bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonlethal Raine Syndrome in a Newborn Boy Caused by a Novel FAM20C Variant
Authors: Eras Nazan , Celik Yalcin
Published: March 2021

Raine syndrome (RS) is a rare genetic disorder characterized by osteosclerotic bone dysplasia caused by a homozygous mutation, compound heterozygous mutation, or microdeletion in the FAM20C gene. In the present study, the MiSeq next-generation sequencing platform was used to perform the FAM20C gene sequence analysis. A novel homozygous variant c.1255T>C (p.W419R) in the FAM20C gene was diagnosed, and a nonlethal RS phenotype was confirmed, thus contributing to the expansion of the nonlethal RS phenotype. Since there is limited information about rare diseases, we believe that these studies will contribute to the literature and to the understanding of how these disorders develop and progress.
Atrial Fibrillation and Mortality in the Oldest Old after Surgery for Hip Fractures
Authors: Frenkel Amit , Zeldetz Vladimir , Gat Roni , Binyamin Yair , Acker Asaf , Frenkel Merav , Klein Moti , Novack Victor , Schwarzfuchs Dan
Published: March 2021

Introduction: One-year mortality following hip fractures increases steeply with age, from 2% in the 60- to 69-year-old population up to 28% in the oldest old (older than 90 years). Of the various factors that contribute to hip fractures, atrial fibrillation (AF) is an independent risk factor at any age. Objective: The objective of this study was to assess the association of AF with mortality among the oldest old with hip fractures. Method: This is a retrospective cohort study of 701 persons above age 90 years who underwent orthopedic repair for a hip fracture during 2000–2018. Of them, 218 (31%) had AF at hospital admission. The primary outcome was survival following surgery. We compared patient characteristics and 30-day, 180-day, 1-year, and 3-year survival between patients with and without AF. Results: The adjusted odds ratio for 30-day postoperative mortality for those with AF versus without AF group was 1.03 (95% confidence interval [CI] 0.63–1.66). Survival estimates were higher among those without AF than with AF at 180 days postoperative: 0.85 (95% CI 0.82–0.89) versus 0.68 (95% CI 0.61–0.74), p < 0.001; at 1 year postoperative: 0.68 (95% CI 0.63–0.72) versus 0.48 (95% CI 0.42–0.55), p < 0.001; and at 3 years postoperative: 0.47 (95% CI 0.42–0.52) versus 0.28 (95% CI 0.27–0.34), p < 0.001. Conclusions: Among individuals aged >90 years, operated for hip fractures, mortality was similar for those with and without AF at 30 days postoperative. However, the survival curves diverged sharply after 180 days. Our findings suggest that AF is not an immediate surgical risk factor, but rather confers increased long-term risk in this population.
Predictors of Nodal Pathological Complete Response in Asian Women with Stage II–III Node-Positive Breast Cancer
Authors: Montagna Giacomo , Tong Yiwei , Ritter Mathilde , Levi Jeremy , Weber Walter P. , Chen Xiaosong , Shen Kunwei
Published: March 2021

Background: Neoadjuvant chemotherapy (NAC) is increasingly used to treat node-positive (N+) breast cancer. Predictors of nodal pathological complete response (pCR) in Asian women are poorly described and there is variety in the management of the axilla after NAC. We evaluated predictors of nodal pCR and axillary management in a cohort of Asian N+ patients. Methods: Consecutive biopsy-proven N+ breast cancer patients treated with NAC were identified from the Shanghai Ruijin Hospital in China. Axillary lymph node dissection was performed on all patients, irrespective of the nodal response to NAC. Results: A total of 323 patients were included. Nodal pCR was achieved in 105 patients (33%), 15% of HR+/HER2– tumors, 38% of HR+/HER2+ tumors, 49% of HR–/HER2+ tumors, and 42% of HR–/HER2–tumors (p < 0.001). Factors associated with nodal pCR were (1) receptor status (HR+/HER2– [referent]: OR 3.42, 95% CI 1.43–8.16, p = 0.006 for HR+/HER2+; OR 4.19, 95% CI 1.85–9.50, p = 0.001 for HR–/HER2+; and OR 2.94, 95% CI 1.11–7.74, p = 0.029 for HR–/HER2–), (2) breast pCR (no pCR [referent]: OR 15.22, 95% CI 6.29–36.79, p < 0.001), and (3) absence of lymphovascular invasion (LVI [referent]: OR 9.04, 95% CI 2.09–39.18, p = 0.003). Conclusion: This study confirmed expected predictors of nodal pCR in Asian women and the benefit of NAC in downstaging the axilla independently of ethnicity.
Elevated Faecal Calprotectin in Patients with a Normal Colonoscopy: Does It Matter in Clinical Practice? A Retrospective Observational Study
Authors: Hovstadius Henrik , Lundgren David , Karling Pontus
Published: March 2021

