Prevalence estimates of tuberculosis infection in adults in Denmark: a retrospective nationwide register-based cross-sectional study, 2010 to 2018.

BackgroundTuberculosis (TB) elimination requires identifying and treating persons with TB infection (TBI).AimWe estimate the prevalence of positive interferon gamma release assay (IGRA) tests (including TB) and TBI (excluding TB) in Denmark based on TBI screening data from patients with inflammatory bowel disease (IBD) or inflammatory rheumatic disease (IRD).MethodsUsing nationwide Danish registries, we included all patients with IBD or IRD with an IGRA test performed between 2010 and 2018. We estimated the prevalence of TBI and positive IGRA with 95% confidence intervals (CI) in adolescents and adults aged 15-64 years after sample weighting adjusting for distortions in the sample from the background population of Denmark for sex, age group and TB incidence rates (IR) in country of birth.ResultsIn 13,574 patients with IBD or IRD, 12,892 IGRA tests (95.0%) were negative, 461 (3.4%) were positive and 221 (1.6%) were indeterminate, resulting in a weighted TBI prevalence of 3.2% (95% CI: 2.9-3.5) and weighted positive IGRA prevalence of 3.8% (95% CI: 3.5-4.2) among adults aged 15-64 years in the background population of Denmark. Unweighted TBI prevalence increased with age and birthplace in countries with a TB IR higher than 10/100,000 population.ConclusionEstimated TBI prevalence is low in Denmark. We estimate that 200,000 persons have TBI and thus are at risk of developing TB. Screening for TBI and preventive treatment, especially in persons born in high TB incidence countries or immunosuppressed, are crucial to reduce the risk of and eliminate TB.

Bacterial aerobic respiration is a major consumer of oxygen in sputum from patients with acute lower respiratory tract infection.

Bacterial aerobic respiration may determine the outcome of antibiotic treatment in experimental settings, but the clinical relevance of bacterial aerobic respiration for the outcome of antibiotic treatment has not been tested. Therefore, we hypothesized that bacterial aerobic respiration is higher in sputum from patients with acute lower respiratory tract infections (aLRTI), than in sputum from patients with chronic LRTI (cLRTI), where the bacteria persist despite antibiotic treatment. The bacterial aerobic respiration was determined according to the dynamics of the oxygen (O2 ) concentration in sputum from aLRTI patients (n = 52). This result was evaluated by comparison to previously published data from patients with cLRTI. O2 consumption resulting in anoxic zones was more frequent in sputum with detected bacterial pathogens. The bacterial aerobic respiration in aLRTI sputum approximated 55% of the total O2 consumption, which was significantly higher than previously published for cLRTI. The bacterial aerobic respiration in sputum was higher in aLRTI patients than previously seen in cLRTI patients, indicating the presence of bacteria with a sensitive physiology in aLRTI. These variations in bacterial physiology between aLRTI patients and cLRTI patients may contribute the huge difference in treatment success between the two patient groups.

Use of opioids among pregnant women 1997-2016: A Danish drug utilization study.

OBJECTIVE: Use of opioids in pregnancy is of concern yet little is known on opioid prescription patterns in Denmark. The aim of this drug utilization study was to describe prescription patterns for opioids during pregnancy in Denmark from 1997 to 2016. STUDY DESIGN: Using the nationwide health care registers, we obtained information on all women with a registered pregnancy in the period 1 January 1997 to 31 December 2016. Opioids were grouped in four: opioids (N02A except codeines), opioid dependency medications (N07BC), cough medications (R05DA except codeines), and codeines (N02AJ06, N02AJ07, N02BA75, and R05DA04). We used logistic regression analyses to identify factors associated with opioid use in pregnancy and cumulative oral morphine equivalent (OMEQ) to estimate volume of use in pregnancy. RESULTS: Prescription patterns were similar for women with live births, non-live births, and terminations. Total use of opioids among women with live born deliveries remained stable at 19.8 per 1000 pregnancies from 1997 to 2016. Codeine use declined from 2008 onwards, while use of other opioids increased from 2007 onwards. This was dominated by a threefold increase in tramadol use (2.0-7.6 per 1000 pregnancies with live births). Codeine was the most used opioid, followed by tramadol and codeine combined with paracetamol. The number of women, who used opioids before pregnancy and continued into their pregnancy, was reduced as the pregnancy progressed. The cumulative oral morphine equivalent during pregnancy was stable until 2007, after which, use prior to pregnancy and during the first two trimesters increased. The odds ratios for opioid use were higher in pregnancies of women of lower socioeconomic status or older age. For live births, odds ratios for opioid use in pregnancy were higher among women with obesity or smoking. CONCLUSIONS: Overall use of opioids was stable from 2007 to 2016. This covers a decline in the use of codeine, but a 3-fold increase in tramadol. The number of pregnant women who continued use throughout pregnancy decreased, while OMEQ among persistent users increased. The real-world data suggest an unmet need of specific focus in local Danish Outpatient Clinics and Multidisciplinary Pain Centers both pre-conceptionally and during pregnancy.

SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. DISCUSSION: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. TRIAL REGISTRATION: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Hormone replacement in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is defined as loss of ovarian function in women less-than 40 years. This review summarises the causes and the possible treatment options. POI can be idiopathic, caused by genetic, autoimmune, or metabolic disease, or be induced by cancer therapy or surgery. POI causes infertility, increased morbidity and mortality, and decreased quality of life. Hormonal replacement therapy (HRT) can alleviate symptoms of POI and should be initiated at diagnosis. The benefit of HRT outweighs the minor side effects in most cases and should be continued until age of natural menopause.

Short-course antibiotic therapy of 5 days in community-acquired pneumonia (CAP5): study protocol for a randomised controlled trial.

INTRODUCTION: The optimal duration of antibiotic therapy for community-acquired pneumonia (CAP) is unsettled. Short-course therapy has proved successful in clinical trials but is not yet implemented in everyday clinical practice. Validation of results from randomised controlled trials is crucial to evaluate existing evidence and provide clinicians with assurance of using new treatment strategies. In a pragmatic framework, we aim to assess the use of short-course antibiotic therapy guided by the onset of clinical stability in patients hospitalised with CAP. METHODS AND ANALYSIS: This study is a randomised controlled trial with a non-inferiority design that will examine the efficacy of short-course antibiotic therapy in patients hospitalised with CAP. From six hospitals across Denmark, we plan to enrol 564 patients between 2019 and 2024. Within 3-5 days after initiating antibiotic therapy, participants will be randomised 1:1 to parallel treatment arms: (1) short-course antibiotic therapy of 5 days or (2) antibiotic therapy of at least 7 days. The primary outcome will be 90-day readmission-free survival and will be estimated as an absolute risk difference with a predefined non-inferiority margin of -6%. Secondary outcomes will comprise other safety measures including new antibiotics, adverse events, length of hospital stay and postdischarge outpatient visits. Both intention-to-treat and per-protocol analyses will be performed. ETHICS AND DISSEMINATION: This study has been approved by the Health Research Ethics Committee of the Capital Region of Denmark (identifier number: H-19014479). Trial data will be made available in anonymous form when the trial has ended. TRIAL REGISTRATION NUMBER: NCT04089787, ClinicalTrials.Gov.

Non-pharmacological treatment of reduced quality of life in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is the spontaneous or induced loss of ovarian function in women under the age of 40. POI increases the risk of reduced quality of life. Hormone replacement therapy may be beneficial in POI, but some women have contraindications. Recent studies indicate that exercise, yoga, meditation, acupuncture, and mindfulness may improve quality of life in women with POI. Phyto-oestrogens are not recommended in the treatment of POI since the physiological level of oestrogen cannot be achieved, and phyto-oestrogens should be avoided in women with present or previous breast cancer.

Short course antibiotic treatment of Gram-negative bacteraemia (GNB5): a study protocol for a randomised controlled trial.

