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Objective: To evaluate the effects of uncoupling protein (UCP) 1, UCP2 and UCP3 gene variants on body composition and metabolic changes in response to chronic overfeeding and the recovery after the period of overfeeding. Subjects and design: Twenty-four normal weight men (21±2 y), who constituted 12 pairs of identical twins, ate a 4.2 MJ/day energy surplus, 6 days a week, during a period of 100 days. The subjects were asked to return to the laboratory for testing at 4 months and for a final examination 5 y after completion of the overfeeding protocol. Methods: Resting metabolic rate (RMR) measurements were performed before and after overfeeding. A 4.2 MJ test meal was consumed, after which calorimetric measurements were continued for 240 min. Total body fat was assessed by hydrodensitometry and total subcutaneous fat by the sum of eight skinfolds. Polymorphisms were typed by PCR and PCR-RFLP-techniques. Thyroid stimulating hormone (TSH) concentrations after a thyrotropin releasing hormone (TRH) injection were measured by radioimmunoassay (RIA). Results: The changes in body weight and adiposity were not different between UCP1 Bcl I, UCP2 alanine to valine (A55V), UCP2 insertion/deletion (I/D) or UCP3 Rsa I genotypes. However, the recovery from overfeeding was worse among G-allele carriers of the UCP1 Bcl I, I allele non-carriers of the UCP2 I/D, AV heterozygote subjects of the UCP2 A55V and CC subjects of the UCP3 Rsa I polymorphisms. RMR was lower both before (P=0.01) and after (P=0.001) overfeeding in subjects with the CC genotype of the UCP3 Rsa I polymorphism. Moreover, after overfeeding, the UCP2 A55V heterozygote and UCP3 Rsa I CC homozygote subjects had significantly higher respiratory quotient (RQ) values at rest (P

Objective: To study the relationship between consumption of milk and milk products, calcium, lactose and vitamin D and occurrence of colorectal cancers. Design: Prospective cohort study. Subjects: A total of 9959 men and women aged 15 y or older without history of cancer at baseline. During a 24 y follow-up, 72 new cancers of the large bowel (38 in the colon and 34 in the rectum) were detected. Results: Consumption of milk and total milk products was suggested to be inversely related to colon cancer incidence, whereas no similar association was seen for rectal cancer. The relative risk between the highest and lowest quartiles of intake adjusted for potential confounding factors was 0.46 (95% confidence interval 0.14–1.46, P for trend 0.09) for milk and 0.37 (95% CI=0.12–1.39, P for trend 0.06) for total milk products. Lactose intake showed a similar inverse relationship with colon cancer: the relative risk was 0.31 (95% CI=0.08–1.15, P for trend 0.03). Intake of vitamin D or total dietary calcium was not significantly related to colorectal cancer risk, whereas calcium provided by fermented milk products was associated with increased colorectal cancer incidence; in the highest quartile the multivariate adjusted relative risk for colorectal cancer was 2.07 (95% CI=1.00–4.28). Conclusions: Our results indicate that individuals showing high consumption of milk have a potentially reduced risk of colon cancer; however, the association does not appear to be due to intake of calcium, vitamin D, or to specific effects of fermented milk. Sponsorship: This study was supported by a grant from the Swedish Cancer Foundation. European Journal of Clinical Nutrition (2001) 55, 1000–1007

Objective: To demonstrate sexual dimorphism in serum leptin levels not only during puberty, but also in childhood in Japan. Design: Cross-sectional study. Setting: Hamamatsu-Hokuen study in Japan. Subjects: Body weight and height were measured in normal-weight Japanese children and adolescents (143 boys, 178 girls), and 161 boys and 129 girls whose percentage of overweight for the standard (%Wt) was more than+25%. Serum leptin levels were compared with %Wt. Subjects were divided into group 1 (6–10 y of age) and group 2 (11–15 y of age) according to their age. Results: In overweight subjects, leptin was more highly correlated with %Wt in boys of group 2 (r=0.67, P

Females have long been underrepresented in preclinical research and clinical drug trials. Directives by the U.S. National Institutes of Health have increased female participation in research protocols, although analysis of outcomes by sex remains infrequent. The long-held view that traits of female rats and mice are more variable than those of males is discredited, supporting equal representation of both sexes in most studies. Drug pharmacokinetic analysis reveals that, among subjects administered a standard drug dose, women are exposed to higher blood drug concentrations and longer drug elimination times. This contributes to increased adverse drug reactions in women and suggests that women are routinely overmedicated and should be administered lower drug doses than men. The past decade has seen progress in female inclusion, but key subsequent steps such as sex-based analysis and sex-specific drug dosing remain to be implemented.

Background: Beta blockers, mainly propranalol, are usually administered to control heart rate in patients with thyrotoxicosis, especially when congestive heart failure presents. However, when thyrotoxicosis is not controlled, heart rate may be difficult to control even with maximal doses of propranolol. This presentation alerts physicians to the possibility of using ivabradine, a selective inhibitor of the sinoatrial pacemaker, for the control of heart rate. Case presentation: We present a 37-year-old woman with thyrotoxicosis and congestive heart failure whose heart rate was not controlled with a maximal dose of beta blockers during a thyroid storm. The addition of ivabradine, a selective inhibitor of the sinoatrial pacemaker, controlled her heart rate within 48 hours. Conclusion: Ivabradine should be considered in patients with thyrotoxicosis, including those with heart failure, in whom beta blockers are insufficient to control heart rate

Findley first proposed the presence of age-related dysfunction of the hypothalamic-neurohypophyseal-renal axis more than 60 years ago. More sophisticated studies have since corroborated his findings. As a result, it is now clear that multiple abnormalities in water homeostasis occur commonly with aging, and that the elderly are uniquely susceptible to disorders of body volume and osmolality. This article summarizes the distinct points along the hypothalamic-neurohypophyseal-renal axis where these changes have been characterized, as well as the clinical significance of these changes, with special attention to effects on cognition, gait instability, osteoporosis, fractures, and morbidity and mortality.

