Search

Resumen Introduccion y objetivos La colangitis esclerosante primaria (CEP) es una enfermedad hepatica colestasica rara, que tipicamente afecta a varones de mediana edad con colitis ulcerosa (CU). No obstante, estudios recientes apuntan a cambios epidemiologicos. Nuestro objetivo es determinar si la epidemiologia, presentacion clinica y curso evolutivo de pacientes con CEP seguidos en un centro de referencia se asemejan a lo descrito en la literatura. Pacientes y metodos Busqueda retrospectiva de pacientes con diagnostico de CEP atendidos en nuestro centro entre los anos 2000 y 2019. Resultados Cohorte de 55 pacientes (media de edad: 37 anos), el 44% mujeres, afectos de CEP, el 79% de ducto grande. Casi dos tercios fueron diagnosticados a partir de 2011. En el momento del diagnostico, un 63% de los pacientes se encontraba asintomatico. La mediana de tiempo desde la sospecha hasta el diagnostico fue de 2 anos. Un 34% desarrollo cirrosis en el seguimiento, y un 25% requirio trasplante hepatico (TH) tras una media de tiempo de 7 anos; entre estos, la enfermedad recurrio en un 46%. Un 45% presentaba una enfermedad inflamatoria intestinal (EII), sobre todo CU. Si bien no se alcanzo significacion estadistica, la CEP en mujeres se caracterizo por mayor tasa de presentacion asintomatica, mayor asociacion con CU frente a otras formas de EII, asi como cirrosis al diagnostico y necesidad de TH con mayor frecuencia que los varones. Conclusiones La epidemiologia de la CEP esta cambiando. El numero de mujeres afectas es mayor al descrito previamente, objetivandose un aumento reciente de la incidencia. Podrian existir diferencias entre sexos en la forma de presentacion y evolucion que deberan confirmarse en estudios posteriores.

BACKGROUND: Selection of patients for upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) has to be improved. OBJECTIVE: To evaluate a new scoring system for the prediction of overall mortality (OM) in mRCC patients undergoing CN. DESIGN, SETTING, AND PARTICIPANTS: We identified a total of 519 patients with synchronous mRCC undergoing CN between 2005 and 2019 from a multi-institutional registry (Registry for Metastatic RCC [REMARCC]). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazard regression was used to test the main predictors of OM. Restricted mean survival time was estimated as a measure of the average overall survival time up to 36 mo of follow-up. The concordance index (C-index) was used to determine the model's discrimination. Decision curve analyses were used to compare the net benefit from the REMARCC model with International mRCC Database Consortium (IMDC) or Memorial Sloan Kettering Cancer Center (MSKCC) risk scores. RESULTS AND LIMITATIONS: The median follow-up period was 18 mo (interquartile range: 5.9-39.7). Our models showed lower mortality rates in obese patients (p = 0.007). Higher OM rates were recorded in those with bone (p = 0.010), liver (p = 0.002), and lung metastases (p < 0.001). Those with poor performance status (

Objective Intermittent photic stimulation (IPS) is an activation procedure performed during electroencephalography (EEG) to detect photosensitive patients. This procedure is recommended in routine EEGs but the benefit of IPS in the general population is not clearly ascertained. Methods We retrospectively analyzed 7683 EEGs of patients referred for a routine EEG to the Clinical Physiology Department of Lariboisiere hospital, mainly from the emergency ward and the department of neurology, not specifically involved in epilepsy. All EEGs were performed with a standardized protocol. Photic driving response, photomyoclonic response and photoparoxysmal response (PPR) were specifically collected. A correlation analysis was performed between the response induced by IPS, demographical and clinical data, and current treatment or recreational drug use. Results Median age was 56.4 years (41.7-71.2); 3,042 (39.6%) of patients were female; 1,208 patients (15.7%) had a past medical history of epilepsy. Photic driving response occurred in 67 EEGs (0.9%), and PPR in 6 EEGs (0.1%), all with a known history of epilepsy. Thus 0.5% (6/1,208) of epilepsy patients had a PPR. Photomyoclonic responses were not observed. Juvenile myoclonic epilepsy was the only factor associated with the presence of PPR (RR=75.26 [11.82-479.21]). PPR was not associated with clinical symptoms or seizures. There was no correlation with the type of treatment or recreational drug use. Conclusions Our results confirm that responses to IPS are rare in adult patients and especially PPR. Moreover, all patients with a PPR had a known previous history of epilepsy. These results question the benefit of IPS in adult patients with no history of epilepsy.