Introduction: Faecal calprotectin (FC) is commonly used as a diagnostic tool for patients with gastrointestinal (GI) symptoms. However, there is uncertainty in daily clinical practice how to interpret an elevated FC in patients with a normal colonoscopy. We investigated if patients with a normal colonoscopy but with an elevated FC more often were diagnosed with a GI disease in a 3-year follow-up period. Methods: Patients referred for colonoscopy (n = 1,263) to the Umeå University Hospital endoscopy unit between 2007 and 2013 performed a FC test (CALPRO®) on the day before bowel preparation. A medical chart review was performed on all patients who had normal findings on their colonoscopy (n = 585, median age 64 years). Results: Thirty-four percent of the patients (n = 202) with normal colonoscopy had elevated FC (>50 μg/g), and these patients were more frequently diagnosed with upper GI disease during the follow-up period than patients with normal FC levels (9.9 vs. 4.7%; p = 0.015). The upper GI diseases were mainly benign (i.e., gastritis). In a binary logistic regression analysis controlling for age, gender, nonsteroid anti-inflammatory drug use, and proton-pump inhibitor use, there was no difference for a new diagnosis of upper GI disease in the follow-up period (multivariate OR 1.70; 95% CI: 0.77–3.74). There was no difference in a new diagnosis of lower GI disease (6.4 vs. 5.2%; p = 0.545) or cardiovascular disease/death (multivariate OR 1.68; 95% CI: 0.83–3.42) in the follow-up period between patients with elevated versus normal FC levels. Conclusions: In patients with a normal colonoscopy, a simultaneously measured increased FC level was not associated with an increased risk for significant GI disease during a follow-up period of 3 years.
Effects of Exercise Dose and Detraining Duration on Mobility at Late Midlife: A Randomized Clinical Trial
Authors: Hortobágyi Tibor , Deák Dorina , Farkas Dóra , Blényesi Eszter , Török Katalin , Granacher Urs , Tollár József
Published: March 2021

Background: Office workers near retirement tend to be sedentary and can be prone to mobility limitations and diseases. We examined the dose effects of exergaming volume and duration of detraining on motor and cognitive function in office workers at late midlife to reduce sedentariness and mobility limitations. Methods: In an assessor-blinded randomized trial, 160 workers aged 55–65 years performed physically active video games in a nonimmersive form of virtual reality (exergaming) in small, supervised groups for 1 h, 1×, 2×, or 3×/week for 8 weeks followed by detraining for 8 and 16 weeks. Exergaming comprises high-intensity, full-body sensorimotor coordination, balance, endurance, and strengthening exercises. The primary outcome was the 6-minute walk test (6MWT), and secondary outcomes were body mass, self-reported physical activity, sleep quality, Berg Balance Scale, Short Physical Performance Battery, fast gait speed, dynamic balance, heart rate recovery after step test, and 6 cognitive tests. Results: The 3 groups were not different in any of the outcomes at baseline (all p > 0.05). The outcomes were stable and had acceptable reliability (intraclass correlation coefficients ≥0.334) over an 8-week control period. Training produced an inverted U-shaped dose response of no (1×), most (2×), and medium (3×/week) effects of exergaming volume in most motor and selected cognitive outcomes. The distance walked in the 6MWT (primary outcome) increased most (94 m, 19%, p < 0.05), medium (57 m, 12%, p < 0.05), and least (4 m, 1%) after exergaming 2×, 3×, or 0× (control) (all different p < 0.05). The highest responders tended to retain the exercise effects over 8 weeks of detraining, independent of training volume. This maintenance effect was less consistent after 16 weeks of detraining. Conclusion: Less was more during training and lasted longer after detraining. A medium dose volume of exergaming produced the largest clinically meaningful improvements in mobility and selected cognitive tests in 60-year-old office workers with mild mobility limitations and intact cognition.
Analyses of Increased Mortality in New and Known Diabetes in Patients with Coronary Disease Enrolled in the NORSTENT Randomized Study
Authors: Mølstad Per , Nordrehaug Jan Erik , Steigen Terje , Wilsgaard Tom , Wiseth Rune , Bønaa Kaare H.
Published: March 2021

Background: NORSTENT trial randomized 9,013 patients to percutaneous coronary intervention with drug-eluting stents (DES) or bare-metal stents (BMS) with a 5-year follow-up. Among the patients, 5,512 had measured either fasting glucose level or percent glycated hemoglobin (HbA1c) at the index procedure. That cohort constitutes the present study population analyzing mortality and evaluating treatment heterogeneity of randomized stent in diabetic versus nondiabetic subgroups. Results: The cohort consisted of 4,174 (75.7%) patients without diabetes, 716 (13.0%) with known diabetes, and 622 (11.3%) with no diabetes in history but elevated fasting glucose level >7.0 mmol/L or HbA1c >6.5% and therefore defined as new diabetes. Patients with known diabetes had a significantly increased all-cause (hazard ratio [HR] 1.99, 95% CI 1.51–2.62, p < 0.001), cardiac (subhazard ratio [SHR] 2.47, 95% CI 1.55–3.93, p < 0.001), and noncardiac (SHR 1.74, 95% CI 1.23–2.44, p = 0.002) mortality after adjustment for baseline variables. In the follow-up of 5 years, patients with new diabetes, however, had a marginally increased all-cause (HR 1.40, 95% CI 1.01–1.93, p = 0.043) and significantly increased noncardiac mortality (SHR 1.52, 95% CI 1.06–2.20, p = 0.025), but no increase in cardiac mortality (SHR 1.06, 95% CI 0.53–2.12, p = 0.86) after the same adjustment. The majority of the mortality was cardiac in the first 1–2 years after intervention; thereafter, noncardiac mortality dominated. However, the time period for when noncardiac mortality became the dominating cause varied considerably and significantly between the groups. There was no heterogeneity in mortality in response to randomized stent between diabetics and nondiabetics. Conclusion: Known diabetes has increased cardiac and noncardiac mortality in contrast to new diabetes which is only associated with increased noncardiac mortality during the 5-year follow-up. Diabetic and nondiabetic patients have the same response to the treatment with BMS or DES.
Preoperative Evaluation of the ADNEX Model for the Prediction of the Ovarian Cancer Risk of Adnexal Masses at Siriraj Hospital
Authors: Poonyakanok Vitcha , Tanmahasamut Prasong , Jaishuen Atthapon , Wongwananuruk Thanyarat , Asumpinwong Chutimon , Panichyawat Nalinee , Chantrapanichkul Panicha
Published: March 2021