PurposeStudies on the association between peripheral neuropathy (PN) and patient-reported outcomes have mostly overlooked sleep quality. Therefore, we aimed to assess the association between PN and sleep quality in a population-based sample of colorectal cancer (CRC) patients up two years after diagnosis. MethodsAll newly diagnosed CRC patients from four Dutch hospitals were eligible for participation. Patients (N=340) completed questionnaires about PN (EORTC QLQ-CIPN20) and sleep (PSQI) before initial treatment (baseline) and one and two years after diagnosis. ResultsPatients who developed sensory PN (n=76) or motor PN (n=79) after treatment more often reported poor sleeping scores (PSQI>5) compared with those who did not develop SPN or MPN at 1-year (SPN: 38% vs. 261%, MPN: 37% vs. 14%) and 2-year follow-up (SPN: 38 vs. 23%, MPN: 37% vs. 18%) (all pConclusionsBoth SPN and MPN were significantly associated with the course of sleep quality among CRC patients up to two years after diagnosis. Clinicians should be encouraged to discuss sleep quality with their patients who either report PN or are at risk of developing PN. Implications for survivors: Improving sleep quality among survivors with PN is important, either by reducing PN symptoms, or directly targeting sleep

This review will detail the embryology and morphology of the heart. We will begin with the heart's origin in the lateral plate mesoderm of the early embryo, review its fusion into a linear heart tube, followed by looping and remodeling to create a four-chambered organ with pulmonary and systemic venous inflow and pulmonary and systemic arterial outflow. We will discuss important concepts in heart development at genetic, cellular, and physiologic levels and review some key experimental models and methods important to the study of cardiac development. This review will also serve to introduce some of the congenital heart defects that can result from abnormalities in development and some of the genetic syndromes that are linked to congenital heart defects.

Thrombocytopenia is, after anemia, the most frequent hematological problem among sick neonates. In this population, thrombocytopenia has traditionally been defined as a platelet count 9 /L, and has been classified as mild (100–150 × 10 9 /L), moderate (50–99 × 10 9 /L), and severe ( 9 /L). However, large population-based studies have shown that platelet counts increase with advancing gestational age, and platelet counts between 100 and 150 × 10 9 /L are more frequent among otherwise healthy extremely preterm infants than among full term neonates or older children. This suggests that different definitions of thrombocytopenia and thrombocytosis should be applied to preterm infants. The diagnostic approach to a thrombocytopenic neonate is facilitated if the thrombocytopenia is categorized as “early onset” (within the first 72 hours of life, usually secondary to congenital or intrauterine abnormalities) or “late onset” (after 72 hours, usually due to acquired conditions). Importantly, infection/sepsis should always be considered near the top of the differential diagnosis, as any delay in diagnosis and treatment can have life-threatening consequences. While in vitro studies have clearly shown that neonatal platelets are hyporesponsive to most agonists, this platelet hyporeactivity is well compensated by factors in neonatal blood that increase clotting (i.e. high hematocrit, high VWF concentrations), resulting in adequate primary hemostasis. The risk of bleeding in thrombocytopenic neonates is poorly predicted by the platelet count; gestational age

• Infants born with ambiguous genitalia or nonpalpable testes need to be evaluated for congenital adrenal hyperplasia as it can be life threatening. • Adrenal steroid levels vary with gestational age. • Adrenal insufficiency should be treated with hydrocortisone to avoid adrenal crisis. High doses of hydrocortisone contain mineralocorticoid activity.

Chemotherapy can result in toxic side effects in the brain. Intake of marine-based omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alter brain fatty acids, potentially improving brain function. However, it is unclear if alpha-linolenic acid (ALA), the plant-based n-3, affects brain PUFAs during chemotherapy. The objective of this study was to examine the effects of dietary ALA, EPA and DHA, with high or low sucrose, on brain PUFAs in a mouse model of chemotherapy. Secondarily, the use of liver PUFAs as surrogate measures of brain PUFAs was examined. Lipid peroxidation (4-HNE) and neurotrophic markers (BDNF) were assessed. Female C57Bl/6 mice (n = 90) were randomized to 1 of 5 diets (high EPA + DHA/high or low sucrose, high ALA/high or low sucrose, or control with no EPA + DHA/low ALA/low sucrose) and injected with doxorubicin-based chemotherapy or saline. Brain EPA and DHA were greater (p < 0.0001) with high EPA + DHA diets, regardless of sucrose; there were no significant differences in brain PUFAs between high ALA diets and control. Chemotherapy-treated mice had higher brain and liver DHA (p < 0.05) and lower brain and liver linoleic acid (p < 0.0001). Brain n-3 and n-6 PUFAs were strongly correlated with liver n-3 (r = 0.8214, p < 0.0001) and n-6 PUFAs (r = 0.7568, p < 0.0001). BDNF was correlated with brain total PUFAs (r = 0.36; p < 0.05). In conclusion, dietary ALA in proportions approximately two times greater than consumed by humans did not appreciably increase brain n-3 PUFAs compared to low ALA intake. Liver PUFAs may be a useful surrogate marker of brain PUFAs in this mouse model.

Objective To compare outcomes after surgery between patients who were not prescribed opioids and patients who were prescribed opioids. Summary of background data Postoperative opioid prescriptions carry significant risks. Understanding outcomes among patients who receive no opioids after surgery may inform efforts to reduce these risks. Methods We performed a retrospective study of adult patients who underwent surgery between January 1, 2019 and October 31, 2019. The primary outcome was the composite incidence of an emergency department visit, readmission, or reoperation within 30 days of surgery. Secondary outcomes were postoperative pain, satisfaction, quality of life, and regret collected via postoperative survey. A multilevel, mixed-effects logistic regression was performed to evaluate differences between groups. Results In a cohort of 22,345 patients, mean age (standard deviation) was 52.1 (16.5) years and 13,269 (59.4%) patients were female. About 3175 (14.2%) patients were not prescribed opioids, of whom 422 (13.3%) met the composite adverse event endpoint compared to 2255 (11.8%) of patients not prescribed opioids (P = 0.015). Patients not prescribed opioids had a similar probability of adverse events {11.7% [95% confidence interval (CI) 10.2%-13.2%] vs 11.9% (95% CI 10.6%-13.3%]}. Among 12,872 survey respondents, patients who were not prescribed an opioid had a similar rate of high satisfaction [81.7% (95% CI 77.3%-86.1%) vs 81.7% (95% CI 77.7%-85.7%)] and no regret [(93.0% (95% CI 90.8%-95.2%) vs 92.6% (95% CI 90.4%-94.7%)]. Conclusions Patients who were not prescribed opioids after surgery had similar clinical and patient-reported outcomes as patients who were prescribed opioids. This suggests that minimizing opioids as part of routine postoperative care is unlikely to adversely affect patients.