Background Cytoreductive nephrectomy (CN) plays an important role in the treatment of a subgroup of metastatic renal cell carcinoma (mRCC) patients. Objective We aimed to evaluate morbidity associated with this procedure and identify potential predictors thereof to aid patient selection for this procedure and potentially improve patient outcomes. Design, setting, and participants Data from 736 mRCC patients undergoing CN at 14 institutions were retrospectively recorded in the Registry for Metastatic RCC (REMARCC). Outcome measurements and statistical analysis Logistic regression analysis was used to identify predictors for intraoperative, any-grade (AGCs), low-grade, and high-grade (HGCs) postoperative complications (according to the Clavien-Dindo classification) as well as 30-d readmission rates. Results and limitations Intraoperative complications were observed in 69 patients (10.9%). Thrombectomy (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.08–1.75, p = 0.009) and adjacent organ removal (OR 2.7, 95% CI 1.38–5.30) were significant predictors of intraoperative complications at multivariable analysis. Two hundred seventeen patients (29.5%) encountered AGCs, while 45 (6.1%) encountered an HGC, of whom 10 (1.4%) died. Twenty-four (3.3%) patients had multiple postoperative complications. Estimated blood loss (EBL; OR 1.49, 95% CI 1.08–2.05, p = 0.01) was a significant predictor of AGCs at multivariable analysis. CN case load (OR 0.13, 95% CI 0.03–0.59, p = 0.009) and EBL (OR 2.93, 95% CI 1.20–7.15, p = 0.02) were significant predictors solely for HGCs at multivariable analysis. Forty-one patients (11.5%) were readmitted within 30 d of surgery. No significant predictors were identified. Results were confirmed in a subanalysis focusing solely on patients treated in the contemporary targeted therapy era. Conclusions Morbidity associated with CN is not negligible. Predictors of high-grade postoperative morbidity are predominantly indicators of complex surgery. EBL is a strong predictor of postoperative complications. CN case load correlates with lower high-grade morbidity and highlights the benefit of centralization of complex surgery. However, risks and benefits should be balanced when considering CN in mRCC patients. Patient summary We studied patients with metastatic renal cancer to evaluate the outcomes associated with the surgical removal of the primary kidney tumor. We found that this procedure is often complex and adverse events are not uncommon. High intraoperative blood loss and a small number of cases performed at the treating center are associated with a higher rate of postoperative complications.

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Background Pierre Robin sequence (PRS) is a heterogeneous condition involving retro(micro)gnathia, glossoptosis and upper airway obstruction, very often with posterior cleft palate. Patients with PRS, either isolated or associated with Stickler syndrome have good intellectual prognosis. Nevertheless, the quality of life in adolescence and the phonatory and morphological outcomes are rarely analysed. We assessed the phonatory and morphological outcomes of 72 cognitively unimpaired adolescents with PRS, studied their oral (COHIP-SF19), vocal (VHI-9i) and generic quality of life (QoL; KIDSCREEN-52), and searched for determinants of these outcomes. Results Two-thirds of our adolescents retained low or moderate phonation difficulties, but risk factors were not identified. For 14%, morphological results were considered disharmonious, with no link to neonatal retrognathia severity. Only one vs two-stage surgery seemed to affect final aesthetic results. The oral QoL of these adolescents was comparable to that of control patients and was significantly better than that of children with other craniofacial malformations (COHIP-SF19 = 17.5, 15.4 and 25.7, respectively). The oral QoL of the adolescents with non-isolated PRS was significantly worse (COHIP-SF19 = 24.2) than that of control patients and close to that of children with other craniofacial malformations. The vocal QoL of the adolescents (mean [SD] VHI-9i = 7.5 [5.4]) was better than that of patients with other voice pathologies and better when phonation was good. The generic QoL of the adolescents was satisfactory but slightly lower than that of controls, especially in dimensions concerning physical well-being, relationships and autonomy. QoL results were lower for adolescents with non-isolated than isolated PRS. Only non-isolated PRS and low oral QoL affected generic QoL. Conclusion Morphological or phonatory impairments remain non-rare in adolescents with PRS but do not seem to be directly responsible for altered QoL. These adolescents, especially those with non-isolated PRS, show self-confidence and social-relation fragility. We must focus on long-term functional and psychological results for PRS patients and improve therapy protocols and follow-up, notably those affecting the oral aspects of the disease.

BACKGROUND: The 2019 coronavirus disease (COVID-19) pandemic drastically reduced learning opportunities for medical students. We sought to determine the cost and success of implementation of a podcast for a surgical department in a large academic hospital. METHODS: We created a podcast series for Israeli medical students during the COVID-19 epidemic based on the Medical Student Core Curriculum of the American College of Surgeons / Association for Surgical Education. Episodes were available for free download or streaming on a designated website and popular podcast platforms. Podcast analytics were used to measure public listeners and uptake. RESULTS: Total development time was 90 hours at an estimated cost of $7091 USD. A total of 10 episodes were released between March 21, 2020 and August 31, 2020. An average of 9 ± 1.26 h (range 2-6) was required to generate each episode, including 3.4 ± 1.26 h (2-6) for content review and 5.6 ± 2 h (4-10) for audio production. An average episode ran for 35.9 ± 4.3 min (28-42). Podcasts recorded a total of 5678 downloads, with an average of 228 and 336 downloads per episode in the first 30 and 90 days, respectively. The average daily downloads before the students returned to clinical rotations (March 21-April 30) was 48 ± 58.3 (7-283;) compared to 16 ± 7.4 after their return (1-38; P< 0.01). Estimated costs to produce a video-based education series would have been significantly more. CONCLUSION: Podcasts can serve as a cost-effective and quickly produced instructional tool to supplement online learning. Further research is required to determine the efficacy of podcasts versus video-based education modules.

Beauty care (BTC) is offered at many cancer hospitals having a great uptake among patients. Nevertheless, its benefits in the Quality of life (QoL) of cancer survivors have not been assessed so far. Our study aims to determine whether BTC improves patients’ QoL related to their body image measured by the BRBI scale of the QLQ-BR23 questionnaire at the end of adjuvant chemotherapy, after breast cancer (BC) surgery. The BEAUTY study is a prospective, randomized, controlled intervention trial. The following patient-reported outcomes were filled before initiation of chemotherapy (T1) and after their last cycle (T2): EORTC QLQ-C30, QLQ-BR23, and Body Image Scale (BIS). Primary objective was improvement in the BIS of BR23 (BRBI). A qualitative assessment of patients' experience was performed at each cycle through a relevant questionnaire. In total, 269 (67%) patients filled BRBI at T1 and T2. Mean BRBI scores substantially decreased between T1 and T2 and were not different with or without BTC (p = 0.88). Qualitative assessment suggests impact of BTC in physical well-being and avoids thoughts related to the disease. A substantial proportion of patients have a poor body image and chemotherapy induced a substantial degradation of BRBI scores. Although BTC does not seem to impact BRBI scores, the qualitative assessment suggests some benefit of BTC in other domains. Our study highlights the need to assess patients-perceived body image and build tailored interventions at this critical phase of their disease and generates hypothesis for the impact of BTC among BC patients. Clinical trial registration The study is registered at ClinicalTrials.gov under the NCT01459003 number since October 25, 2011