INTRODUCTION: Prolonged use of antibiotics is closely related to antibiotic-associated infections, antimicrobial resistance and adverse drug events. The optimal duration of antibiotic treatment for Gram-negative bacteremia (GNB) with a urinary tract source of infection is poorly defined. METHODS AND ANALYSIS: Investigator-initiated multicentre, non-blinded, non-inferiority randomised controlled trial with two parallel treatment arms. One arm will receive shortened antibiotic treatment of 5 days and the other arm will receive antibiotic treatment of 7 days or longer. Randomisation will occur in equal proportion (1:1) no later than day 5 of effective antibiotic treatment as determined by antibiogram. Immunosuppressed patients and those with GNB due to non-fermenting bacilli (Acinetobacter spp, Pseudomonas spp), Brucella spp, Fusobacterium spp or polymicrobial growth are ineligible.The primary endpoint is 90-day survival without clinical or microbiological failure to treatment. Secondary endpoints include all-cause mortality, total duration of antibiotic treatment, hospital readmission and Clostridioides difficile infection. Interim safety analysis will be performed after the recruitment of every 100 patients. Given an event rate of 12%, a non-inferiority margin of 10%, and 90% power, the required sample size to determine non-inferiority is 380 patients. Analyses will be performed on both intention-to-treat and per-protocol populations. ETHICS AND DISSEMINATION: The study is approved by the Danish Regional Committee on Health Research (H-19085920) and the Danish Medicines Agency (2019-003282-17). The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov:NCT04291768.

Treatment effect modifiers in hospitalised patients with COVID-19 receiving remdesivir and dexamethasone.

BACKGROUND: The combined effectiveness of remdesivir and dexamethasone in subgroups of hospitalised patients with COVID-19 is poorly investigated. METHODS: In this nationwide retrospective cohort study, we included 3826 patients with COVID-19 hospitalised between February 2020 and April 2021. The primary outcomes were use of invasive mechanical ventilation and 30-day mortality, comparing a cohort treated with remdesivir and dexamethasone with a previous cohort treated without remdesivir and dexamethasone. We used inverse probability of treatment weighting logistic regression to assess associations with progression to invasive mechanical ventilation and 30-day mortality between the two cohorts. The analyses were conducted overall and by subgroups based on patient characteristics. RESULTS: Odds ratio for progression to invasive mechanical ventilation and 30-day mortality in individuals treated with remdesivir and dexamethasone compared to treatment with standard of care alone was 0.46 (95% confidence interval, 0.37-0.57) and 0.47 (95% confidence interval, 0.39-0.56), respectively. The reduced risk of mortality was observed in elderly patients, overweight patients and in patients requiring supplemental oxygen at admission, regardless of sex, comorbidities and symptom duration. CONCLUSIONS: Patients treated with remdesivir and dexamethasone had significantly improved outcomes compared to patients treated with standard of care alone. These effects were observed in most patient subgroups.

The ratio of neutrophil-to-lymphocyte and platelet-to-lymphocyte and association with mortality in community-acquired pneumonia: a derivation-validation cohort study.

RATIONALE: The ratio of neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR) and platelet-to-lymphocyte (PLR) are biomarkers that have shown potential for predicting mortality in several diseases. For patients hospitalized with community-acquired pneumonia (CAP), the prognostic capabilities of these biomarkers are unknown. OBJECTIVE: Investigate whether NLR, MLR or PLR were associated with 90-day mortality in CAP. Further, investigate whether the prediction rule CURB-65 could be improved by adding these biomarkers. METHODS: A derivation-validation study using a Danish multicentre retrospective cohort as the derivation cohort (N = 831) and a European multicentre prospective cohort as the validation cohort (N = 2463). Associations between biomarkers and mortality were assessed using Cox proportional hazard models with adjustments for sex, CURB-65 and comorbidities. A cut-off value for biomarkers was determined using Youden's J Statistics. The performance of CURB-65 with added biomarkers was evaluated using receiver-operating characteristics. RESULTS: In both cohorts increasing NLR and PLR were associated with 90-day mortality. In the derivation cohort, the hazard ratios for NLR and PLR were 1.016 (95% confidence interval (CI) 1.001-1.032, P = 0.038) and 1.001 (95% CI 1.000-1.001, P = 0.035), respectively. Adding these biomarkers to CURB-65 did not improve its performance. CONCLUSIONS: NLR and PLR were associated with 90-day mortality in CAP, but did not improve CURB-65.

Lyme neuroborreliosis with encephalitis: A rare case.

Encephalitis caused by Borrelia burgdorferi sensu lato is a rare clinical manifestation of Lyme neuroborreliosis and only in few cases have brain parenchymal inflammation been documented. Here, we present a case of Lyme neuroborreliosis with encephalitis with significant parenchymal inflammation on magnetic resonance imaging (MRI) in an immunosuppressed patient.

Use and development of contraceptive apps.