Objective To examine the relationship between enoxaparin dose adequacy, quantified with anti-Factor Xa (aFXa) levels, and 90-day symptomatic venous thromboembolism (VTE) and post-operative bleeding. Summary background data Surgical patients often develop "breakthrough" VTE events-those which occur despite receiving chemical anticoagulation. We hypothesize that surgical patients with low aFXa levels will be more likely to develop 90-day VTE, and those with high aFXa will be more likely to bleed. Methods Pooled analysis of eight clinical trials (N = 985) from a single institution over a four year period. Patients had peak steady state aFXa levels in response to a known initial enoxaparin dose, and were followed for 90 days. Survival analysis log-rank test examined associations between aFXa level category and 90-day symptomatic VTE & bleeding. Results Among 985 patients, 2.3% (n = 23) had symptomatic 90-day VTE, 4.2% (n = 41) had 90-day clinically relevant bleeding, and 2.1% (n = 21) had major bleeding. Patients with initial low aFXa were significantly more likely to have 90-day VTE than patients with adequate or high aFXa (4.2% vs. 1.3%, p = 0.007). In a stratified analysis, this relationship was significant for patients who received twice daily (6.2% vs. 1.5%, p = 0.003), but not once daily (3.0% vs. 0.7%, p = 0.10) enoxaparin. No association was seen between high aFXa and 90-day clinically relevant bleeding (4.8% vs. 2.9%, p = 0.34) or major bleeding (3.6% vs. 1.6%, p = 0.18). Conclusions This manuscript establishes inadequate enoxaparin dosing as a plausible mechanism for breakthrough VTE in surgical patients, and identifies anticoagulant dose adequacy as a novel target for process improvement measures.

OBJECTIVE: To evaluate whether pathologic complete response (pCR) exclusively defines major pathologic response to treatment with improved survival. SUMMARY BACKGROUND DATA: pCR following trimodality therapy for esophagogastric adenocarcinoma is infrequent but associated with improved prognosis. Yet most clinical trials and correlative studies designate pCR as the primary endpoint. METHODS: We analyzed our prospectively maintained database for patients who underwent trimodality therapy for locally advanced esophageal adenocarcinoma between 1995 and 2017. Overall survival (OS) was examined by percentage treatment response (TR) in the primary tumor bed and pathologic nodal stage (ypN0) using Kaplan-Meier plots. Optimal thresholds of TR for differentiating patients in terms of OS were investigated with descriptive plots using restricted cubic spline functions; associations were quantified using Cox multivariable analysis. RESULTS: Among 788 patients, median follow-up was 37.5 months (range, 0.4–210.6); median OS was 48.3 months (95% CI, 42.2–58.8). Absence of residual nodal disease was independently associated with improved survival (P

Background: The optimal vasopressor management for septic patients with left ventricular (LV) dysfunction has not been well established, and current evidence is conflicting regarding the optimal vasopressor discontinuation order. Objective: The objective was to evaluate the impact of LV dysfunction on the hemodynamic management of septic shock by assessing the incidence of clinically significant hypotension after vasopressor discontinuation. Methods: In this single-center, retrospective cohort study, adult patients were included if they met the Sepsis-3 definition of septic shock, had LV dysfunction (defined as an ejection fraction ≤40%), and received norepinephrine and vasopressin as the last vasopressors discontinued. The primary outcome was the incidence of clinically significant hypotension following discontinuation of vasopressin or norepinephrine. Clinically significant hypotension was defined as a MAP less than 60 mmHg and the need for either: 1) the reinstitution of the previously discontinued agent at any dosage, 2) the receipt of at least 500 mL of a crystalloid at a rate of at least 500 mL/hour, 3) or the receipt of at least 25 grams of albumin 5% at a rate of at least 25 gram/hour. Secondary outcomes included intensive care unit (ICU) and hospital lengths of stay, and ICU and hospital mortality. Results: A total of 78 patients met inclusion criteria, with 37 patients having vasopressin discontinued first and 41 having norepinephrine discontinued first. Clinically significant hypotension occurred in 28 patients (76%) following the discontinuation of vasopressin, compared to 28 patients (81%) following the discontinuation of norepinephrine (p = 0.61). ICU length of stay was 9 days in the vasopressin discontinued first cohort, compared to 15 days in the norepinephrine discontinued first cohort (p = 0.01). There was no statistically significant difference in mortality observed. Conclusion: The discontinuation order of norepinephrine and vasopressin did not impact the incidence of clinically significant hypotension in patients with septic shock and LV dysfunction, but may influence ICU length of stay, although other factors may have impacted this finding.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disease caused by activating mutations in the arginine vasopressin (AVP) receptor-2 (AVPR2) gene. Affected patients excrete concentrated urine despite very low levels of AVP, and consequently develop euvolemic hyponatremia. Due to its low frequency, patients may be misdiagnosed and treated incorrectly. We report two related male infants with NSIAD that was initially confused with hyporeninemic hypoaldosteronism (HH). First, a 2-month-old male presented with hyponatremia, low plasma osmolality, relatively high urine osmolality, and low plasma renin-aldosterone levels. These clinical and laboratory findings were compatible with syndrome of inappropriate antidiuretic hormone secretion without apparent cause. Consequently,fludrocortisone was initiated with a presumptive diagnosis of HH While correction of hyponatremia, fludrocortisone treatment led to hypertension and discontinued in a short time. The second patient at age of 1 year was admitted with a history of oligohydramnios, four times hospitalizations due to hyponatremia since birth, and a diagnosis of epilepsy. Similarly, the second infant had clinical and laboratory findings compatible with syndrome of inappropriate antidiuretic hormone secretion with no apparent cause. Fluid restriction normalized his serum sodium despite plasma AVP level was undetectable. In both infants, AVPR2 gene analysis revealed a known mutation (c.409C>T; p.R137C) and confirmed the diagnosis of NSIAD. In conclusion, NSIAD should be considered in all patients with unexplained euvolemic hyponatremia despite high urine osmolality. In case of unawareness from NSIAD, plasma renin-aldosterone profile can be confused with HH, especially in the infants. 34645113

Variants of the melanocortin-4 receptor (MC4R) gene are the most common cause of monogenic obesity. In this situation; while obesity cannot be controlled with diet and exercise, it was shown that Glucagon-like-peptide-1 receptor agonists (GLP-1 RA) provide weight loss in short term. In this paper, we present our experience with Liraglutide treatment in an adolescent patient carrying MC4R gene variant. A female patient had admitted first at the age of 12.5 years with a complaint of progressive weight gain. She had a marked excess of appetite since infancy. In the physical examination of the pubertal female patient with a body mass index (BMI) of 36.1kg/m2 (3.48 SDS), there was no pathological finding except diffuse acanthosis nigricans. Laboratory examinations revealed only insulin resistance. Weight loss couldn't be achieved with lifestyle changes, metformin and orlistat treatments In genetic examination, a sporadic heterozygous c.206T>G(p.I69R) variant (reported previously) was found in the MC4R gene. GLP-1 RA Liraglutide treatment was initiated and a loss of 19.2% reduction was achieved in the patient's body weight and BMI at the end of 32 weeks. However, the patient, whose treatment compliance was disrupted due to significant gastrointestinal complaints, returned to her former weight within a few months after treatment was stopped. In our case carrying a pathogenic variant in the MC4R gene, decrease of appetite and weight loss were achieved with Liraglutide treatment, but this situation could not be maintained. In such cases, there is a need for effective and tolerable treatment options.