Purpose To evaluate the performance of combined PET and multiparametric MRI (mpMRI) radiomics for the group-wise prediction of postsurgical Gleason scores (psGSs) in primary prostate cancer (PCa) patients. Methods Patients with PCa, who underwent [68 Ga]Ga-PSMA-11 PET/MRI followed by radical prostatectomy, were included in this retrospective analysis (n = 101). Patients were grouped by psGS in three categories: ISUP grades 1–3, ISUP grade 4, and ISUP grade 5. mpMRI images included T1-weighted, T2-weighted, and apparent diffusion coefficient (ADC) map. Whole-prostate segmentations were performed on each modality, and image biomarker standardization initiative (IBSI)-compliant radiomic features were extracted. Nine support vector machine (SVM) models were trained: four single-modality radiomic models (PET, T1w, T2w, ADC); three PET + MRI double-modality models (PET + T1w, PET + T2w, PET + ADC), and two baseline models (one with patient data, one image-based) for comparison. A sixfold stratified cross-validation was performed, and balanced accuracies (bAcc) of the predictions of the best-performing models were reported and compared through Student’s t-tests. The predictions of the best-performing model were compared against biopsy GS (bGS). Results All radiomic models outperformed the baseline models. The best-performing (mean ± stdv [%]) single-modality model was the ADC model (76 ± 6%), although not significantly better (p > 0.05) than other single-modality models (T1w: 72 ± 3%, T2w: 73 ± 2%; PET: 75 ± 5%). The overall best-performing model combined PET + ADC radiomics (82 ± 5%). It significantly outperformed most other double-modality (PET + T1w: 74 ± 5%, p = 0.026; PET + T2w: 71 ± 4%, p = 0.003) and single-modality models (PET: p = 0.042; T1w: p = 0.002; T2w: p = 0.003), except the ADC-only model (p = 0.138). In this initial cohort, the PET + ADC model outperformed bGS overall (82.5% vs 72.4%) in the prediction of psGS. Conclusion All single- and double-modality models outperformed the baseline models, showing their potential in the prediction of GS, even with an unbalanced cohort. The best-performing model included PET + ADC radiomics, suggesting a complementary value of PSMA-PET and ADC radiomics.

Intravesical therapy for the treatment of superficial urinary bladder tumors is promising. However, it is also challenging, due to bladder contraction and relaxation and drug elimination via urination or dilution by urine production. We developed a biodegradable drug-eluting device positioned in the renal pelvis as an alternative strategy for bladder instillation. The urine drains from the renal pelvis into the ureter, collects the eluted drug, and transports it into the bladder. The combination of the renal pelvis and the bladder creates a two-compartment system. The drug is administered into the depot compartment, the renal pelvis, and is instantly and homogeneously distributed into the central compartment, the bladder. This results in an increase in its residence time and in gradual adsorption into the urothelium. The device is inserted through the ureter, followed by upset bulging after reaching the renal pelvis in order to guarantee fixation, while preventing urinary obstruction. The device is made of electrospun poly(lactic-co-glycolic acid) (PLGA) fibers that encapsulate a chemotherapeutic drug, cisplatin (1.17-2.34% w/w). Experimental studies of the stresses developed during the bulging and simulations of the urine flow interaction with the device demonstrated structural longevity and operational safety of the device. Sustained release of 94% of the device content was demonstrated after 1 week in vitro with a flow rate of 30 mL/h. We believe that the drug-eluted device may offer a significant advantage over existing therapies for treatment of nonmuscle invasive bladder cancer.

Aims/hypothesis The hyperinsulinaemic–hypoglycaemic glucose clamp technique has been developed and applied to assess effects of and responses to hypoglycaemia under standardised conditions. However, the degree to which the methodology of clamp studies is standardised is unclear. This systematic review examines how hyperinsulinaemic–hypoglycaemic clamps have been performed and elucidates potential important differences. Methods A literature search in PubMed and EMBASE was conducted. Articles in English published between 1980 and 2018, involving adults with or without diabetes, were included. Results A total of 383 articles were included. There was considerable variation in essential methodology of the hypoglycaemic clamp procedures, including the insulin dose used (49-fold difference between the lowest and the highest rate), the number of hypoglycaemic steps (range 1−6), the hypoglycaemic nadirs (range 2.0–4.3 mmol/l) and the duration (ranging from 5 to 660 min). Twenty-seven per cent of the articles reported whole blood glucose levels, most venous levels. In 70.8% of the studies, a dorsal hand vein was used for blood sampling, with some form of hand warming to arterialise venous blood in 78.8% of these. Key information was missing in 61.9% of the articles. Conclusions/interpretation Although the hyperinsulinaemic–hypoglycaemic clamp procedure is considered the gold standard to study experimental hypoglycaemia, a uniform standard with key elements on how to perform these experiments is lacking. Methodological differences should be considered when comparing results between hypoglycaemic clamp studies. PROSPERO registration This systematic review is registered in PROSPERO (CRD42019120083). Graphical abstract

