in the Clinical Information System. We used cross-sectional and cohort analyses to examine the BMI distribution and its association with demographic characteristics, comorbidities, medication use, tobacco smoking, reasons for admission, and 30-day mortality., Results: Among 92,027 acutely admitted patients (median age 62 years, 49% female) with a BMI measurement, 4% had a BMI (kg/m2) <18.5, 42% a BMI between 18.5 and 25, 34% a BMI between 25 and 30, and 20% a BMI ≥30. Compared with normal-weight patients, 30-day mortality was high among patients with BMI <18.5 (7.5% vs. 2.8%, age- and smoking-adjusted odds ratio (aOR) 2.4; 95% confidence interval (CI): 2.0-2.9, whereas patients with overweight (aOR 0.7; 95% CI: 0.6-0.8) and obesity class I (aOR 0.8; 95% CI: 0.6-0.9)). Compared with the total population, patients with BMI <18.5 were older (68 years median); more were female (73%); more had comorbidities (Charlson Comorbidity Index score >0 in 42% vs. 33% overall), more were current smokers (45% vs. 27% overall), and acute admissions due to respiratory diseases or femoral fractures were frequent. In contrast, patients with BMI ≥30 were relatively young (59 years median), fewer smoked (24%): type 2 diabetes, sleep disorders, cholelithiasis, and heart failure were frequent diagnoses. Prevalence of therapies for metabolic syndrome, pain, and psychiatric disorders increased with higher BMI, while patients with BMI <18.5 frequently used asthma medications, glucocorticoids, and antibiotics., Conclusion: In patients acutely admitted to general hospitals, reasons for hospital admission and associated clinical characteristics differ substantially according to BMI range. BMI <18.5 is a clinical predictor of high short-term mortality.

Aim: Venous thromboembolism (VTE) has long been regarded as a marker of underlying malignancy in the general population. Patients with diabetes mellitus are at increased risk of developing VTE, but it is unclear whether VTE in diabetes patients is also a harbinger of occult cancer., Methods: From Danish medical health databases, we identified all diabetes patients (N=8783) with a first-time diagnosis of VTE during 1978-2011. We followed the patients until a first-time diagnosis of cancer, emigration, death, or study end, whichever came first. We calculated one-year absolute cancer risk and overall and site-specific standardized incidence ratios (SIRs) for cancer based on national cancer incidence., Results: During the total study period 878 cancers were observed. The one-year absolute cancer risk was 4.1% and the corresponding SIR was 3.28 (95% confidence interval [CI]: 2.94-3.64). The highest SIRs were observed for cancers of the gallbladder and biliary tract (SIR 13.59; 6.77-24.31), the pancreas (SIR 10.16; 6.85-14.50), the ovary (SIR 9.85; 5.63-16.00), and the liver (SIR 9.39; 4.30-17.84). After the first year of follow-up, the overall cancer SIR associated with VTE and diabetes decreased to 1.05 (95% CI: 0.97-1.15)., Conclusions: VTE may be a marker of underlying cancer in patients with diabetes mellitus., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Previous studies have indicated that women with diabetes mellitus are at higher risk to develop sexual dysfunctions. In the current study, we hypothesized that lower genital arousal response-as a consequence of diabetes-related damage to nerves and blood vessels-might play a part in these higher prevalence rates. Vaginal blood flow, subjective sexual response, and clitoral sensitivity were compared between women with diabetes and healthy controls, and associations with diabetes complications were investigated. In pre- and postmenopausal women with type 1 diabetes (n = 42) and healthy controls (n = 46), vaginal blood flow was measured as vaginal pulse amplitude (VPA). VPA was assessed at rest, during erotic film viewing, and during vibrotactile clitoral stimulation. Subjective sexual arousal was measured using a questionnaire. Clitoral sensitivity was assessed by a vibration perception test. Data on diabetes complications were obtained from medical records, and neuropathy was assessed by quantitative sensory testing. VPA, subjective sexual arousal, and clitoral sensitivity were not significantly different between women with diabetes and controls. Nevertheless, women with diabetes who had retinopathy showed significantly lower VPA than women without retinopathy, and women with diabetes who had neuropathy showed significantly higher sensation thresholds for vibrotactile clitoral stimulation. The results do not support the hypothesis of a disrupted genital arousal response in women with diabetes. However, the observed associations between retinopathy and vaginal blood flow, and between neuropathy and clitoral sensitivity, suggest that diabetes-related complications might adversely affect the physiological basis of female sexual response.

Objectives: Fibrinogen concentrate is increasingly used in cardiac surgery when bleeding is anticipated or ongoing. Since randomized clinical studies to support this are lacking, it is relevant to know whether lower fibrinogen levels are associated with excessive bleeding. We performed a systematic review and meta-analysis to define the association between fibrinogen levels and blood loss after cardiac surgery., Methods: A database search (January 2013) was performed on publications assessing the association between pre- and postoperative fibrinogen levels and postoperative blood loss in adult patients undergoing cardiac surgery. Cohort studies and case-control studies were eligible for inclusion. The main outcome was the pooled correlation coefficient, calculated via Fisher's Z transformation scale, in a random-effects meta-analysis model stratified for the time point at which fibrinogen was measured., Results: A total of 20 studies were included. The pooled correlation coefficient of studies (n = 9) concerning preoperative fibrinogen levels and postoperative blood loss was -0.40 (95% confidence interval: -0.58, -0.18), pointing towards more blood loss in patients with lower preoperative fibrinogen levels. Among papers (n = 16) reporting on postoperative fibrinogen levels and postoperative blood loss, the pooled correlation coefficient was -0.23 (95% confidence interval: -0.29, -0.16)., Conclusions: Our meta-analysis indicated a significant but weak-to-moderate correlation between pre- and postoperative fibrinogen levels and postoperative blood loss in cardiac surgery. This moderate association calls for appropriate clinical studies on whether fibrinogen supplementation will decrease postoperative blood loss.