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and a whole gene deletion in the other) with early growth impairment in infancy. Growth hormone deficiency was confirmed at 20 months of life. Recombinant growth hormone treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia ( P ≤ .001); febrile neutropenia ( P = .002); and alopecia ( P < .001) were significantly lower, whereas grade 3 or 4 nausea ( P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Introduction GOLD 2017 report proposed that the combined COPD assessment should be done according only to symptom burden and exacerbation history in the previous year. Objective This study aims to investigate the change in the COPD groups after the GOLD 2017 revision and also to discuss the evaluation of group C and D as a single group after the GOLD 2019 report. Method The study was designed as a cross-sectional. 251 stable COPD patients admitted to our out-patient clinic; aged ≥40 years, at least one-year diagnosis of COPD and ≥10 pack-year smoking history were consecutively recruited for the study. Results In GOLD 2017, a significant difference was found between the distribution of all groups compared to GOLD 2011 (P = 0,001). 31 patients included in group C were reclassified into group A and 37 patients in group D were reclassified into group B. The FEV1 values of group A and B patients were significantly low and group C and D patients had had exacerbations in more frequently the previous year in GOLD 2017 compared to GOLD 2011. Conclusion After the GOLD 2017 revision, the rate of group C patients decreased even more compared to GOLD 2011 and the group C and D may be considered as a single group in terms of the treatment recommendations with the GOLD 2019 revision. We think that future prospective studies are needed to support this suggestion.

INTRODUCTION Advances in the treatment of myasthenia gravis (MG) have improved quality of life and prognosis for the majority of patients. However, 10%-20% of patients present refractory MG, with frequent relapses and significant functional limitations. PATIENTS AND METHODS Patients with refractory MG were selected from a cohort of patients diagnosed with MG between January 2008 and June 2019. Refractory MG was defined as lack of response to treatment with prednisone and at least 2 immunosuppressants, inability to withdraw treatment without relapse in the last 12 months, or intolerance to treatment with severe adverse reactions. RESULTS We identified 84 patients with MG, 11 of whom (13%) met criteria for refractory MG. Mean (standard deviation) age was 47 (18) years; 64% of patients with refractory MG had early-onset generalised myasthenia (as compared to 22% in the group of patients with MG; P

We performed a retrospective analysis of the patients assessed at our memory unit for whom Alzheimer disease (AD) cerebrospinal fluid biomarker results were available. We selected patients diagnosed with mild cognitive impairment due to AD (National Institute on Aging-Alzheimer's Association clinical criteria), confirmed neuropsychological deficit, a Global Deterioration Scale score of 3, and an abnormal profile of cerebrospinal fluid biomarkers. Of the 588 cases reviewed, 110 met the inclusion criteria. During follow-up, 50 cases (45.45%) progressed to dementia due to AD. Baseline levels of total and phosphorylated tau were higher in the group of patients that progressed to dementia than in those remaining with mild cognitive impairment. After adjusting for age, sex, history of hypertension, diabetes, and educational level, a 10% increase in total tau protein values was associated with a 7.60% increase in the risk of progression to dementia (hazard ratio: 2.22; 95% confidence interval, 1.28-3.84]; P = .004). Among patients with mild cognitive impairment due to AD and abnormal cerebrospinal fluid biomarker profiles, progressively higher concentrations of total or phosphorylated tau were associated with increased risk of progression to dementia.

Background The aim of this study was to review, systematically, evidence concerning the link between the ACTN3 R577X polymorphism and the rates and severity of non-contact injuries and exercise-induced muscle damage in athletes and individuals enrolled in exercise training programs. Methods A computerized literature search was performed in the electronic databases PubMed, Web of Science, and SPORTDiscus, from inception until November 2020. All included studies compared the epidemiological characteristics of non-contact injury between the different genotypes of the ACTN3 R577X polymorphism. Results Our search identified 492 records. After the screening of titles, abstracts, and full texts, 13 studies examining the association between the ACTN3 genotypes and the rate and severity of non-contact injury were included in the analysis. These studies were performed in 6 different countries (Spain, Japan, Brazil, China, Republic of Korea, and Italy) and involved a total participant pool of 1093 participants. Of the studies, 2 studies involved only women, 5 studies involved only men, and 6 studies involved both men and women. All the studies included were classified as high-quality studies (≥6 points in the Physiotherapy Evidence Database (PEDro) scale score). Overall, evidence suggests there is an association between the ACTN3 R577X genotype and non-contact injury in 12 investigations. Six studies observed a significant association between ACTN3 R577X polymorphism and exercise induced muscle damage: two with non-contact ankle injury, three with non-contact muscle injury, and one with overall non-contact injury. Conclusion The present findings support the premise that possessing the ACTN3 XX genotype may predispose athletes to a higher probability of some non-contact injuries, such as muscle injury, ankle sprains, and higher levels of exercise-induced muscle damage.

Background: Fetal development is crucially dependent on thyroid hormone (TH). Maternal-to-fetal transfer of TH is a prerequisite for fetal TH availability, particularly in the first half of pregnancy. The mechanisms of transplacental transport of TH, however, are yet poorly understood. We, therefore, investigated the TH transport processes across human placentas using an ex vivo perfusion system. Methods: Intact cotyledons from term placentas of uncomplicated pregnancies were cannulated within 30 minutes after delivery and the maternal and fetal circulations were re-established. One hundred nanomolar thyroxine (T4) was added to either the maternal or fetal circulation and perfusions run up to three hours during which samples were taken from both circulations at different time points. Variables included addition of iopanoic acid (IOP) to block activity of the deiodinase type 3 (D3) and bovine serum albumin (BSA) to trap released T4. T4 and 3,3',5'-triiodothyronine concentrations in the perfusates were measured by radioimmunoassays. Results: Maternal-to-fetal transfer was slow, with T4 barely detectable in the fetal circulation unless D3 was blocked by IOP. Fetal T4 was detected after three hours perfusion (10.6 ± 0.6 nM) when BSA (34 g/L) was added in the fetal circulation to trap the released T4. In contrast, fetal-to-maternal transfer of T4 was rapid and maternal T4 increased to 43.6 ± 5.5 nM. Conclusions: Maternal-to-fetal T4 transport is limited, whereas fetal-to-maternal transport is rapid indicating that T4 transport across human term placenta is an asymmetrical process. With the high D3 activity, our observations are compatible with a protective role of the placental barrier. Future studies should reveal how the placenta exerts its gatekeeper function in ensuring optimal TH passage to the fetus.