Objective The consequences of the COVID-19 pandemic may lead to exceptional stress in pregnant women. In order to evaluate stress levels of pregnant woman in this difficult time, the Pandemic-Related Pregnancy Scale (PREPS) was introduced in the US. The present study introduces and validates the German version of the PREPS. Study design In total, 1364 German-speaking pregnant women from Germany and Switzerland took part in this online cohort study and completed the PREPS as well as gave information on sociodemographic, obstetric and other psychological factors. Results A confirmatory factor analysis of the PREPS showed very good psychometric values and confirmed the structure of the original questionnaire. The PREPS comprises three dimensions: Infection Stress (5 items), Preparedness Stress (7 items) and Positive Appraisal (3 items). Furthermore, correlations between the PREPS and other psychological factors such as Pregnancy Specific Stress and Fear of Childbirth highlight convergent validity. The sensitivity of the questionnaire was demonstrated by its associations with several obstetric and COVID-19 related factors. Conclusion The German PREPS showed good psychometric properties and is a useful instrument for future studies which aim to investigate the impact of pandemic-related stress on birth outcomes and postpartum factors.

Old patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought for the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥65 years) were categorized according to age: “young” (

The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006–2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan–Meier survival curves with log-rank test were used for statistical analyses. Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Background The early diagnosis of prostate cancer (PCa) is mainly based on prostate-specific antigen (PSA) blood levels and digital rectal examination. However, this approach may result in a high rate of negative biopsies and increased detection of clinically insignificant PCa (CS-PCa). An important prognostic biomarker, PSA density (PSA-D) demonstrated improved performance in PCa detection compared to PSA. The relationship between prostate volume and the prognostic accuracy of PSA-D remains mostly unclear. The aim of our study is to investigate the PSA-D predictive value of CS-PCa detection at different prostate volumes. Methods Using our local radical prostatectomy registry, patients were divided into three prostate size subgroups based on preoperative sonographic prostate volume assessment: less than 50, 50-75, and more than 75 cc. Patients' and PCa characteristics were recorded, including age, body mass index, PSA at diagnosis, prostate volume, PSA-D, D'Amico risk classification, Gleason grade group, and pathological staging following surgery. Results The study cohort included 364 patients who underwent Robotic Radical prostatectomy for biopsy-proven clinically localized PCa. 221 (61%) and 143 (39%) patients had PSA-D less than 0.15 and PSA-D more than 0.15, respectively. ISUP GG 1-2 PCa (CS-PCa) was observed in 220 patients (60%), while 144 (40%) had ISUP GG 3-5 PCa at final pathology. PSA-D correlated with CS-PCa only in small and medium-size prostates, but not in large glands (p = .03, p = .01, and p = .36, respectively). The highest sensitivity (72.7%) was observed in small prostates, compared to 3.2% in large prostates. The highest specificity (89.4%) was noted in large prostates. Positive predictive value in small and medium-size prostates was similar (~50%), compared to 20% in large glands. The negative predictive value was slightly better for small and medium-size prostates compared with large glands (68.9%, 73.7%, and 53.1%, respectively). An association between PSA-D and harboring CS-PCa was detected only in small and medium-size glands (72.7% and 43%, respectively). Conclusion PSA-D is associated with CS-PCa detection in radical prostatectomy specimens in small and medium-size prostates. The level of PSA-D is directly associated with the ISUP PCa grade group. Therefore, PSA-D is a beneficial, available, and cost-effective tool during decision-making in patients with small and medium-size prostate when considering treatment for PCa.

Background Meningiomas are the most common primary central nervous system tumors. Potential risk factors include obesity, height, history of allergy/atopy, and autoimmune diseases, but findings are conflicting. This study sought to assess the role of the different risk factors in the development of meningioma in adolescents/young adults. Methods The cohort included 2,035,915 Jewish men and women who had undergone compulsory physical examination between 1967 and 2011, at age 16 to 19 years, prior to and independent of actual military enlistment. To determine the incidence of meningioma, the military database was matched with the Israel National Cancer Registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, and history of allergic or autoimmune disease. Results A total of 480 subjects (328 females) were diagnosed with meningioma during a follow-up of 40,304,078 person-years. Median age at diagnosis was 42.1 ± 9.4 years (range 17.4–62.6). On univariate analysis, female sex (p Conclusions This large population study showed that sex and adolescent height in males (> 1.85 m) were associated with an increased risk of meningioma in adulthood.

To compare the ability of 68Ga -PSMA PET/CT (PSMA PET/CT) and multiparametric MRI (mpMRI) to exclude lymph node invasion (LNI) in patients who undergo radical prostatectomy (RP). A multicenter cohort of patients who underwent PSMA PET/CT and pelvic mpMRI prior to RP with pelvic lymph node dissection (PLND) was analyzed. Increased Ga68-PSMA uptake on PET/CT and enlarged (> 10 mm) or abnormal lymph nodes on mpMRI were considered positive findings. The final surgical pathology served as the standard of reference. The negative predictive value (NPV) was calculated for each modality separately, as well as the combined value. Included were 89 patients with D’Amico intermediate (45%) or high-risk (55%) prostate cancer. The median number of extracted LN was 9 (IQR 6-14). LNI was found in 12 (13.5%) patients. The NPV of mpMRI, PSMA PET/CT, and the two tests combined were 87%, 89%, and 90%, in the entire cohort, 95%, 97%, and 97% in patients with intermediate-risk disease, and 80%, 82%, and 83% in patients with high-risk disease, respectively. The median diameter of LN missed by both imaging and the median intranodal tumor diameter was 5.5 (IQR 3–10) mm and 1 (IQR 1–3) mm, respectively. PSMA PET/CT and mpMRI demonstrated similar performance in excluding pelvic LNI with NPV of approximately 90%. The combination of both tests does not improve NPV significantly. Therefore, even in the era of advanced imaging, PLND is still recommended for accurate staging, especially in the high-risk population.