Introduction: Distinguishing benign adnexal masses from malignant tumors plays an important role in preoperative planning and improving patients’ survival rates. The International Ovarian Tumor Analysis (IOTA) group developed a model termed the Assessment of Different NEoplasias in the adneXa (ADNEX). Objective: Our objective was to evaluate the performance of the ADNEX model in distinguishing between benign and malignant tumors at a cutoff value of 10%. Methods: This was a prospective diagnostic study. 357 patients with an adnexal mass who were scheduled for surgery at Siriraj Hospital were included from May 1, 2018, to May 30, 2019. All patients were undergoing ultrasonography, and serum CA125 was measured. Data were calculated by the ADNEX model via an IOTA ADNEX calculator. Results: Of the 357 patients, 296 had benign tumors and 61 had malignant tumors. The area under the receiver operating characteristic curve for using the ADNEX model was 0.975 (95% confidence interval, 0.953–0.988). At a 10% cutoff, the sensitivity was 98.4% and specificity was 87.2%. The best cutoff value was at 16.6% in our population. Conclusions: The performance of the ADNEX model in differentiating benign and malignant tumors was excellent.
Association between Speech Recognition in Noise and Risk Factors of Cardiovascular Disease
Authors: Goderie Thadé , van Wier Marieke F. , Stam Mariska , Lissenberg-Witte Birgit I. , Merkus Paul , Smits Cas , Kramer Sophia E.
Published: March 2021

Introduction: Risk factors for cardiovascular disease (CVD) are associated with sensorineural hearing loss. CVD risk factors are known to cluster and interact, thereby increasing the cumulative risk for CVD. Previously, using the database of the Netherlands Longitudinal Study on Hearing (NL-SH), an association was found between a history of smoking and an increased decline in speech recognition in noise over 10 years of follow-up. Prospectively limited data are available on the association between CVD risk factors, interactions of these risk factors, and hearing loss. In this study, data from the NL-SH were used to study the association between CVD risk factors and speech recognition in noise longitudinally. Methods: Baseline, 5-year, and 10-year follow-up data of the NL-SH were included. The NL-SH is a web-based prospective cohort study which started in 2006. Participants were aged 18–70 years at baseline. Speech recognition in noise was determined with an online digit-triplet speech-in-noise test. In addition, participants completed online questionnaires on demographic, lifestyle, and health-related characteristics. The association of the ability to recognize speech in noise with CVD risk factors (i.e., obesity, rheumatoid arthritis [RA], hypertension, diabetes mellitus, and dyslipidemia) was analyzed longitudinally. We also analyzed the interaction between these risk factors (including age, sex, and history of smoking) and speech recognition in noise. Results: None of the CVD risk factors or interactions of 2 CVD risk factors was significantly associated with a decline in SRT over time. Obesity (p = 0.016), RA (p = 0.027), and hypertension (p = 0.044) were associated with overall higher (more unfavorable) SRTs. No overall interactions between CVD risk factors were found. Conclusion: Obesity, RA, and hypertension were overall associated with a higher SRT, but no longitudinal associations between these or other CVD factors with SRTs were found. Also, no interactions between 2 CVD risk factors and SRTs were found. Although no longitudinal associations between CVD risk factors and decline in SRTs were found, clinicians should be alert about the concurrent association between CVD risk factors and hearing loss.
Hyperfunctioning Papillary Thyroid Carcinoma with a BRAF Mutation: The First Case Report and a Literature Review
Authors: Shinkai Shinsuke , Ohba Kenji , Kakudo Kennichi , Iwaki Takayuki , Mimura Yoshihiro , Matsushita Akio , Kuroda Go , Sakai Yuki , Nishino Nobuhiko , Umemura Kazuo , Suda Takafumi , Sasaki Shigekazu
Published: March 2021

Introduction: Hyperfunctioning papillary thyroid carcinoma (PTC) is rare and consequently, little information on its molecular etiology is available. Although BRAF V600E (BRAF c.1799T>A, p.V600E) is a prominent oncogene in PTC, its mutation has not yet been reported in hyperfunctioning PTC. Case Presentation: Ultrasonography detected a 26-mm nodule in the right lobe of the thyroid gland of a 48-year-old man. Thyroid function tests indicated that he was hyperthyroid with a TSH level of 0.01 mIU/L (reference range: 0.05–5.00) and a free thyroxine level of 23.2 pmol/L (reference range: 11.6–21.9). TSHR autoantibodies were <0.8 IU/L (reference value: <2.0 IU/L). The 99mTc thyroid scintigram revealed a round, right-sided focus of tracer uptake by the nodule with a decreased uptake in the remainder of the gland. The patient underwent total thyroidectomy because fine-needle aspiration cytology revealed a malignancy. The histopathological diagnosis was conventional PTC. Subsequent mutational analysis of BRAF (exon 15), TSHR (exons 1–10), GNAS (exons 7–10), EZH1 (exon 16), KRAS, NRAS, HRAS (codons 12, 13, and 61), and TERT promoter (C250T and C228T) identified a heterozygous point mutation in BRAF V600E in a tumor tissue sample. In addition, we identified a TSHR D727E polymorphism (TSHR c.2181C>G, p.D727E) in both the tumor and the surrounding normal thyroid tissue. Discussion and Conclusions: We report a case of hyperfunctioning PTC with a BRAF V600E mutation for the first time. Our literature search yielded 16 cases of hyperfunctioning thyroid carcinoma in which a mutational analysis was conducted. We identified TSHR mutations in 13 of these cases. One case revealed a combination of TSHR and KRAS mutations; the other case revealed a TSHR mutation with a PAX8/PPARG rearrangement. These findings suggest that the concomitant activation of oncogenes (in addition to constitutive activation of the TSHR-cyclic AMP cascade) are associated with the malignant phenotype in hyperfunctioning thyroid nodules.
Serum GDF15 Level Is Independent of Sarcopenia in Older Asian Adults
Authors: Nga Ha Thi , Jang Il-Young , Kim Da Ae , Park So Jeong , Lee Jin Young , Lee Seungjoo , Kim Jeoung Hee , Lee Eunju , Park Jin Hoon , Lee Young-Ho , Yi Hyon-Seung , Kim Beom-Jun
Published: March 2021