This state-of-the-art review evaluates whether contraceptive apps could improve knowledge resulting in greater interest and use of long-acting contraception, what type of information an app should contain, and who may benefit most from apps. The studies found a high interest in easy accessibility and respect for privacy. Science-based information and facilitation of knowledge about all contraceptives were desired. Contraceptive apps were useful in presenting women with validated information and complement professional advice.

Short-course antibiotic therapy for hospitalized patients with early clinical response in community-acquired pneumonia: a multicentre cohort study.

OBJECTIVES: To explore whether short-course antibiotic therapy is efficient and safe in routine clinical settings among patients hospitalized with community-acquired pneumonia (CAP) who achieve an early clinical response. METHODS: During 2017-2019, we conducted a cohort study of patients admitted with CAP to four hospitals in Denmark. Data were prospectively gathered from medical records and enriched with data from nationwide registries. In the present study, we included patients with early clinical response and divided them into treatment groups based on antibiotic duration, as decided by the attending physician: short-course (4-7 days) or prolonged-course (8-14 days). The primary outcome was post-treatment mortality within 30 days. Secondary outcomes included readmissions or new antibiotics. Logistic regression models were used to estimate ORs with 95% CIs, and inverse probability weighting was applied to adjust for confounding. RESULTS: The study cohort included 1151 patients with a median age of 74 years, predominantly presenting with mild-moderate disease. The 30-day post-treatment mortality was 3.36% (11/327) in the short-course group and 3.40% (28/824) in the prolonged-course group (adjusted OR 1.05, 95% CI 0.38-1.88). Readmission occurred in 15.6% (42/269) vs. 14.0% (102/727) (adjusted OR 1.07, 95% CI 0.75-1.69) and new prescription of antibiotics in 11.9% (32/269) vs. 12.1% (88/727) (adjusted OR 0.99, 95% CI 0.61-1.49). DISCUSSION: In patients hospitalized with CAP and early clinical response, similar outcomes were observed between short-course and prolonged-course therapies. These results support the use of short-course therapy in routine clinical settings.

Myoinositol vs. Metformin in Women with Polycystic Ovary Syndrome: A Randomized Controlled Clinical Trial.

Polycystic ovary syndrome (PCOS) is associated with insulin resistance. Few randomized controlled trials (RCT) compared myoinositol (MI) with metformin (MET) regarding insulin resistance in PCOS. This was an open-label six-month RCT in women with PCOS (n = 45) with interventions MI 4 g/day or MET 2 g/day. Primary outcome was the homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were fasting glucose, weight, cycle length, lipids, testosterone, adverse effects, quality of life, and depression scores. Median age was 26 years. Body mass was index was 34.4 kg/m2. HOMA-IR was unchanged during MI (p = 0.31) and MET (p = 0.11) (MI vs. MET, p = 0.09). Median fasting glucose changed +0.2 mmol/L during MI (p < 0.001) and −0.1 mmol/L during MET (p = 0.04) (MI vs. MET p < 0.001). Median weight changed −2.3 kg during MI (p = 0.98) and −6.1 kg during MET (p < 0.001) (MI vs. MET, p = 0.02). Median cycle length decreased nine days during MI (p = 0.03) and 13 days during MET (p = 0.03) (MI vs. MET, p = 0.93). High-density lipoprotein (HDL) changed +0.1 mmol/L during MET (p = 0.04) (MI vs. MET, p = 0.07). All other blood parameters and scores of quality of life and depression remained unchanged during MI and MET (all p > 0.06) (MI vs. MET, all p > 0.27). Adverse effects appeared in four women during MI and 16 women during MET (MI vs. MET, p = 0.001). In conclusion, there was no effect on the metabolic outcomes during MI, but positive effects on fasting blood glucose, weight, and HDL during MET. The effect on cycle length was comparable during MI and MET. Adverse effects were less frequent during MI.

Tuberculosis screening among newly arrived asylum seekers in Denmark.

