The purpose of this study was to investigate the clinical significance of the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) defined stage 1 hypertension (systolic blood pressure (SBP) 130–139 mmHg or diastolic blood pressure (DBP) 80–89 mmHg), and increase in BP from previously normal BP in Korean adults. We conducted a retrospective analysis of 60,866 participants from a nationally representative claims database. Study subjects had normal BP (SBP < 120 mmHg and DBP < 80 mmHg), no history of anti-hypertensive medication, and cardiovascular disease (CVD) in the first period (2002–2003). The BP change was defined according to the BP difference between the first and second period (2004–2005). We used time-dependent Cox proportional hazards models in order to evaluate the effect of BP elevation on mortality and CVD with a mean follow-up of 7.8 years. Compared to those who maintained normal BP during the second period, participants with BP elevation from normal BP to stage 1 hypertension had a higher risk for CVD (adjusted hazard ratio (aHR) 1.23; 95% confidence interval (CI), 1.08–1.40), and ischemic stroke (aHR 1.32; 95% CI, 1.06–1.64). BP elevation to 2017 ACC/AHA defined elevated BP (SBP 120–129 mmHg and DBP < 80 mmHg) was associated with an increased risk of CVD (aHR 1.26; 95% CI, 1.06–1.50), but stage 1 isolated diastolic hypertension (SBP < 130 and DBP 80–89 mmHg) was not significantly related with CVD risk (aHR 1.12; 95% CI, 0.95–1.31). Full article

Statins are reported to reduce the risk of cancer, but the results of various published studies have been contradictory. We carried out an umbrella review to provide an overview and understand the strength of evidence, extent of potential biases, and validity of claimed associations between the use of statins and cancer incidence. We comprehensively re-analyzed the data of meta-analyses of randomized controlled trials (RCTs) and observational studies on associations between statin use and cancer incidence. We also assessed the strength of evidence of the re-analyzed outcomes, which were determined from the criteria including statistical significance of the p-value of random-effects, as well as fixed-effects meta-analyses, small study effects, between-study heterogeneity, and a 95% prediction interval. Using a conventional method to assess the significance of meta-analysis (p-value < 0.05), statins had a statistically significant effect on reducing cancer incidence in 10 of 18 types of cancer. When we graded the level of evidence, no cancer type showed convincing evidence, and four cancers (esophageal cancer, hematological cancer, leukemia, and liver cancer) showed suggestive evidence of a preventive effect. There was weak evidence of an association with six cancers, and no significance for the remaining eight cancers. None of the meta-analyses of RCTs on the association of statin and cancer incidence showed a statistical significance. Although there was a preventive effect of statin on cancer incidence in 10 of the 18 cancer types, the evidence supporting the use of statins to reduce cancer incidence was low. Therefore, the associations between statin use and cancer incidence should be carefully considered by clinicians. Full article

Spontaneous cerebellar hemorrhage (SCH) is associated with high patient mortality and morbidity, but the clinical and radiographic predictors of the postoperative outcome have not been widely addressed in the literature. The purpose of this study was to define the prognostic factors for the two-year postoperative outcome in patients with SCH. We conducted a retrospective study of 48 consecutive patients with SCH who underwent neurosurgical intervention. Correlation analysis was performed to examine the possible link between clinical and radiographic parameters, and the National Institutes of Health Stroke Scale (NIHSS) score at each patient’s discharge and the two-year postoperative outcome as defined according to the Glasgow outcome scale (GOS). A total of 48 patients with SCH underwent neurological surgery, which included suboccipital craniectomy and/or external ventricular drainage (EVD). The mean patient age was 63 years. Nine patients underwent suboccipital craniectomy only; 38 underwent both suboccipital craniectomy and EVD. The overall mortality rate was 35.4%. Fourteen patients (29.2%) had good outcomes. A good outcome on the GOS at 2 years after surgical treatment of SCH was associated with the NIHSS score at discharge. An increase of one point in a patient’s NIHSS score at discharge following neurological surgery will increase the probability of a poor two-year postoperative outcome by 28.5%. Full article