Background: Growth differentiation factor 15 (GDF15), induced by tissue inflammation and mitochondrial stress, has received significant attention as a biomarker of mitochondrial dysfunction and has been implicated in various age-related diseases. However, the association between circulating GDF15 and sarcopenia-associated outcomes in older adults remains to be established. Aim: To validate previous experimental data and to investigate the possible role of GDF15 in aging and muscle physiology in humans, this study examined serum GDF15 levels in relation to sarcopenia-related parameters in a cohort of older Asian adults. Methods: Muscle mass and muscle function-related parameters, such as grip strength, gait speed, chair stands, and short physical performance battery score were evaluated by experienced nurses in 125 geriatric participants with or without sarcopenia. Sarcopenia was diagnosed using the Asian-specific cutoff points. Serum GDF15 levels were measured using an enzyme immunoassay kit. Results: Serum GDF15 levels were not significantly different according to sarcopenia status, muscle mass, muscle strength, and physical performance and were not associated with the skeletal muscle index, grip strength, gait speed, time to complete 5 chair stands, and short physical performance battery score, regardless of adjustments for sex, age, and BMI. Conclusions: These findings indicate that the definite role of GDF15 on muscle metabolism observed in animal models might not be evident in humans and that elevated GDF15 levels might not predict the risk for sarcopenia, at least in older Asian adults.
Diagnostic Accuracy and Therapeutic Efficacy of Digital Single-Operator Cholangioscopy for Biliary Lesions and Stenosis
Authors: Weigand Kilian , Küchle Merlin , Zuber-Jerger Ina , Müller Martina , Kandulski Arne
Published: March 2021

Background/Aims: Digital single-operator cholangioscopy (dSOC) has revolutionized bile duct visualization. Interventions like electrohydraulic or laser lithotripsy, inspection of suspicious areas, and targeted biopsies have become possible quick and easy. One main indication for dSOC remains the evaluation of indeterminate biliary strictures. Objective and Methods: We analyzed 180 consecutive dSOCs procedures performed in a high-volume tertiary center to evaluate sensitivity, specificity as well as positive and negative predictive values (PPV and NPV) for indeterminate strictures. Furthermore, technical success and complications were analyzed. Results: In 92–97%, the region of interest was reached and successfully visualized. In 83–100%, targeted biopsies were obtained from the suspicious area. Only the distal bile duct was less successful with only 84 and 62%, respectively. In general, dSOC procedures were safe. Cholangitis was the main complication. Regarding the diagnostic accuracy of dSOC of indeterminate biliary strictures, we found a sensitivity of 0.87 and specificity of 0.88, over all. Within the whole cohort, the investigators’ assessment directly after dSOC had a PPV of 0.63 and a NPV of 0.97. In patients with biliary lesions or stenosis suspicious for malignancy, the dSOC-based visual diagnosis revealed a very high diagnostic accuracy with sensitivity and specificity of 1.0 (95% CI 0.86–1.0) and 0.76 (95% CI 0.56–0.9) with a PPV of 0.77 (95% CI 0.59–0.9) and a high NPV of 1.0 (95% CI 0.85–1.0). Conclusions: Our study demonstrates that dSOC has a high diagnostic accuracy as well as a favorable safety profile. Therefore, dSOC should be discussed as standard of care during endoscopic retrograde cholangiography for indeterminate biliary lesions.
Myometrial Responses to Beta-Adrenoceptor Antagonists in Gynecological Malignancies
Authors: Modzelewska Beata , Jóźwik Marcin , Kleszczewski Tomasz , Sulkowski Stanisław , Jóźwik Maciej
Published: March 2021

Objective: The aim of the study was to determine the influence of beta-adrenoceptor (ADRB) antagonists on contractile activity of the nonpregnant human uterus in patients affected by gynecological malignancies. Design: This was a controlled and prospective ex vivo study. Setting: The work was conducted as a collaboration between 4 academic departments. Materials and Methods: Myometrial specimens were obtained from women undergoing hysterectomy for benign gynecological disorders (reference group; N = 15), and ovarian (N = 15), endometrial (N = 15), synchronous ovarian-endometrial (N = 3), and cervical cancer (N = 10). Contractions of myometrial strips in an organ bath before and after applications of ADRB antagonists (propranolol, bupranolol, SR 59230A, and butoxamine) were studied under isometric conditions. Results: Propranolol and bupranolol attenuated contractions in the endometrial and cervical cancer groups similar to that in the reference group (all p < 0.05), whereas opposite effects were observed in the ovarian and synchronous ovarian-endometrial cancer groups. SR 59230A and butoxamine significantly increased contractions in the ovarian cancer group (both p < 0.001). Limitations: These results require now to be placed into a firm clinical context. Conclusions: Our study indicates that ovarian cancer considerably alters contractile activity of the nonpregnant human uterus in response to ADRB antagonists. This suggests a pathogenetic role of beta-adrenergic pathways in this malignancy. Furthermore, propranolol and bupranolol substantially influence spontaneous uterine contractility.
The Association of Cognitive and Visual Function in a Nationally Representative Study of Older Adults in India
Authors: Ehrlich Joshua R. , Ndukwe Tochukwu , Chien Sandy , Lee Jinkook
Published: March 2021