Kidney disease is frequent in HIV-patients. We present a case of a 44-year-old woman, with known uncontrolled HIV infection and chronic kidney disease due to HIV-associated nephropathy. After starting dolutegravir, the patient developed eosinophilia and worsening kidney function. A kidney biopsy confirmed the diagnosis of acute interstitial nephritis. Given the time relation with dolutegravir introduction, it was deemed the culprit medication. Dolutegravir was stopped, and corticosteroids were initiated, with moderate improvement in renal function. To our knowledge, this is the first reported case of acute interstitial nephritis to dolutegravir, which should raise awareness of previously undocumented renal effects of antiretroviral therapy.

Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R0.50; adjusted p0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.

Introduction Thrombectomy in the carotid artery territory was recently shown to be effective up to 24 hours after symptoms onset. Methods We conducted a retrospective review of a prospective registry of patients treated at our stroke reference centre between November 2016 and April 2019 in order to assess the safety and effectiveness of mechanical thrombectomy performed beyond 6 hours after symptoms onset in patients with acute ischaemic stroke and large vessel occlusion in the carotid artery territory. Results Data were gathered from 59 patients (55.9% women; median age, 71 years). In 33 cases, stroke was detected upon awakening; 57.6% of patients were transferred from another hospital. Median baseline NIHSS score was 16, and median ASPECTS score was 8, with 94.9% of patients presenting > 50% of salvageable tissue. Satisfactory recanalisation was achieved in 88.1% of patients, beyond 24 hours after onset in 5 cases. At 90 days of follow-up, 67.8% were functionally independent; those who were not were older and presented higher prevalence of atrial fibrillation, greater puncture-to-recanalisation time, and higher NIHSS scores, both at baseline and at discharge. Conclusion In our experience, mechanical thrombectomy beyond 6 hours was associated with good 90-day functional outcomes. Age, NIHSS score, puncture-to-recanalisation time, and presence of atrial fibrillation affected functional prognosis. The efficacy of the treatment beyond 24 hours after onset merits study.

PURPOSE: Hip fractures among elderly patients are surgical emergencies. During COVID-19 pandemic time, many such patients could not be operated at early time because of the limitation of the medical resources, the risk of infection and redirection of medical attention to a severe infective health problem. METHODS: A search of electronic databases (PubMed, Medline, CINAHL, EMBASE and the Cochrane Central Register of Controlled Trials) with the keywords "COVID", "COVID-19″, "SARS-COV-2", "Corona", "pandemic", "hip fracture", "trochanteric fracture" and "neck femur fracture" revealed 64 studies evaluating treatment of hip fracture in elderly patients during COVID-19 pandemic time. The 30-day mortality rate, inpatient mortality rate, critical care/special care need, readmission rate and complications rate in both groups were evaluated. Data were analyzed using Review Manager (RevMan) V.5.3. RESULTS: After screening, 7 studies were identified that described the mortality and morbidity in hip fractures in both COVID-19 infected (COVID-19 +) and non-infected (COVID-19 -) patients. There were significantly increased risks of 30-day mortality (32.23% COVID-19 + death vs. 8.85% COVID-19 - death) and inpatient mortality (29.33% vs. 2.62%) among COVID-19 + patients with odds ratio (OR) of 4.84 (95% CI: 3.13-7.47, p

Background High flow oxygen therapy (HFO) is a widely used intervention for pulmonary complications. Amid the coronavirus infectious disease 2019 (COVID-19) pandemic, HFO became a popular alternative to conventional oxygen supplementation therapies. Risk stratification tools have been repurposed –and new ones developed– to estimate outcome risks among COVID-19 patients. This study aims to provide a simple risk stratification system to predict invasive mechanical ventilation (IMV) or death among COVID-19 inpatients on HFO. Methods Among 529 adult inpatients with COVID-19 pneumonia, we selected unadjusted clinical risk factors for developing the composite endpoint of IMV or death. The risk for the primary outcome by each category was estimated using a Cox proportional hazards model. Bootstrapping was used to validate the results. Results Age above 62, eGFR under 60 ml/min, room air SpO2 ≤89 % upon admission, history of hypertension, history of diabetes, and any comorbidity (cancer, cardiovascular disease, COPD/ asthma, hypothyroidism, or autoimmune disease) were considered for the score. Each of the six criteria scored 1 point. The score was further simplified into 4 categories: 1) 0 criteria, 2) 1 criterion, 3) 2-3 criteria, and 4) ≥4 criteria. Taking the first category as the reference, risk estimates for the primary endpoint were HR; 2.94 [1.67 – 5.26], 4.08 [2.63 – 7.05], and 6.63 [3.74 – 11.77], respectively. In ROC analysis, the AUC for the model was 0.72. Conclusions Our score uses simple criteria to estimate the risk for IMV or death among COVID-19 inpatients with HFO. Higher category reflects consistent increases in risk for the endpoint.

Introduction and Objectives Obstructive sleep apnea (OSA) is a prevalent sleep condition which is very heterogeneous although not formally characterized as such, resulting in missed or delayed diagnosis. Cluster analysis has been used in different clinical domains, particularly within sleep disorders. We aim to understand OSA heterogeneity and provide a variety of cluster visualizations to communicate the information clearly and efficiently. Materials and Methods We applied an extension of k-means to be used in categorical variables: k-modes, to identify OSA patients’ groups, based on demographic, physical examination, clinical history, and comorbidities characterization variables (n = 40) obtained from a derivation and validation cohorts (211 and 53, respectively) from the northern region of Portugal. Missing values were imputed with k-nearest neighbours (k-NN) and a chi-square test was held for feature selection. Results Thirteen variables were inserted in phenotypes, resulting in the following three clusters: Cluster 1, middle-aged males reporting witnessed apneas and high alcohol consumption before sleep; Cluster 2, middle-aged women with increased neck circumference (NC), non-repairing sleep and morning headaches; and Cluster 3, obese elderly males with increased NC, witnessed apneas and alcohol consumption. Patients from the validation cohort assigned to different clusters showed similar proportions when compared with the derivation cohort, for mild (C1: 56 vs 75%, P = 0.230; C2: 61 vs 75%, P = 0.128; C3: 45 vs 48%, P = 0.831), moderate (C1: 24 vs 25%; C2: 20 vs 25%; C3: 25 vs 19%) and severe (C1: 20 vs 0%; C2: 18 vs 0%; C3: 29 vs 33%) levels. Therefore, the allocation supported the validation of the obtained clusters. Conclusions Our findings suggest different OSA patients’ groups, creating the need to rethink these patients’ stereotypical baseline characteristics.