(1) Background: Overt and subclinical hypothyroidism has been associated with increased cardiometabolic risks. Here we further explore whether thyroid function within normal range is associated with cardiometabolic risk factors in a large population-based study. (2) Methods: We screened 24,765 adults participating in health examinations in Taiwan. Participants were grouped according to high-sensitive thyroid-stimulating hormone (hsTSH) level as: <50th percentile (0.47–1.48 mIU/L, the reference group), 50–60th percentile (1.49–1.68 mIU/L), 60–70th percentile (1.69–1.94 mIU/L), 70–80th percentile (1.95–2.3 mIU/L), 80–90th percentile (2.31–2.93 mIU/L), and >90th percentile (>2.93 mIU/L). Cardiometabolic traits of each percentile were compared with the reference group. (3) Results: Elevated hsTSH levels within normal range were dose-dependently associated with increased body mass index, body fat percentage, waist circumferences, blood pressure, hemoglobin A1c (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), high homeostasis model of assessment of beta-cell (HOMA-β), triglycerides, total cholesterols, fibrinogen, and uric acids (p-for-trend <0.001), but not with fasting glucose levels. The association remained significant after adjustment of age, sex, and lifestyle. As compared to the reference group, subjects with the highest hsTSH percentile had significantly increased risk of being overweight (adjusted odds ratio (adjOR): 1.35), increased body fat (adjOR: 1.29), central obesity (adjOR: 1.36), elevated blood pressure (adjOR: 1.26), high HbA1c (adjOR: 1.20), hyperinsulinemia (adjOR: 1.75), increased HOMA-IR (adjOR: 1.45), increased HOMA-β (adjOR: 1.40), hypertriglyceridemia (adjOR: 1.60), hypercholesterolemia (adjOR: 1.25), elevated hsCRP (adjOR: 1.34), increased fibrinogen (adjOR: 1.45), hyperuricemia (adjOR: 1.47), and metabolic syndrome (adjOR: 1.42), but significant risk of low fasting glucose (adjOR: 0.89). Mediation analysis indicates that insulin resistance mediates the majority of the association between thyroid hormone status and the metabolic syndrome. (4) Conclusion: Elevated hsTSH within the normal range is a cardiometabolic risk marker associated with central obesity, insulin resistance, elevated blood pressure, dyslipidemia, hyperuricemia, inflammation, and hypercoagulability. Full article

Methicillin-resistant Staphylococcus aureus (MRSA) causes superficial infections such as cellulitis or invasive infections such as osteomyelitis; however, differences in MRSA isolates from cellulitis (CL-MRSA) and from osteomyelitis (OM-MRSA) at the same local area remain largely unknown. A total of 221 MRSA isolates including 106 CL-MRSA strains and 115 OM-MRSA strains were collected at Chang-Gung Memorial Hospital in Taiwan between 2016 and 2018, and their genotypic and phenotypic characteristics were compared. We found that OM-MRSA isolates significantly exhibited higher rates of resistance to multiple antibiotics than CL-MRSA isolates. Genotypically, OM-MRSA isolates had higher proportions of the SCCmec type III, the sequence type ST239, and the spa type t037 than CL-MRSA isolates. Besides the multidrug-resistant lineage ST239-t037-SCCmecIII more prevalent in OM-MRSA, higher antibiotic resistance rates were also observed in several other prevalent lineages in OM-MRSA as compared to the same lineages in CL-MRSA. Furthermore, when prosthetic joint infection (PJI) associated and non-PJI-associated MRSA strains in osteomyelitis were compared, no significant differences were observed in antibiotic resistance rates between the two groups, albeit more diverse genotypes were found in non-PJI-associated MRSA. Our findings therefore suggest that deep infections may allow MRSA to evade antibiotic attack and facilitate the convergent evolution and selection of multidrug-resistant lineages. Full article