Introduction: Due to population aging, India is poised to experience a large increase in the burden of both dementia and vision impairment (VI). Prior studies from other settings suggest that VI may be a modifiable risk factor for cognitive decline and dementia. However, to date, no studies have examined the association of impaired visual acuity and cognition in India. Methods: A total of 3,784 participants in wave 1 of the population-based Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India underwent visual acuity testing and a cognitive test battery. Multivariable linear regression was used to model the cross-sectional associations of mild (<6/12–6/16), moderate (<6/18–6/60), and severe visual acuity impairment/blindness (<6/60) with cognitive performance scores corresponding to total cognition, orientation, memory, language/fluency, executive function, and informant-reported cognitive status. Models were adjusted for demographic, socioeconomic, and health characteristics. Results: The weighted percentage of participants with any VI was 52.6%. VI was independently associated with lower cognitive scores across all domains, even after adjustment for known dementia risk factors. In fully adjusted models of total cognition (mean score: 130.7), mild, moderate, and severe VI/blindness were associated with a significant change of −3.5 (95% CI: −6.3, −0.6), −8.2 (95% CI −10.5, −5.6), and −16.8 (95% CI −22.3, −11.3) units, respectively. A dose-response association between level of VI and cognitive function was observed for all cognitive outcomes except for language/fluency domain scores. Associations were robust when cognitive tests dependent on visual function were excluded. Across each fully adjusted model of total, domain-specific, and informant-reported cognitive performance, moderate VI was equivalent to 5–9 years of cognitive aging. Discussion/Conclusion: This study illustrates that VI is cross-sectionally associated with lower cognitive performance, largely in a dose-response pattern, across various cognitive domains in the Indian population. These findings are important for informing future longitudinal and interventional studies.
SIRT1 Alleviates Aldosterone-Induced Podocyte Injury by Suppressing Mitochondrial Dysfunction and NLRP3 Inflammasome Activation
Authors: Jiang Mingzhu , Zhao Min , Bai Mi , Lei Juan , Yuan Yanggang , Huang Songming , Zhang Yue , Ding Guixia , Jia Zhanjun , Zhang Aihua
Published: March 2021

Background: Podocyte injury contributes to progressive glomerulosclerosis. Previously, we demonstrated the important role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mediating the podocyte injury induced by aldosterone. Silent mating type information regulation 2 homolog 1 (SIRT1) is an NAD+-dependent deacetylase that is associated with the regulation of cellular inflammation. However, whether the activation of the NLRP3 inflammasome in podocytes is regulated by SIRT1, and the mechanism involved, remains unknown. Methods: In this study, we detected SIRT1 expression in patients with podocyte disease and performed an aldosterone infusion model in podocyte-specific Sirt1 knockout mice. In cultured podocytes, we used plasmids to overexpress SIRT1 and treated the podocyte with aldosterone. Results: SIRT1 was significantly decreased in the glomeruli of patients with podocyte disease. Sirt1-deficient mice showed significant urinary albumin excretion after aldosterone infusion, and the severity of the glomerular injury was significantly greater in podocyte-specific Sirt1 knockout mice than in the wild-type mice. Moreover, podocyte conditional Sirt1 knockout aggravated NLRP3 inflammasome activation and mitochondrial dysfunction (MtD). In vitro, overexpression of SIRT1 inhibited NLRP3 activation, protected against MtD and podocyte injury. Conclusion: Taken together, these findings revealed a novel regulatory mechanism of the NLRP3 inflammasome by SIRT1 by promoting mitochondrial function, which provides some potential targets for the treatment of glomerular diseases.
Decreasing Attacks and Improving Quality of Life through a Systematic Management Program for Patients with Hereditary Angioedema
Authors: Nunes Fernanda Leonel , Ferriani Mariana P.L. , Moreno Adriana S. , Langer Sarah S. , Maia Luana S.M. , Ferraro Maria Fernanda , Sarti Willy , Bessa Junior José de , Cunha Deborah , Suffritti Chiara , Dias Marina M. , Januário Yunan C. , daSilva Luis L.P. , Aragon Davi Casale , Caballero Teresa , Arruda L. Karla
Published: March 2021

Introduction: Prevention of attacks is a major goal in management of patients with hereditary angioedema (HAE). We aimed to investigate the effects of a systematic intervention for HAE patients. Methods: Thirty-three patients with HAE with C1-inhibitor deficiency, belonging to a single family, participated in a management program coordinated by an allergist/immunologist. Angioedema attacks before intervention were ascertained by interviews and emergency room charts and recorded prospectively by patients or caregivers after enrollment. Mean number of attacks/month was compared at 12 months preintervention and 8 and 14 months within intervention. Patient-reported outcome instruments were used to assess quality of life, including HAE Quality of Life (HAE-QoL) questionnaire, psychological conditions, and work impairment, at baseline and 8 and 14 months within intervention. Data were stored in REDCap platform and analyzed by adjusted Bayesian models of double Poisson regression. Results: Mean number of attacks/month significantly decreased (95% credible interval [CrI] excluding 0) from 1.15 preintervention to 0.25 and 0.23, 8 and 14 months within intervention, with mean decreases of −0.89 (95% CrI: −1.21 to −0.58) and −0.92 (95% CrI: −1.22 to −0.60), respectively. HAE-QoL scores showed mean total increases of 15.2 (95% CrI: 1.23–29.77) and 26 (95% CrI: 14.56–39.02) at 8 and 14 months within the study, as compared to baseline, revealing marked improvement in quality of life. Significant increase in role-emotional and reduction of depression, stress, and anxiety were observed at 14 months. Conclusion: A systematic approach integrating HAE-specific care with effective handling of psychological issues decreased the number of attacks and improved quality of life, targets for best practice in HAE.
Challenges in Evaluation and Management of Children with Myocardial Bridging
Authors: Erol Nurdan
Published: March 2021