BACKGROUND: Tuberculosis (TB) screening programmes among asylum seekers tend to focus on chest radiography (CXR) for early diagnosis, whereas knowledge on sputum examination is limited. We evaluated active TB screening using CXR and sputum culture among asylum seekers arriving in Denmark. In addition, we assessed the coverage of a voluntary health assessment. METHODS: Between 1 February 2017 and 31 March 2019, all newly arrived asylum seekers in Denmark ≥ 18 years from TB high-incidence countries or risk groups, who attended a voluntary general health assessment, were offered active TB screening with CXR and spot sputum examination. Sputum samples were examined by culture and smear microscopy. RESULTS: Coverage of the general health assessment was 65.1%. Among 1,154 referred for active TB screening, 923 (80.0%) attended. Of these, 854 were screened by CXR and one case of active TB was identified equivalent to a yield of 0.12%. Sputum samples were collected from 758 and one M. tuberculosis culture-positive TB case (also identified by CXR) was identified, equivalent to a yield of 0.13%. No cases were found by sputum culture screening only. In addition, screening found three cases of malignant disease. CONCLUSION: We suggest that TB screening should focus on asylum seekers from TB high-incidence countries. Furthermore, early health assessments should be of high priority to ensure migrant health.

Prospective Risk of Type 2 Diabetes in Normal Weight Women with Polycystic Ovary Syndrome.

Background: Polycystic ovary syndrome (PCOS) is associated with obesity and increased risk for type 2 diabetes (T2D). However, the prospective risk of T2D in normal weight women with PCOS is debated, together with the relevant prospective screening programs for T2D in normal weight women with PCOS. Aim: To review and discuss prospective risk of T2D in normal weight women with PCOS, and to give recommendations regarding prospective screening for T2D in normal weight women with PCOS. Methods: Systematic review. Results: A systematic literature search resulted in 15 published prospective studies (10 controlled studies and 5 uncontrolled studies) regarding risk of T2D in study cohorts of PCOS, where data from normal weight women with PCOS were presented separately. In controlled studies, higher risk of T2D in normal weight women with PCOS compared to controls was reported in 4/10 studies, which included one study where T2D diagnosis was based on glucose measurement, two register-based studies, and one study where diagnosis of T2D was self-reported. Six of the 10 controlled studies reported no increased risk of T2D in normal weight women with PCOS. Four of these studies based the diagnosis of T2D on biochemical measurements, which supported the risk of surveillance bias in PCOS. In uncontrolled studies, 2/5 reported a higher risk of T2D in lean women with PCOS compared to the general population. We discuss the evidence for insulin resistance and ß-cell dysfunction in normal weight women with PCOS, and aggravation in the hyperandrogenic phenotype, ageing women, and women with Asian ethnicity. Impaired glucose tolerance could be an important metabolic and vascular risk marker in PCOS. Conclusions: The risk of T2D may be increased in some normal weight women with PCOS. Individual risk markers such as hyperandrogenism, age >40 years, Asian ethnicity, and weight gain should determine prospective screening programs in normal weight women with PCOS.

Dysglycaemia among tuberculosis patients without known diabetes in a low-endemic setting.

With a high prevalence of dysglycaemia (29.1%) among tuberculosis patients without previously known diabetes, this study highlights the importance of comanagement of tuberculosis and diabetes, even in a low-endemic setting https://bit.ly/3Gj0gmN.

Bacterial biofilms predominate in both acute and chronic human lung infections.

BACKGROUND: A basic paradigm of human infection is that acute bacterial disease is caused by fast growing planktonic bacteria while chronic infections are caused by slow-growing, aggregated bacteria, a phenomenon known as a biofilm. For lung infections, this paradigm has been thought to be supported by observations of how bacteria proliferate in well-established growth media in the laboratory-the gold standard of microbiology. OBJECTIVE: To investigate the bacterial architecture in sputum from patients with acute and chronic lung infections. METHODS: Advanced imaging technology was used for quantification and direct comparison of infection types on fresh sputum samples, thereby directly testing the acute versus chronic paradigm. RESULTS: In this study, we compared the bacterial lifestyle (planktonic or biofilm), growth rate and inflammatory response of bacteria in freshly collected sputum (n=43) from patient groups presenting with acute or chronic lung infections. We found that both acute and chronic lung infections are dominated by biofilms (aggregates of bacteria within an extracellular matrix), although planktonic cells were observed in both sample types. Bacteria grew faster in sputum from acute infections, but these fast-growing bacteria were enriched in biofilms similar to the architecture thought to be reserved for chronic infections. Cellular inflammation in the lungs was also similar across patient groups, but systemic inflammatory markers were only elevated in acute infections. CONCLUSIONS: Our findings indicate that the current paradigm of equating planktonic with acute and biofilm with chronic infection needs to be revisited as the difference lies primarily in metabolic rates, not bacterial architecture.