Background: Sleeve gastrectomy (SG) is an effective treatment for obesity and type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD); however, the mechanism is not completely understood. Bile acids and fibroblast growth factors (FGFs) are involved in the regulation of energy metabolism. Methods: We investigated the roles of total bile acid and FGF 19 in T2DM remission and NAFLD improvement in obese subjects undergoing SG. A total of 18 patients with obesity and T2DM undergoing laparoscopic SG were enrolled in this study. Serial plasma total bile acid and FGF 19 levels were measured, while the fatty liver index was calculated before and after surgery. Results: The FGF 19 level significantly increased, and the total bile acid level and fatty liver index decreased 1 year after surgery. The complete T2DM remission rate was 66.7% one year after surgery; the complete remitters had significantly lower FGF 19 levels and higher insulin levels than the non-complete remitters. The complete remitters also had significantly decreased total bile acid levels and increased FGF 19 levels 1 year after surgery compared with those before surgery. The fatty improvers had significantly decreased total bile acid levels and increased FGF 19 levels 1 year after surgery compared with those before surgery. Conclusion: The total bile acids level and fatty liver index decreased, and the FGF 19 levels increased 1 year after SG. Both T2DM complete remitters and NAFLD improvers showed significantly decreased total bile acid levels and increased FGF 19 levels 1 year after SG. Plasma total bile acids and FGF 19 might have roles in T2DM remission and NAFLD improvement. Low preoperative FGF 19 levels might be a predictor for NAFLD improvement after SG. Full article

Osseointegration is likely the result of an immunologically driven bone reaction to materials such as titanium. Osseointegration has resulted in the clinical possibility to anchor oral implants in jaw bone tissue. However, the mechanisms behind bony anchorage are not fully understood and complications over a longer period of time have been reported. The current study aims at exploring possible differences between copper (Cu) and polyetheretherketone (PEEK) materials that do not osseointegrate, with osseointegrating cp titanium as control. The implants were placed in rabbit tibia and selected immune markers were evaluated at 10 and 28 days of follow-up. Cu and PEEK demonstrated at both time points a higher immune activation than cp titanium. Cu demonstrated distance osteogenesis due to a maintained proinflammatory environment over time, and PEEK failed to osseointegrate due to an immunologically defined preferential adipose tissue formation on its surface. The here presented results suggest the description of two different mechanisms for failed osseointegration, both of which are correlated to the immune system. Full article

Although it is necessary to culture Mycobacterium tuberculosis from tuberculous lymphadenitis (TBL) patients for definitive therapy, based on the drug-sensitivity test (DST), substantial cases remain culture-negative. Limited data are available regarding the treatment outcomes after standard anti-tuberculosis therapy in culture-negative TBL. The aim of this study was to compare the recurrence rates between definitive anti-tuberculosis therapy, based on DST and standard anti-tuberculosis therapy in culture-negative TBL. A multicenter retrospective cohort study was performed from 2011 to 2015 in South Korea. The study population was divided into two groups according to treatment type. A total of 234 patients with TBL were analyzed, who were treated with definitive (84 patients) and standard anti-tuberculosis (150 patients) therapy, respectively. During a 28.0 (24.0–43.0) month follow-up period, nine cases (3.8%) had recurrence of TB after treatment completion. The recurrence rate was not significantly different between the two groups (2/84, 2.4% in definitive anti-tuberculosis therapy group versus 7/150, 4.7% in standard anti-tuberculosis therapy group, p = 0.526). The recurrence in all nine cases was diagnosed as clinical recurrence rather than microbiological recurrence. Therefore, culture-negative TBL can be treated with standard anti-TB medication, although DST is not available but clinically stable after initiation of treatment. Full article

Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Methods: We prospectively recruited two LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the NAT2, CYP2E1, and AADAC SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 h after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, NAT2 rs1041983 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 7.00 [2.03–24.1]) and CYP2E1 rs2070673 (AA vs. TT+TA, OR [95% CI]: 3.50 [1.02–12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 h after 3HP administration (OR [95% CI]: 1.61 [1.15–2.25]) was associated with SDRs. Additionally, the association between the NAT2 SNP and SDRs was validated in the PK cohort (rs1041983 TT vs. CC+CT, OR [95% CI]: 4.43 [1.30–15.1]). Conclusions: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection. Full article