Myocardial bridging (MB) is a congenital anomaly where a coronary artery branch or group of branches extends inside a tunnel consisting of myocardium. Although it is mostly considered “benign,” it is reported that MB may lead to significant cardiac problems and sudden cardiac deaths. While it is a congenital anomaly, its symptoms usually arise at further ages rather than childhood. The literature on MB in children is in the form of case reports or small case series. This is why pediatric cases are assessed in the light of information obtained from adults. This review compiled the literature on MB in adults and children and compared it, as well as discussing questions arising regarding the clinic, diagnosis, and treatment of MB.
Ribosome Incorporation Induces EMT-like Phenomenon with Cell Cycle Arrest in Human Breast Cancer Cell
Authors: Kudo Mikiko , Anam Mohammad Badrul , Istiaq Arif , Ahmad Shah Adil Ishtiyaq , Ito Naofumi , Ohta Kunimasa
Published: March 2021

Although ribosomes are generally known to be a translational machinery, some ribosomal proteins also have accessory functions involving early development and differentiation. Previously, we reported that ribosome incorporation into human dermal fibroblasts generated embryoid body-like cell clusters, altered cellular fate, and differentiated into cells of all 3 germ layers. However, the molecular phenomena induced by ribosome incorporation in the cell remained unknown. Here, we demonstrate that ribosome incorporation into human breast cancer cell MCF7 leads to ribosome-induced cell clusters (RICs) formation accompanying with epithelial-mesenchymal transition (EMT)-like gene expression. Following ribosome incorporation, MCF7 cells cease proliferation, which is caused by inhibition of cell cycle transition from G0 to G1 phase. Further, MCF7 RICs show induced expression of EMT markers, TGF-β1 and Snail along with autophagy markers and tumor suppressor gene p53. These findings indicate that the incorporation of ribosome into cancer cells induces an EMT-like phenomenon and changes the cancer cell characteristics.
Do Informal Caregivers Expect to Die Earlier? A Longitudinal Study with a Population-Based Sample on Subjective Life Expectancy of Informal Caregivers
Authors: Zwar Larissa , König Hans-Helmut , Hajek André
Published: March 2021

Introduction: Subjective life expectancy is a good predictor of health and could therefore be a relevant factor in the informal caregiving context. However, no research has been conducted on the perception of life expectancy by informal caregivers. This is the first study that examines the association between transitioning into, and out of, informal caregiving, and subjective life expectancy, and the relevance of employment status and gender for these associations. Methods: A longitudinal study was conducted with data from the German Ageing Survey (waves 2008, 2011, 2014, and 2017). Up to 20,774 observations pooled over all waves were included in the main models. In total, 1,219 transitions into and 1,198 transitions out of informal caregiving were observed. Fixed effects (FE) regression analysis was used. Moderator and stratified analyses were conducted with gender and employment status used as moderator variables and to stratify the sample. Sociodemographic information, health, and lifestyle factors were controlled for. Results: Results of adjusted FE regression analyses indicated a significant reduction of subjective life expectancy when transitioning into informal caregiving. No significant change was found when transitioning out of informal caregiving. Subjective life expectancy was significantly decreased when employed individuals transitioned into informal caregiving and significantly increased when they transitioned out of caregiving. Findings for women transitioning into informal caregiving indicated a significant decrease in subjective life expectancy, while no significant change was found among men. Conclusion: The study’s findings indicate that informal caregivers, female and employed caregivers in particular, perceive informal care provision as dangerous for their longevity and expect to die earlier when transitioning into informal caregiving. Thus, supportive interventions for informal caregivers, particularly employed and female informal caregivers, are recommended.
Transillumination: A Diagnostic Tool to Assess Subungual Glomus Tumors
Authors: Tsiogka Aikaterini , Belyayeva Helena , Sianos Stavros , Rigopoulos Dimitrios
Published: March 2021

Diagnosis of subungual glomus tumors is mainly based on clinical symptoms, including paroxysmal pain, tenderness, and cold intolerance. Dermoscopy, ultrasonography, and MRI constitute further diagnostic tools, commonly performed to demarcate the tumor before surgery. Herein, we present 2 cases of subungual glomus tumors, which could be diagnosed after fingertip transillumination, highlighting that this technique can serve as an easy, noninvasive, and cost-effective adjuvant diagnostic tool, to facilitate the clinical diagnosis of subungual glomus tumors as well as their localization during preoperative assessment.
Risk Factors for Development of Acute Kidney Injury in COVID-19 Patients: A Retrospective Observational Cohort Study
Authors: See Yong Pey , Young Barnaby Edward , Ang Li Wei , Ooi Xi Yan , Chan Chi Peng , Looi Wan Limm , Yeo See Cheng , Lye David Chien
Published: March 2021

Introduction: Acute kidney injury (AKI) in coronavirus infection disease (COVID-19) is associated with disease severity. We aimed to evaluate risk factors associated with AKI beyond COVID-19 severity. Methods: A retrospective observational study of COVID-19 patients admitted to a tertiary hospital in Singapore. Logistic regression was used to evaluate associations between risk factors and AKI (based on Kidney Disease Improving Global Outcomes criteria). Dominance analysis was performed to evaluate the relative importance of individual factors. Results: Seven hundred seven patients were included. Median age was 46 years (interquartile range [IQR]: 29–57) and 57% were male with few comorbidities (93%, Charlson Comorbidity Index [CCI] <1). AKI occurred in 57 patients (8.1%); 39 were in AKI stage 1 (68%), 9 in stage 2 (16%), and 9 in stage 3 (16%). Older age (adjusted odds ratio [aOR] 1.04; 95% confidence interval [CI]: 1.01–1.07), baseline use of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) (aOR 2.86; 95% CI: 1.20–6.83), exposure to vancomycin (aOR 5.84; 95% CI: 2.10–16.19), use of nonsteroidal anti-inflammatory drugs (NSAIDs) (aOR 3.04; 95% CI: 1.15–8.05), and severe COVID-19 with hypoxia (aOR 13.94; 95% CI: 6.07–31.98) were associated with AKI in the multivariable logistic regression model. The 3 highest ranked predictors were severe COVID-19 with hypoxia, vancomycin exposure, and age, accounting for 79.6% of the predicted variance (41.6, 23.1, and 14.9%, respectively) on dominance analysis. Conclusion: Severe COVID-19 is independently associated with increased risk of AKI beyond premorbid conditions and age. Appropriate avoidance of vancomycin and NSAIDs are potentially modifiable means to prevent AKI in patients with COVID-19.
The Role of 3D Reconstruction of the Skull in Patients with Suspected Shunt Malfunction
Authors: Roth Jonathan , Jonas Kimchi Tali , Shofty Ben , Agur Ariel , Ben-Sira Liat , Constantini Shlomi
Published: March 2021