Uterine contractions during labor and engagement of the fetus in the birth canal can compress the fetal head. Its impact on the fetus is unclear and still controversial. In this integrative physiological review, we highlight evidence that decelerations are uncommonly associated with fetal head compression. Next, the fetus has an impressive ability to adapt to increased intracranial pressure through activation of the intracranial baroreflex, such that fetal cerebral perfusion is well-maintained during labor, except in the setting of prolonged systemic hypoxemia leading to secondary cardiovascular compromise. Thus, when it occurs, fetal head compression is not necessarily benign but does not seem to be a common contributor to intrapartum decelerations. Finally, the intracranial baroreflex and the peripheral chemoreflex (the response to acute hypoxemia) have overlapping efferent effects. We propose the hypothesis that these reflexes may work synergistically to promote fetal adaptation to labor.

Background Acute respiratory infections (ARIs) are responsible for considerable morbidity and mortality among children all over the world. Many of the etiologic agents of the infections especially viral go undiagnosed for lack of requisite facility and the cost factors. We have used a commercially available platform for diagnosis of ARIs in children receiving inpatient and outpatient services in a tertiary care centre. Methods The framework of the study was prospective and observational. In this study, clinical samples of children suffering from ARIs were subjected to real-time multiplex PCR targeting both viral and bacterial pathogens. Results Of 94 samples received at our centre (49 male and 45 female), the positivity for respiratory pathogens was detected in 50 (53.19%) samples. Clinical symptoms of patients and age distribution have been elaborated in text. A single pathogen (n = 29/50), two pathogens (15/50) and three pathogens (n = 6/50) were detected by multiplex RT-PCR. Of 77 isolates detected, maximum numbers were of human rhinovirus (HRV) (n = 14) (18.18%) Streptococcus pneumoniae (n = 14) (18.18%) followed by Staphylococcus aureus (n = 10) (12.98%). Conclusion The epidemiology of ARIs considering viral etiologies is poorly understood due to less number of studies especially in Indian subcontinent. The advent of latest advanced molecular methods has made it possible to identify common respiratory pathogens and has contributed to cover the gap in existing knowledge.

Objectives: Potential thrombotic and antifibrinolytic influence of endometriosis on haemostasis has been recently reported in the literature, as well as increased cardiovascular morbidity in women suffering from the disease. We performed a pilot study to assess the influence of endometriosis on the thrombus formation process under in vitro flow conditions. Material and methods: This study compared women with confirmed endometriosis (n = 23) surgically and control healthy subjects (n = 10). In both groups, the same exclusion criteria were used: a prior episode of thrombosis diagnosed as acquired or inherited thrombophilia, neoplasm, and an uncertain family history of thrombosis. We evaluated the whole blood thrombogenicity using T-TAS® at a shear rate of 240 s-1 (Total-Thrombus Analysis System, Zacros, Japan). Results: The blood clot formation initiation time (T10) and occlusion time (OT) were significantly shortened in the endometriosis group (p < 0.05). The area under the curve (AUC30) of blood clot time formation values (BCTF) was substantially higher in the patients suffering from a disease (p = 0.03). An increase in AUC (TTAS) values by 100 increases the risk of developing endometriosis by 1.56-fold [adjusted OR = 1.56 (p = 0.01);(95% CI: 1.10–2.18)]. Inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), and the leucocyte, neutrophil, basophil, and neutrophil concentrations) were also substantially higher in the endometriosis group (p < 0.05). Conclusions: The alteration of the T-TAS and NLR values supports the thesis of a shift of the equilibrium towards thrombosis in women who have endometriosis. This phenomenon links to a state of chronic inflammation. It is detectable using a novel system for the quantitative assessment of the platelet thrombus formation process under flow conditions in vitro .

PURPOSE Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm ( P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months ( P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm ( P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Background: Cardiac magnetic resonance imaging (CMR) remains underutilized as an exercise imaging modality, mostly because of the limited availability of MR-compatible exercise equipment. This study prospectively evaluates the clinical feasibility of a newly developed MR-conditional pedal ergometer for exercise CMR Methods: Ten healthy volunteers (mean age 44 ± 16 years) and 11 patients (mean age 60 ± 9 years) with known or suspected coronary artery disease (CAD) underwent rest and post-exercise cinematic 3T CMR. Visual analysis of wall motion abnormalities (WMA) was rated by 2 experienced radiologists, and volumes and ejection fractions (EF) were determined. Image quality was assessed by a 4-point Likert scale for visibility of endocardial borders. Results: Median subjective image quality of real-time Cine at rest was 1 (IQR 1–2) and 2 (IQR 2–2.5) for post-exercise real-time Cine (p = 0.001). Exercise induced a significant increase in heart rate (62 [62–73] to 111 [104–143] bpm, p < 0.0001). Stroke volume and cardiac index increased from resting to post-exercise conditions (85 ± 21 to 101 ± 19 mL and 2.9 ± 0.7 to 6.6 ± 1.9 L/min/m 2 , respectively; both p < 0.0001), driven by a reduction in end-systolic volume (55 ± 20 to 42 ± 21 mL, p < 0.0001). Patients (2/11) with inducible regional WMA at high-resolution post-exercise cine imaging revealed significant coronary artery stenosis in subsequently performed invasive coronary angiography. Conclusion: Exercise-CMR using our newly developed 3T MR-conditional pedal ergometer is clinically feasible. Imaging of both cardiac response and myocardial ischemia, triggered by dynamic stress, is rapidly conducted while the patient is near their peak heart rate.

Background: Cardiac amyloidosis (CA), following a non-invasive diagnosis, constitutes an increasingly prevalent heart failure (HF) etiology. This study aims to determine which echocardiography findings help to diagnose cardiac amyloidosis in patients with left ventricular hypertrophy (LVH) admitted for decompensated HF. M ethods: The present study is a retrospective observational study on a cohort of 85 LVH patients admitted for HF decompensation, in which 99m Tc-DPD scanning was performed to rule out transthyretin CA. The echocardiographic findings obtained were compared between CA and non-CA groups. Results: From a total number of 85 patients, 49 (57.6%) met the CA criteria and 36 (42.3%) were ruled out for the disease. Interventricular septum thickness (16 ± 3 mm vs. 14 ± 3 mm), left ventricular posterior wall thickness (14 ± 3 mm vs. 11 ± 2 mm), left ventricular mass (259 ± 76 g vs. 224 ± 53 g), left ventricular telediastolic diameter (48 ± 7 mm vs. 53 ± 6 mm), left ventricular telediastolic indexed volume (51 ± 18 cm 3 /m 2 vs. 59 ± 16 cm 3 /m 2 ), tricuspid annular plane systolic excursion (16 ± 5 mm vs. 20 ± 4 mm), right atrial area (27.4 ± 8.4 cm 2 vs. 22.2 ± 5.7 cm 2 ) and strain relative apical sparing (2.2 ± 0.9 vs. 1.03 ± 0.4; p = 0.04) were significantly associated with the diagnosis of CA. Conclusions: In patients with LVH admitted for HF decompensation, there are several echocardiographic features (LVH, reduced left ventricular cavity size, strain relative apical sparing, right atrial dilation, and altered right ventricular function) that are associated with the diagnosis of cardiac amyloidosis.