Background Pregnant women are at increased risk of hypoxaemia during general anaesthesia. Our aim was to determine the incidence and the risk factors that contribute to hypoxaemia in this setting. Methods Every woman 18 yr or older who underwent a non-elective Caesarean section under general anaesthesia was eligible to participate in this multicentre observational study. The primary endpoint was the incidence of hypoxaemia defined as the SpO2 ≤95%. The secondary endpoint was the incidence of difficult intubation defined as more than two attempts or failed intubation. Results During the study period, 895 women were prospectively included in 17 maternity hospitals, accounting for 79% of women who had general anaesthesia for non-elective Caesarean section. Maternal hypoxaemia was observed in 172 women (19%; confidence interval [CI], 17–22%). Risk factors associated with hypoxaemia in the multivariate analysis were difficult or failed intubation (adjusted odds ratio [aOR]=19.1 [8.6–42.7], P 35 kg m−2 (aOR=0.53 [0.28–0.998], P=0.0495). Intubation was difficult in 40 women (4.5%; CI, 3.3–6%) and failed intubation occurred in five women (0.56%; CI, 0.1–1%). In the multivariate analysis, use of a hypnotic drug other than propofol was associated with difficult or failed intubation (aOR=25 [2–391], P=0.02). A propensity score confirmed that propofol was associated with a significant decreased risk of difficulty or failure to intubate (P Conclusions Hypoxaemia during Caesarean sections was observed in 19% of women and was significantly associated with difficult or failed intubation. The use of propofol may protect against the occurrence of difficult intubation.

This study was performed to test a protocol for trans-implant treatment of chronic recurrent maxillary sinusitis (CRS), via implants with an internal removable sealing screw. The appropriate indications for treatment, optimal number of treatment sessions, and general schedule of treatment and follow-up were assessed. This was a retrospective study of 31 patients with CRS who were managed with trans-implant lavage. Of these patients, 28 (referred for a sinus elevation procedure) underwent a simultaneous implantation procedure and treatment of the sinusitis. Three patients received treatment for sinusitis via an already existing implant. The suggested sinusitis treatment protocol includes the drainage of pus through the punctured sinus floor and three sessions of antral irrigation/lavage, four cone beam computed tomography scans, and four transnasal endoscopic observations. The suggested combined protocol includes the simultaneous evaluation of the implant status and the sinusitis treatment results on days 30 and 60 after surgery. Of the 31 patients, 28 (90%) had complete relief of most of their symptoms (nasal obstruction/discharge, anosmia/hyposmia) up to day 30 postoperative. Follow-up nasal endoscopy demonstrated no evidence of active sinus disease. Twenty-seven implants were well-osseointegrated and were still in use for prosthetic purposes. In one case, the implantation failed because of poor bone quality. For the remaining 30 cases, both clinical and radiological results showed stability of the implants and no CRS recurrence during the whole follow-up period. The dental implant with an internal central port and an integral sealing screw may be used for drainage, irrigation, observation, and further treatment of the maxillary sinus in cases of CRS.

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.

Purpose To assess the role of left ventricular overload and cumulated fluid balance in the development weaning-induced pulmonary edema (WIPO). Methods Ventilated patients in sinus rhythm with COPD and/or heart failure (ejection fraction ≤ 40%) were studied. Echocardiography was performed immediately before and during a 30-min spontaneous breathing trial (SBT) using a T-tube. Patients who failed were treated according to echocardiography results before undergoing a second SBT. Results Twelve of 59 patients failed SBT, all of them developing WIPO. Patients who succeeded SBT had lower body weight (− 2.5 kg [− 4.8; − 1] vs. + 0.75 kg [− 2.95; + 5.57]: p = 0.02) and cumulative fluid balance (− 2326 ml [− 3715; + 863] vs. + 143 ml [− 2654; + 4434]: p = 0.007) than those who developed WIPO. SBT-induced central hemodynamic changes were more pronounced in patients who developed WIPO, with higher E wave velocity (122 cm/s [92; 159] vs. 93 cm/s [74; 109]: p = 0.017) and E/A ratio (2.1 [1.2; 3.6] vs. 0.9 [0.8; 1.4]: p = 0.001), and shorter E wave deceleration time (85 ms [72; 125] vs. 147 ms [103; 175]: p = 0.004). After echocardiography-guided treatment, all patients who failed the first SBT were successfully extubated. Fluid balance was then negative (− 2224 ml [− 7056; + 100] vs. + 146 ml [− 2654; + 4434]: p = 0.005). Left ventricular filling pressures were lower (E/E′: 7.3 [5; 10.4] vs. 8.9 [5.9; 13.1]: p = 0.028); SBT-induced increase in E wave velocity (+ 10.6% [− 2.7/ + 18] vs. + 25.6% [+ 12.7/ + 49]: p = 0.037) and of mitral regurgitation area were significantly smaller. Conclusion In high-risk patients, WIPO appears related to overloaded left ventricle associated with excessive fluid balance. SBT-induced central hemodynamic changes monitored by CCE help in guiding therapy for successful weaning. Electronic supplementary material The online version of this article (10.1007/s00134-020-06061-y) contains supplementary material, which is available to authorized users.

Overlapping syndromes such as Noonan, Cardio-Facio-Cutaneous, Noonan syndrome (NS) with multiple lentigines and Costello syndromes are genetically heterogeneous conditions sharing a dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway and are known collectively as the RASopathies. PTPN11 was the first disease-causing gene identified in NS and remains the more prevalent. We report seven patients from three families presenting heterozygous missense variants in PTPN11 probably responsible for a disease phenotype distinct from the classical Noonan syndrome. The clinical presentation and common features of these seven cases overlap with the SHORT syndrome. The latter is the consequence of PI3K/AKT signaling deregulation with the predominant disease-causing gene being PIK3R1. Our data suggest that the phenotypic spectrum associated with pathogenic variants of PTPN11 could be wider than previously described, and this could be due to the dual activity of SHP2 (ie, PTPN11 gene product) on the RAS/MAPK and PI3K/AKT signaling.