Background: Mechanical shunt malfunction may lead to significant morbidity and mortality. Shunt series assessments help evaluate shunt integrity; however, they are of limited value in the area of the skull due to skull curvature, thickness, and air sinuses. We describe the role of 3D bone reconstruction CT (3DCT) in demonstrating the shunt integrity over the skull, comparing this technique to skull X-rays (SXR). Methods: Data were collected retrospectively for shunted patients with concurrent SXR and 3DCT and for patients presenting with shunt failures at the region of the skull, including clinical course and radiological findings. We compared the SXR and 3DCT findings. The 3DCT was reconstructed from standard diagnostic CT protocols performed during evaluation of suspected shunt malfunction and not thin-slice CT protocols. Results: Forty-eight patients with 57 shunts underwent SXR and 3DCT. Interobserver agreement was high for most variables. Both SXR and 3DCT had a high sensitivity, specificity, and accuracy identifying tubing disconnections (between 0.83 and 1). Full valve type and setting were significantly more accurate based on SXR versus 3DCT (>90 vs. <20%), and valve integrity was significantly more readily verified on 3DCT versus SXR (100 vs. 52%). Conclusions: 3DCT and SXR complement each other in diagnosing mechanical shunt malfunctions over the skull. The main limitation of 3DCT is identification of valve type and settings, which are clearer on SXR, while the main limitation of SXR is a less ability to evaluate valve integrity. 3DCT also enables an intuitive 3D understanding of the shunt tubing over the skull.
Stress Hormones as Predictors of Response to Cognitive Behavior Therapy in Panic Disorder
Authors: Masdrakis Vasilios G. , Legaki Emilia-Maria , Papageorgiou Charalambos , Markianos Manolis
Published: March 2021

Objective: Data regarding the potential association between the outcome of psychotherapy of panic disorder (PD) and biological parameters are few. In 21 (16 females) consecutively referred, medication-free, acutely ill PD outpatients, without comorbidities, except agoraphobia, we systematically explored for potential neuroendocrine and clinical correlates of response to a brief cognitive behavior therapy (CBT). Methods: Cortisol and adrenocorticotropic hormone (ACTH) basal plasma levels were measured. Measures of psychopathology: (a) Symptom Checklist–90-Revised (SCL-90-R), (b) Clinical Global Impressions-Improvement (CGI-I) Scale, (c) Agoraphobic Cognitions Questionnaire (ACQ), and (d) Mobility Inventory (MI)-alone subscale. Results: Nonresponders to CBT (CGI-I >2; N = 6) – as compared to the responders (CGI-I ≤2; N = 15) – demonstrated significantly higher cortisol and ACTH basal plasma concentrations. These differences were much stronger when only female patients (nonresponders = 4; responders = 12) were taken into consideration. Regarding psychopathology, nonresponders to CBT suffered from more severe agoraphobia (MI-alone) at baseline. On the contrary, more intense manifestations of anger (SCL-90-R) at baseline were associated with a better treatment outcome. Response to CBT was associated with significant reductions in all SCL-90-R subscales, more pronounced for “phobic anxiety” and “anxiety” subscales. Conclusions: This study suggests that in acutely ill, medication-free PD patients, response to CBT may be associated with certain hormonal and clinical parameters at baseline.
Impact of Allergic Rhinitis on Voice in Children
Authors: Sahin Onder Serap , Savran Fatih , Karabulut Burak , Surmeli Mehmet , Cetemen Aysen
Published: March 2021

Introduction: The purpose of the present study was to determine the possible effect of allergic rhinitis (AR) on voice change in children with acoustic analysis and Turkish children’s voice handicap index-10 (TR-CVHI-10). Methods: This is a case-control study. Forty-one children with AR, and a positive skin prick test, as well as 39 children of controls who had produced a negative skin prick test and lacked a history of allergic disease, were selected for the study. Each assessment included recordings for the purposes of acoustic voice analysis (fundamental frequency [f0], jitter %, shimmer %, and harmonics-to-noise ratio (HNR)), and aerodynamic analysis (maximum phonation time (MPT) and s/z ratio). All participants completed TR-CVHI-10. Results: The mean TR-CVHI-10 score of the AR group was significantly higher than the control group (p = 0.013). No difference was observed between the AR and control groups in terms of jitter, shimmer, HNR, and MPT values and s/z ratio (p > 0.05). Conversely, the f0 value was more pronounced in controls (270.9 ± 60.3 Hz) than in the AR group (237.7 ± 54.3 Hz) (p = 0.012). Conclusion: The study’s results revealed that AR can have an effect on fundamental frequency and voice quality in children. The diagnostic process should include AR as a potential cause of voice disorders in children.
A Meta-Analysis of Brain-Derived Neurotrophic Factor Effects on Brain Volume in Schizophrenia: Genotype and Serum Levels
Authors: Ahmed Anthony O. , Kramer Samantha , Hofman Naama , Flynn John , Hansen Marie , Martin Victoria , Pillai Anilkumar , Buckley Peter F.
Published: March 2021