Background: In patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), the treatment strategy for non-infarct-related artery (non-IRA) remains controversial. Quantitative flow ratio (QFR) is a new angiography-based physiological assessment index. However, there is little evidence on the practical clinical application of QFR. Methods: Two hundred and twenty-nine patients with STEMI and MVD were recruited for this study. Patients were randomly assigned to either receive QFR-guided complete revascularization (QFR-G-CR) of non-IRA or receive no further invasive treatment. The primary (1o) endpoint analyzed included death due to all causes, non-fatal myocardial infarction (MI), and ischemia-induced revascularization at 12 months post-surgery. Secondary (2o) endpoints included cardiovascular death, unstable angina, stent thrombosis, New York Heart Association (NYHA) class IV heart failure (HF), and stroke at 1 year post surgery. Massive bleeding and contrast-associated acute kidney injury (CAKI) were used as safety endpoints. Results: Around the 12 month follow up, the 1o outcome was recorded in 11/115 patients (9.6%) in the QFR-G-CR population, relative to 23/114 patients (20.1%) in the IRA-only PCI population (hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.22–0.92; p = 0.025). Unstable angina in 6 (5.2%) and 16 (14.0%) patients (HR: 0.36; 95% CI: 0.14–0.92; p = 0.026), respectively. No marked alterations were found in the massive bleeding and CAKI categories. Conclusions: In conclusion, STEMI and MVD patients can benefit from QFR-G-CR of non-IRA lesions in the initial stages of acute MI. This can help reduce incidences of major adverse cardiovascular events and unstable angina, relative to IRA treatment only. Chinese Clinical Trial Registration number: ChiCTR2100044120.

Background: Current guidelines recommend electrical cardioversion (ECV) in patients with atrial fibrillation (AF) after at least 3 weeks of adequate non-vitamin K antagonist oral anticoagulant (NOAC) treatment without prior transesophageal echocardiography (TEE). However, in clinical practice in some centres, TEE is performed before ECV in patients with AF. The aim of the study was to evaluate prevalence of thromboembolic and hemorrhagic complications in patients with AF treated with NOACs and undergoing ECV without prior TEE. Methods: This observational, multicentre study included consecutive patients with AF treated with NOACs who were admitted for ECV without prior TEE. Thromboembolic events and major bleeding complications were investigated during a 30-day follow-up. Results: In the study group there were 611 patients, mean age was 66.3 ± 9.2 years, 40% were women. 52 (8.5%) patients had a low thromboembolic risk, 148 (24.2%) patients had an intermediate thromboembolic risk and 411 (67.2%) patients had a high thromboembolic risk. In the study group 253 (41.4%) patients were treated with rivaroxaban, 252 (41.2%) patients were treated with dabigatran and 106 (17.3%) patients were treated with apixaban. Reduced doses of NOACs were administered to 113 (18.9%) patients. In the entire study group, there were no thromboembolic events or major bleeding complications during the in-hospital stay and the 30-day follow-up. Conclusions: In this “real-world” study of AF patients treated with NOACs, it was proved that ECV is safe without a preceding TEE, regardless of the risk of thromboembolic complications and of the type of NOAC used.

Background: The purpose of this study was to compare the safety and clinical outcomes of transcarotid (TC) and transapical access (TA) transcatheter aortic valve implantation (TAVI) patients whom the transfemoral approach (TF) was not feasible. Methods: The analysis included consecutive patients with severe symptomatic aortic stenosis treated from 2017 to 2020 with TC-TAVI or TA-TAVI in two high-volume TAVI centers. The approach was selected by multidisciplinary heart teams after analyzing multislice computed tomography of the heart, aorta and peripheral arteries, transthoracic echocardiography and coronary angiography. Results: One hundred and two patients were treated with alternative TAVI accesses (TC; n = 49 and TA; n = 53) in our centers. The groups were similar regarding age, gender, New York Heart Association class, and echocardiography parameters. Patients treated with TC-TAVI had significantly higher surgical risk. The procedural success rate was similar in both groups (TC-TAVI 98%; TA-TAVI 98.1%; p = 0.95). The rate of Valve Academic Research Consortium-2 defined clinical events was low in both groups. The percentage of new-onset rhythm disturbances and permanent pacemaker implantation was similar in TC and TA TAVI (4.1% vs. 11.3%; p = 0.17 and 10.2% vs. 5.7%; p = 0.39, respectively). In the TA-TAVI group, significantly more cases of pneumonia and blood transfusions were observed (11% vs. 0%; p = 0.01 and 30.2% vs. 12.2%; p = 0.03). The 30-day mortality was similar in TC and TA groups (4.1% vs. 5.7%; p = 0.71, respectively). Conclusion: Both TC and TA TAVI are safe procedures in appropriately selected patients and are associated with a low risk of complications.

Investigating the prognostic value of the Murray law-based quantitative flow ratio (μQFR) on the clinical outcome after treatment of in-stent restenosis (ISR) with a drug-coated balloon (DCB).Patients participating in a previous randomized clinical trial for DCB-ISR were post-hoc analyzed. The primary endpoint was vessel-oriented composite endpoint (VOCE), defined as cardiac death, target vessel-related myocardial infarction, and ischemia-driven target vessel revascularization. μQFRs at baseline and after DCB angioplasty was calculated, and its prognostic value as a predictor of VOCE was explored in Cox regression.A total of 169 lesions in 169 patients were analyzed. At one-year follow-up, 20 VOCEs occurred in 20 patients. Receiver-operating characteristic curve analysis identified a post-procedural μQFR of ≤ 0.89 as the best cut-off to predict VOCE (area under curve [AUC]: 0.74; 95% confidence interval [CI]: 0.67-0.80; p0.001), superior to post-procedural in-stent percent diameter stenosis (DS), which reported an AUC of 0.61 (95% CI: 0.53-0.68; p = 0.18). Post-procedural μQFR was significantly lower in patients with VOCE compared with those without (0.88 [interquartile range: 0.79-0.94] vs. 0.96 [interquartile range: 0.91-0.98], respectively; p0.001). After correction for potential confounders, post-procedural μQFR ≤ 0.89 was associated with a 6-fold higher risk of VOCE than lesions with μQFR0.89 (hazard ratio: 5.94; 95% CI: 2.33-15.09; p0.001).Post-procedural μQFR may become a promising predictor of clinical outcome after treatment of DES-ISR lesions by DCB angioplasty.