Several lines of evidence suggest that insulin-like growth factor 1 (IGF1) is involved in Sertoli cell (SC) proliferation and that its receptor (IGF1R) could mediate follicle-stimulating hormone (FSH) effects. To examine the role of the growth hormone (GH)-IGF1 axis on SC function, we evaluated the effects of GH and IGF1 on basal and FSH-modulated SC proliferation, as well as on anti-Müllerian hormone (AMH) and inhibin B expression and secretion in-vitro. SCs from neonatal pigs were incubated with (1) placebo, (2) 100 nM highly purified urofollitropin (hpFSH), (3) 100 nM recombinant GH (rGH), (4) 100 nM recombinant IGF1 (rIGF1), (5) 100 nM hpFSH plus 100 nM rGH, (6) 100 nM hpFSH plus 100 nM rIGF1, for 48 h. We found that IGF1, but not FSH nor GH, stimulated SC proliferation. Furthermore, an inhibitory effect of FSH, GH and IGF1 on AMH secretion, and a stimulatory role of FSH and IGF1, but not GH, on inhibin B secretion were found. These results suggest that the GH-IGF1 axis influences basal and FSH-modulated SC proliferation and function. We speculate that SC proliferation occurring in childhood might be supported by the increased serum IGF1 levels observed during this period of life. Full article

Background: Residual coronary artery disease (CAD) has been associated with worsened prognosis in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS). The residual SYNTAX Score (rSS) aims to assess residual CAD after PCI. The association between kidney function and rSS has not been investigated in ACS patients. In this study, we sought to determine whether chronic kidney disease (CKD) patients exhibit more incomplete revascularization following stage revascularization procedures by PCI. We evaluated the impact of incomplete revascularization on the occurrence of major cardiovascular events (MACE) at one-year follow-up. Methods: A total of 831 ACS patients undergoing PCI were divided into 3 subgroups according to their estimated Glomerular Filtration Rate (eGFR): 695 with eGFR ≥ 60 mL/min/1.73 m², 108 with eGFR 60–30 mL/min/1.73 m², 28 with eGFR < 30 mL/min/1.73 m². Initial SYNTAX score (SS) and rSS were calculated for all patients. Incomplete revascularization was defined by rSS > 8. The primary endpoint was the occurrence of MACE (all-cause mortality, myocardial infarction (MI), repeated revascularization except from planned revascularization, stroke and definite or probable recurrent stent thrombosis) one year after the index procedure. Results: Severe CKD patients had significantly higher MACE (12.0% vs. 25.9% vs. 35.7%; p < 0.001), all-cause mortality, cardiovascular mortality and heart failure events. Patients with rSS > 8 had higher MACE, all-cause and cardiovascular mortality. CKD was an independent predictive factor of rSS > 8 (HR: 1.65, 95% CI: 1.01 to 2.71; p = 0.048). Multivariate analysis identified rSS > 8, but not CKD, as an independent predictor of cardiac death and MACE. Conclusion: In ACS, CKD is predictive of incomplete revascularization, which stands out as a strong predictor of adverse cardiovascular outcomes including cardiac death and MACE. Full article

There is ongoing debate as to whether the decline of sperm production in recent times may be related to a parallel increase in the rate of obesity and diabetes. Lower anti-Müllerian hormone (AMH) and inhibin B secretion have been observed in young hyperinsulinemic patients compared to healthy controls, suggesting a Sertoli cell (SC) dysfunction. The pathophysiological mechanisms underlying SC dysfunction in these patients are poorly understood. To the best of our knowledge, no evidence is available on the effects of insulin on SC function. Therefore, this study was undertaken to assess the effects of insulin on basal and follicle-stimulating hormone (FSH)-stimulated SC function in vitro. To accomplish this, we evaluated the expression of AMH, inhibin B and FSHR genes, the secretion of AMH and inhibin B and the phosphorylation of AKT473 and SC proliferation on neonatal porcine SC after incubation with FSH and/or insulin. We found that similar to FSH, the expression and secretion of AMH is suppressed by insulin. Co-incubation with FSH and insulin decreased AMH secretion significantly more than with FSH alone. Insulin had no effect on the expression and secretion of the inhibin B gene, but co-incubation with FSH and insulin had a lower effect on inhibin B secretion than that found with FSH alone. FSH and/or insulin increased AKT473 phosphorylation and SC proliferation. In conclusion, the results of this study showed that insulin modulates SC function. We hypothesize that hyperinsulinemia may therefore influence testicular function even before puberty begins. Therefore, particular care should be taken to avoid the onset of hyperinsulinemia in children to prevent a future deleterious effect on fertility. Full article