Background Kaposi sarcoma (KS)–associated herpesvirus (KSHV) subtype depends mostly on patient origin. The current study aimed to assess KSHV diversity in a population of men who have sex with men (MSM) living in France. Methods The study included 264 patients. In 65 MSM, including 57 human immunodeficiency virus (HIV)–infected men with KS, multicentric Castleman disease, or primary effusion lymphoma and 8 HIV-uninfected men receiving HIV preexposure prophylaxis (PrEP), we performed KSHV typing with K1 open reading frame Sanger and KSHV whole-genome sequencing. In 199 other patients, we performed real-time polymerase chain reaction screening for the new variant. Results We found that 51% of KSHV-strains were subtype C (85% C3), and 33% were subtype A. Four patients with severe KSHV disease (2 with visceral KS, 1 with multicentric Castleman disease, and 1 with primary effusion lymphoma) and 1 asymptomatic PrEP user had a new variant resembling the Ugandan subtype F, but with different K1 open reading frame and KSHV whole-genome sequences and a different epidemiological context (MSM vs African population). Its prevalence was 4.5% in Caucasian MSM, and it was absent in other epidemiological groups. Conclusions Subtype C predominated among MSM living in France. The new F variant was identified in Caucasian MSM and associated with severe KSHV disease, suggesting that subtype F could be split into F1 and F2 variants. Careful screening for this variant may be required in MSM, given the severe clinical presentation of associated diseases.

We investigated whether pregnancy/birth anxiety is associated with shorter gestation while maternal chronic stress and depressive symptoms are associated with lower birth weight; we also examined whether experiencing daily uplifts prenatally may contribute to a more favorable birth outcome. Thirty-four healthy second trimester pregnant women responded to questions regarding their experience of pregnancy/birth anxiety, chronic stress, depressive symptoms, and daily uplifts. Information on birth outcome was obtained from medical records. Maternal pregnancy/birth anxiety, depression, and stress were unrelated to birth outcomes. Daily uplifts were associated with gestational age at birth (B = 2.0, p = 0.01), neonatal weight (B = 46.9, p = 0.00), and size (B = 10.6, p = 0.01). Our results suggest that pregnancy/birth anxiety is not associated with shorter gestation as well as depression and stress seem to not predict lower birth weight. We expand the literature by showing that experiencing daily uplifts during mid-gestation may further fetal development.

Background Congenital dyserythropoietic anemia type I (CDA I), is an autosomal recessive disease with macrocytic anemia in which erythroid precursors in the bone marrow exhibit pathognomonic abnormalities including spongy heterochromatin and chromatin bridges. We have shown previously that the gene mutated in CDA I encodes Codanin-1, a ubiquitously expressed and evolutionarily conserved large protein. Recently, an additional etiologic factor for CDA I was reported, C15Orf41, a predicted nuclease. Mutations in both CDAN1 and C15Orf41 genes results in very similar erythroid phenotype. However, the possible relationships between these two etiologic factors is not clear. Results We demonstrate here that Codanin-1 and C15Orf41 bind to each other, and that Codanin-1 stabilizes C15Orf41. C15Orf41 protein is mainly nuclear and Codanin-1 overexpression shifts it to the cytoplasm. Phylogenetic analyses demonstrated that even though Codanin-1 is an essential protein in mammals, it was lost from several diverse and unrelated animal taxa. Interestingly, C15Orf41 was eliminated in the exact same animal taxa. This is an extreme case of the Phylogenetic Profiling phenomenon, which strongly suggests common pathways for these two proteins. Lastly, as the 3D structure is more conserved through evolution than the protein sequence, we have used the Phyre2 alignment program to find structurally homologous proteins. We found that Codanin-1 is highly similar to CNOT1, a conserved protein which serves as a scaffold for proteins involved in mRNA stability and transcriptional control. Conclusions The physical interaction and the stabilization of C15Orf41 by Codanin-1, combined with the phylogenetic co-existence and co-loss of these two proteins during evolution, suggest that the major function of the presumptive scaffold protein, Codanin-1, is to regulate C15Orf41 activities. The similarity between Codanin-1 and CNOT1 suggest that Codanin-1 is involved in RNA metabolism and activity, and opens up a new avenue for the study of the molecular pathways affected in CDAI.