Background Anger has been suggested as a risk factor for stroke. Perceived social support (PSS) may relieve anger, thus reducing the risk of stroke; however, evidence supporting this is limited. We aimed to examine whether PSS modifies the risk of stroke associated with anger expression. Methods A cohort study was conducted among 1,806 community residents aged 40-74 years who received a cardiovascular risk survey including anger expression in 1997. A Cox proportional hazards model was applied to the participants with low and high PSS to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of the risks of total stroke and its subtypes based on total anger expression after adjusting for known stroke risk factors. Results The median follow-up duration was 18.8 years, with 51 incident strokes. Among the participants with low PSS, anger expression had a positive association with the total stroke risk: The multivariable HR per SD increment of total anger expression was 1.43 (95% CI, 1.13-1.82). In contrast, no association was identified among those with high PSS. The corresponding HR was 0.83 (95% CI, 0.49-1.40), with a significant interaction between low and high PSS (p = 0.037). Similar associations regarding the risk of ischemic stroke were found. Conclusions We found an increased risk of stroke associated with anger expression among the participants with low PSS, but not among those with high PSS. Our results suggest that PSS might mitigate the risk of stroke associated with anger.

Objectives Acute and chronic allograft rejection have been continuously an important obstacle in the follow-up of renal transplant recipients. During clinical management, several factors acting simultaneously result in acute rejection and chronic allograft nephropathy. Matrix metalloproteinases and tissue inhibitors of metalloproteinases are responsible for the organization of the extracellular matrix and play roles in cell proliferation and cellular invasion. Changes in matrix metalloproteinase expression levels have been reported to be associated with renal allograft rejection and interstitial fibrosis. In this study, we aimed to investigate functional polymorphisms of MMP2, MMP9, and TIMP2 genes in pediatric renal transplant recipients. Materials and methods Our study included 68 kidney transplant recipients and 58 control patients. The kidney transplant recipient group was further divided into 2 subgroups: no graft rejection (n = 47) and graft rejection (n =21). MMP2 -735C >T (rs2285053), MMP2 -1306C >T (rs243865), MMP2 -1575G >A (rs243866), MMP9 c.-1562C >T (rs3918242), TIMP2 -418G >C (rs8179090), and TIMP2 303C > T (rs2277698) polymorphisms were analyzed with the use of polymerase chain reaction and restriction fragment-length polymorphism methods. Allele prevalence was compared with reference values of the control group, and Hardy-Weinberg equilibrium was tested. Results Mean ages were 16.7 ± 3.9 years for the study group and 14.8 ± 5.6 years for the control group. The mean follow-up time after transplant was 37.7 ± 7.9 months. We compared allele frequencies in the 2 groups and calculated a statistically significant difference in rs2285053, rs243865, rs243866, rs3918242, rs8179090, and rs2277698 polymorphism frequencies between the transplant recipients and control patients. When the transplant recipient group was compared in itself with regard to allograft rejection, all investigated polymorphisms except TIMP2 -418G >C (rs8179090) revealed a statistically significant difference between those with and without rejection (P Conclusions Matrix metalloproteinases and their tissue inhibitors could be important predictive biological markers for the follow-up of kidney transplant recipients.

PURPOSE Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates ( P < .0001) and 3-year overall survival (OS) rates ( P < .0001). TNBC was associated with increased risk for visceral metastases ( P = .0005), lower risk for bone recurrence ( P = .027), and shorter postrecurrence survival ( P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival ( P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC ( P < .0001). CONCLUSION Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

Lysosomal acid lipase (LAL) deficiency is a rare, autosomal recessive disease caused by mutations in the LIPA gene, which produces cholesteryl ester and triglyceride accumulation predominantly in hepatocytes, adrenal glands, and gastrointestinal tract. We describe two new cases occurring in siblings, aged 5 and 7 years, who presented with hepatomegaly, dyslipidemia, and abnormal liver function. Percutaneous liver biopsy revealed portal inflammation, hypertrophic Kupffer cells with a foamy appearance and microvesicular steatosis with fibrosis. Immunostaining for lysosomal markers, cathepsin D and LAMP1 reflected the lysosomal nature of the lipid vacuoles. After enzymatic confirmation, enzyme replacement therapy was initiated for both siblings. Follow-up transaminase levels and lipid profiles showed a notable decrease in AST and ALT and a slight increase in HDL cholesterol. It is crucial to increase awareness of this rare condition among clinicians and pathologists. The expression of lysosomal markers around the lipid vacuoles might help diagnose LAL deficiency in pediatric patients.

Objective The study objective was to determine whether mini-invasive transthoracoscopic atrial fibrillation ablation can delay the progression of atrial fibrillation from paroxysmal to persistent. Methods Patients aged 18 to 80 years with paroxysmal nonvalvular atrial fibrillation and a history of stroke or systemic thromboembolism were consecutively enrolled from September 2014 to June 2019. In the treatment group, patients underwent transthoracoscopic atrial fibrillation ablation plus left atrial appendage excision (atrial fibrillation ablation plus left atrial appendage excision group). Patients unwilling to receive surgical intervention were treated with antiarrhythmic drugs and oral anticoagulants and recruited as a control group (atrial fibrillation plus antiarrhythmic drugs group). The primary end point was the progression of atrial fibrillation from paroxysmal to persistent. Results This study included 49 patients in the atrial fibrillation plus antiarrhythmic drugs group (29 men) and 77 patients in the atrial fibrillation ablation plus left atrial appendage excision group (48 men). In the atrial fibrillation ablation plus left atrial appendage excision group, after a median follow-up of 951 days (interquartile range, 529-1366 days), 8 patients (10.4%) progressed to persistent atrial fibrillation. In the atrial fibrillation plus antiarrhythmic drugs group, after a median follow-up of 835 days (interquartile range, 548-1214 days), 14 patients (28.6%) progressed to persistent atrial fibrillation. The atrial fibrillation ablation plus left atrial appendage excision group had a significantly lower incidence of atrial fibrillation progression than the atrial fibrillation plus antiarrhythmic drugs group during follow-up (3.9 vs 12.3 per 100 person-years, log-rank 8.6, P = .003). Conclusions Patients with paroxysmal nonvalvular atrial fibrillation who chose to undergo transthoracoscopic atrial fibrillation ablation had a lower incidence of progression to persistent atrial fibrillation than patients who chose conservative therapy. This strategy might be especially suitable for patients with paroxysmal nonvalvular atrial fibrillation at high risk of stroke and high risk of bleeding.