Aim: The Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene has established pleiotropic effects on schizophrenia incidence and morphologic alterations in the illness. The effects of brain-derived neurotrophic factor (BDNF) on brain volume measurements are however mixed seeming to be less established for most brain regions. The current meta-analytic review examined (1) the association of the Val66Met SNP and brain volume alterations in schizophrenia by comparing Met allele carriers to Val/Val homozygotes and (2) the association of serum BDNF with brain volume measurements. Method: Studies included in the meta-analyses were identified through an electronic search of PubMed and PsycInfo (via EBSCO) for English language publications from January 2000 through December 2017. Included studies had conducted a genotyping procedure of Val66Met or obtained assays of serum BDNF and obtained brain volume data in patients with psychotic disorders. Nonhuman studies were excluded. Results: Study 1 which included 52 comparisons of Met carriers and Val/Val homozygotes found evidence of lower right and left hippocampal volumes among Met allele carriers with schizophrenia. Frontal measurements, while also lower among Met carriers, did not achieve statistical significance. Study 2 which included 7 examinations of the correlation between serum BDNF and brain volume found significant associations between serum BDNF levels and right and left hippocampal volume with lower BDNF corresponding to lower volumes. Discussion: The meta-analyses provided evidence of associations between brain volume alterations in schizophrenia and variations on the Val66Met SNP and serum BDNF. Given the limited number of studies, it remains unclear if BDNF effects are global or regionally specific.
Acute Generalized Exanthematous Pustulosis Caused by Erlotinib in a Patient with Lung Cancer
Authors: Komiya Natsuko , Takahashi Koichiro , Kato Go , Kubota Mio , Tashiro Hiroki , Nakashima Chiho , Nakamura Tomomi , Iwanaga Kentaro , Kimura Shinya , Sueoka-Aragane Naoko
Published: March 2021

Acute generalized exanthematous pustulosis (AGEP) is a rare drug-related adverse skin reaction caused mainly by antibiotics. Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used to treat lung cancer. A 69-year-old woman with primary lung cancer (adenocarcinoma, cT3N1M1b, stage IVB) developed erythema and multiple skin pustules on her abdomen and both thighs after 7 weeks of erlotinib treatment. She also had fever and general fatigue. Histological examination of a skin biopsy specimen showed intraepidermal pustules with neutrophil and eosinophil infiltration. She was diagnosed with erlotinib-induced AGEP. AGEP resolved by erlotinib discontinuation and systemic corticosteroid treatment. The lung cancer progressed when erlotinib was discontinued, so afatinib, a second-generation EGFR-TKI, was administrated without any skin adverse effects. Afatinib successfully decreased the lung cancer, and maintained the disease stable for 1 year. Although acneiform rash was the most common skin adverse event caused by EGFR, AGEP rarely occurred. The present case also demonstrated that it is possible to switch agents, from erlotinib to afatinib, even though they have the same pharmacological effects. Although AGEP is a rare drug-related skin disorder, physicians should be aware that erlotinib may induce AGEP.
Allogeneic Platelet-Rich Plasma: Is It Safe and Effective for Wound Repair?
Authors: Akbarzadeh Shiva , McKenzie Maxwell B. , Rahman Md. Mostafizur , Cleland Heather
Published: March 2021

Background: Platelet-rich plasma (PRP) and its derivatives are an emerging biotechnology whereby concentrated platelets provide damaged tissue with growth factors, cytokines, and other mediators to improve healing outcomes. Although there is strong evidence in the benefits of autologous PRP for both acute and chronic wounds, allogeneic PRP has been studied far less in comparison. Summary: In this mini-review, we discuss critical steps of allogenic PRP (and its derivatives) preparation. We performed a non-systematic review of the literature to identify animal and human subject studies testing allogenic PRP for wound treatment. We searched OVID Medline and PubMed for articles using the keywords “wound, ulcer, lesion, skin, and cutaneous” and “PRP, or platelet-rich plasma, or platelet-rich fibrin, or PRF, or platelet releasate” and “homologous, allogeneic or allogenic,” which were limited to non-review articles and English language. Two studies in animal models and 8 studies in patients were reviewed. There were inconsistencies in preparation methods, treatment regimens, and some lacked a control group in their studies. Despite these variations, none of the studies identified any major side effects or adverse events. The treatment resulted in a reduced time to heal and/or reduced wound size in most cases. Key Messages: In situations where autologous PRP is not available or suitable, allogeneic PRP appears to provide a safe alternative. Its efficacy, however, requires larger-scale studies with appropriate controls. Standardization in PRP preparation and treatment regime are also needed to be able to interpret allogenic PRP efficacy.
Front-Of-Pack Nutrition Labelling: A Position Statement of the European Academy of Paediatrics and the European Childhood Obesity Group
Authors: Dereń Katarzyna , Dembiński Łukasz , Wyszyńska Justyna , Mazur Artur , Weghuber Daniel , Łuszczki Edyta , Hadjipanayis Adamos , Koletzko Berthold
Published: March 2021

Background: Due to the growing risk of obesity and related diseases in the population of children, effective preventive measures are of great importance. Front-of-pack (FOP) nutrition labelling may contribute to health promotion by increasing consumer awareness on the nutritional qualities of packaged foods and purchasing decisions, and it may stimulate food providers to improve the composition of products. Summary: Appropriate labelling should enable customers to make healthy choices quickly and intuitively. Key Messages: The European Academy of Paediatrics and the European Childhood Obesity Group makes an appeal to European Union legislators to immediately introduce a mandatory, uniform, and interpretative FOP nutrition labelling system.