Background: Breast cancer is the second most common cause of central nervous system (CNS) metastasis, leading to a significant decrease in survival rate. High risk groups for CNS involvement include younger age, human epidermal growth factor 2 (HER2) over-expression, estrogen receptor (ER) and progesterone receptor (PR) negativity, high histologic grade, and presence of systemic metastases. Young age at diagnosis of breast cancer is associated with more aggressive biological behavior and worse prognosis than in the elderly. However, data are limited regarding CNS involvement in this group of patients. Although it could be expected that younger patients would also have a poor prognosis after the diagnosis of CNS metastases, earlier studies have demonstrated conflicting results, some with favorable outcomes for this unique group. In this study we aimed to explore the differences in the patterns and outcome of CNS involvement according to age at diagnosis of breast cancer (≤45 years vs. >45 years). Methods: A retrospective database of consecutive breast cancer patients who were treated in our institute and were diagnosed with CNS metastases during 2006-2019 was generated. Data analyzed included age at diagnosis of breast cancer, age at diagnosis of CNS involvement, histopathological factors (histology, grade, hormone receptor and HER2 status), treatments given before and after CNS involvement, characteristics of CNS involvement (location, number of brain deposits, clinical manifestations), overall survival, time to CNS progression, and survival after diagnosis of CNS disease. Results: Study cohort was comprised of 174 patients: 65 patients were age≤45 and 109 patients were older than 45 at breast cancer diagnosis. The percentage of patients with triple-negative breast cancer was higher among the younger age group (24.6% vs. 14.7%). Median overall survival from breast cancer diagnosis was significantly longer for younger patients [117.1 months (95% CI 67.2-167) vs. 88 months (95% CI 65.6-110.4), p=0.017]. Median time from breast cancer diagnosis to development of CNS metastases was also significantly longer in the younger age group [58.1 months (95% CI 46.5-69.6) vs. 37.5 months (95% CI 22.9-52.2), p=0.021]. Median survival as measured from time of CNS involvement was 18.7 months (95% CI 10.8-26.6) in the younger group vs. 11.1 months (95% CI 7.8-14.5) in the older patients (p=0.341). Survival of patients with triple-negative breast cancer from time of CNS metastases diagnosis was significantly longer for the younger age group [22.5 months (95% CI 1.2-43.8) vs. 7.9 months (95% CI .77-15.1), p=0.033]. The number, location and clinical presentation of CNS metastases were not statistically different between the two groups. Systemic and CNS-directed treatment approaches were also similar. Conclusion: While the presentation of CNS metastasis was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival. Numerically, after diagnosis of CNS involvement younger patients had longer survival, but the difference was statistically significant only for patients with triple-negative disease. Citation Format: Matan Ben-Zion Berliner, Shlomit Yust-Katz, Inbar Lavie, Alexandra Amiel, Dalia Zoref, Daniel Hendler, Hadar Goldvaser, Michal Sarfaty, Ofer Rotem, Olga Ulitsky, Tali Siegal, Victoria Neiman, Rinat Yerushalmi. Central nervous system metastases in breast cancer: The impact of age on patterns of development and outcome [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-41.

Women's increased risk for depression during reproductive transitions suggests an involvement of the hypothalamic-pituitary-ovarian (HPO) axis. This is the first systematic review and meta-analysis of HPO functioning in female mood disorders. Inclusionary criteria were: i) women suffering from premenstrual dysphoric disorder (PMDD) or a depressive disorder, ii) assessment of HPO-axis related biomarkers, iii) a case-control design. Sixty-three studies (N = 5,129) were included. There was evidence for PMDD to be paralleled by lower luteal oestradiol levels. Women with depression unrelated to reproductive transition showed lower testosterone levels than healthy controls and there was some evidence for lower dehydroepiandrosterone sulfate levels. There were no differences in HPO-related parameters between women with pregnancy, postpartum, and perimenopausal depression and controls. Women with PMDD and depression unrelated to reproductive transitions exhibit specific changes in the HPO-axis, which potentially contribute to their symptoms. Further research into reproductive mood disorders characterised by extreme endocrine changes is warranted.

International audience; Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.

BACKGROUND Grade II and III meningiomas are invasive tumors which tend to recur following initial treatment and are associated with shorter survival (relative to grade I). Hemangiopericytoma (HPC) is a dural based tumor that originates in the pericytes. Treatment options for these tumors include surgical resection and radiation. There are no defined standard treatments after failure these modalities, and effective systemic treatments are lacking. This trial concept was developed following previous reports of high PD-L1 levels in anaplastic meningioma. We currently report our initial experience with pembrolizumab for refractory atypical/anaplastic meningioma (RAM) and HPC patients. METHODS This is a single arm, single institute, phase 2 trial. Inclusion criteria included patients with RAM or HPC whose all previous lines of treatment were exhausted. All patients were treated with pembrolizumab (200mg every 3 weeks) until disease progression. Primary endpoint was 6- and 12-months progression free survival (PFS). The study was planned for 25 patients and we report here preliminary results. RESULTS Through February 2021, 12 patients were enrolled to this study (two with HPC, 10 with RAM). After a median follow up of 18.5 months, the 6 and 12 months PFS were 25% and 16.7% respectively, with a median PFS of 2.75 months. Two patients had a partial response while all others progressed, making the overall response rate 16.7%. One of the responders had HPC and has been stable for 30 months, while the second had atypical meningioma and was stable for 13 months. Median survival has not been reached yet; 1 year survival rate was 82.5%. Grade 3 toxicities included hyperglycemia, elevated liver enzymes and fatigue, with no grade 4 or 5 toxicities. CONCLUSIONS Pembrolizumab induced a low response rate for RAM and HPC. However, a subset of patients might benefit from this treatment with a prolonged response period.

Women experience different degrees of subjective cognitive changes during pregnancy. The exact mechanism underlying these changes is unknown, although endocrine alterations and genetics may be contributing factors. We investigated whether multiple pregnancy-related hormones were associated with working memory function assessed with the Digit Span Test (DST) in late pregnancy. Moreover, we examined whether the catechol-O-methyltransferase (COMT) genotype, previously related to working memory, was an effect modifier in this association. In this population-based panel study, we recorded psychiatric history, medication use, socio-demographic characteristics, and psychological well-being, gathered blood and saliva samples, and administered the DST at gestational weeks 35-39 (N = 216). We conducted multivariate linear regressions with DST as outcome, with different hormones and COMT genotype, adjusting for covariates including maternal age, BMI, education, depressive symptoms, and parity. We repeated these analyses excluding women with elevated depressive symptoms. Higher DST total scores were associated with increased free estradiol concentrations (B = 0.01, p = 0.03; B = 0.01, p = 0.02) in all participants and in participants without depressive symptoms, respectively, whereas DST forward was positively associated with free estradiol only in women without depressive symptoms (B = 0.01, p = 0.04). Lower total testosterone concentrations (B = -0.03, p = 0.01) enhanced DST backward performance in non-depressed women. Maternal higher education was significantly associated with the DST subscales in all participants. No significant differences emerged when considering the COMT genotype. Our results suggest differential associations of free estradiol and total testosterone levels with working memory function in late pregnancy.