The thrombotic microangiopathy (TMA) score based on the development and morphological characteristics of schistocytes is a rapid, simple biomarker that is easily obtained from the complete blood cell count by an automated blood cell analyzer. We aimed to determine whether the TMA score is associated with 30-day mortality of patients with early-stage septic shock. This observational cohort study was retrospectively conducted based on a prospective emergency department (ED) registry (June 2015–December 2016). We analyzed the TMA score at ED admission and 24 h later. The primary endpoint was all-cause mortality within 30 days of ED admission. A total of 221 patients were included. Increased TMA scores at time 0 (odds ratio (OR), 1.972; 95% confidence interval (CI), 1.253–3.106; p = 0.003) and at time 24 (OR, 1.863; 95% CI, 1.863–3.066; p = 0.014) were strong predictors of 30-day mortality. Increased predictability of 30-day mortality was closely associated with TMA scores ≥2 at time 0 (OR, 4.035; 95% CI, 1.651–9.863; p = 0.002) and ≥3 at time 24 (OR, 5.639; 95% CI, 2.190–14.519; p < 0.001). Increased TMA scores significantly predicted 30-day mortality for patients with severe sepsis and septic shock and can be helpful when determining the initial treatment strategies without additional costs or effort. Full article

Background: Chronic pain may be treated by medical cannabis. Yet, there is scarce evidence to support the role of medical cannabis in the treatment of fibromyalgia. The aim of the study was to investigate the characteristics, safety, and effectiveness of medical cannabis therapy for fibromyalgia. Methods: A prospective observational study with six months follow-up period based on fibromyalgia patients who were willing to answer questionnaire in a specialized medical cannabis clinic between 2015 and 2017. Results: Among the 367 fibromyalgia patients, the mean age was 52.9 ± 15.1, of whom 301 (82.0%) were women. Twenty eight patients (7.6%) stopped the treatment prior to the six months follow-up. The six months response rate was 70.8%. Pain intensity (scale 0–10) reduced from a median of 9.0 at baseline to 5.0 (p < 0.001), and 194 patients (81.1%) achieved treatment response. In a multivariate analysis, age above 60 years (odds ratio [OR] 0.34, 95% C.I 0.16–0.72), concerns about cannabis treatment (OR 0.36, 95% C.I 0.16–0.80), spasticity (OR 2.26, 95% C.I 1.08–4.72), and previous use of cannabis (OR 2.46 95% C.I 1.06–5.74) were associated with treatment outcome. The most common adverse effects were mild and included dizziness (7.9%), dry mouth (6.7%), and gastrointestinal symptoms (5.4%). Conclusion: Medical cannabis appears to be a safe and effective alternative for the treatment of fibromyalgia symptoms. Standardization of treatment compounds and regimens are required. Full article

Background: The clinical practice shows that many low-dose ACTH-stimulation tests have a false positive result. The aim of the study was to determine the diagnostic accuracy of a low-dose ACTH-stimulation test in the diagnosis of adrenal insufficiency and to define its optimal cut-off. Methods: We analyzed data from 103 patients undergoing 1 µg ACTH-stimulation test. Four patients had adrenal insufficiency (AI) upon follow up: Two primary, and two secondary AI. Cortisol serum levels were evaluated at time 0, 20’, and 30’ after the injection of 1 µg i.v. of ACTH. The sensitivity, specificity, accuracy, and positive and negative predictive values of the test were calculated for both 20’ and 30’ sampling. The receiver operating characteristic (ROC) curve was obtained to assess the sensitivity and specificity of low-dose ACTH-stimulation test in the diagnosis of adrenal insufficiency at different cut-off values. Results: Considering 500 nmol/L as the standard cut-off value, low-dose ACTH stimulation test showed a 100% sensitivity and a 67.3% specificity, with a high rate of false positive results. ROC curve analysis showed that the cut-off of 401.5 nmol/L is the best compromise between sensitivity (100%) and specificity (93.9%). Conclusions: By using a cut-off value of 401.5 nmol/L for the low-dose ACTH stimulation test, the number of false positive patients decreased significantly, but the sensitivity remained high. Full article