International audience; No abstract available

Contains fulltext : 286868.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Hypoglycaemic episodes and fear of hypoglycaemia can be burdensome for adults with type 1 diabetes. This study explored support needs relating to hypoglycaemia among adults with type 1 diabetes living in Denmark, Germany, the Netherlands and the United Kingdom. RESEARCH DESIGN AND METHODS: Respondents participated in a web-based qualitative study involving four open-ended questions that asked what they wished other people understood about hypoglycaemia and what other people could do differently to support them with hypoglycaemia. Responses were analyzed using reflexive thematic analysis. RESULTS: Participants were 219 adults with type 1 diabetes (mean ± SD age 39 ± 13 years; mean ± SD diabetes duration 20 ± 14 years). They described unmet needs relating to: (1) Clinical support, involving access to new diabetes technologies, training on hypoglycaemia prevention, personalised care and psychological support; (2) Practical support, involving family and friends better supporting them with hypoglycaemia management and prevention; (3) Education for other people, involving others becoming more informed about hypoglycaemia; and (4) An appreciation of the burden, involving others recognizing the experience and impact of episodes, and the burden of living with the risk of hypoglycaemia. CONCLUSIONS: Adults with type 1 diabetes report several unmet support needs relating to hypoglycaemia. Service delivery should be person-centred and prioritise the individual's support needs. Clinical conversations are needed to identify the individual's support needs and develop tailored support plans. People with diabetes and their family members should be offered hypoglycaemia-specific education and training.

La hiperplasia estromal pseudoangiomatosa (PASH, por sus siglas en inglés) se presenta entre los 12 y 75 años de edad, siendo prevalente en la edad reproductiva. Se desconoce su etiología. Se caracterizan por ser grandes, deformantes, unilaterales y se les diagnostica por ecografía e histología. En las adolescentes es importante la vigilancia, diagnóstico y manejo tempranos, con la finalidad de evitar cirugías radicales que originen cicatrices grandes, deformidad y asimetría mamaria, que repercuten en el comportamiento y estado emocional de las pacientes. Los tumores de la mama generalmente son benignos en la adolescencia, pero su diagnóstico en este grupo etario es preocupante para la familia y la paciente. Presentamos el caso de una adolescente de 14 años a quien se le realizó abordaje submamario, conservando la simetría mamaria.

Aim People of Black African ancestry, who are known to be at disproportionately high risk of type 2 diabetes (T2D), typically exhibit lower hepatic insulin clearance compared with White Europeans. However, the mechanisms underlying this metabolic characteristic are poorly understood. We explored whether low insulin clearance in Black African (BA) men could be explained by insulin resistance, subclinical inflammation or adiponectin concentrations. Methods BA and White European (WE) men, categorised as either normal glucose tolerant (NGT) or with T2D, were recruited to undergo the following: a mixed meal tolerance test with C-peptide modelling to determine endogenous insulin clearance; fasting serum adiponectin and cytokine profiles; a hyperinsulinaemic–euglycaemic clamp to measure whole-body insulin sensitivity; and magnetic resonance imaging to quantify visceral adipose tissue. Results Forty BA (20 NGT and 20 T2D) and 41 WE (23 NGT and 18 T2D) men were studied. BA men had significantly lower insulin clearance (P = 0.011) and lower plasma adiponectin (P = 0.031) compared with WE men. In multiple regression analysis, ethnicity, insulin sensitivity and plasma adiponectin were independent predictors of insulin clearance, while age, visceral adiposity and tumour necrosis factor alpha (TNF-α) did not significantly contribute to the variation. Conclusion These data suggest that adiponectin may play a direct role in the upregulation of insulin clearance beyond its insulin-sensitising properties.

Purpose Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. Methods Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. Results Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. Conclusion We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

IntroductionAchieving glycemic targets and optimizing quality of life (QoL) are important goals of type 1 diabetes care. Hypoglycemia is a common barrier to achieving targets and can be associated with significant distress. However, the impact of hypoglycemia on QoL is not fully understood. The aim of this study was to explore how adults with type 1 diabetes are impacted by hypoglycemia in areas of life that are important to their overall QoL.Research design and methodsParticipants responded to a web-based qualitative survey involving a novel ‘Wheel of Life’ activity. Responses were analyzed using reflexive thematic analysis.ResultsThe final sample included 219 adults with type 1 diabetes from Denmark, Germany, the Netherlands, and the UK. They had a mean±SD age of 39±13 years and diabetes duration of 20±14 years. Participants identified eight areas of life important to their overall QoL, including relationships and social life, work and studies, leisure and physical activity, everyday life, sleep, sex life, physical health, and mental health. Participants reported emotional, behavioral, cognitive, and social impacts of hypoglycemia within domains. Across domains, participants described interruptions, limited participation in activities, exhaustion, fear of hypoglycemia, compensatory strategies to prevent hypoglycemia, and reduced spontaneity.ConclusionsThe findings emphasize the profound impact of hypoglycemia on QoL and diabetes self-care behaviors. Diabetes services should be aware of and address the burden of hypoglycemia to provide person-centered care. Clinicians could ask individuals how hypoglycemia affects important areas of their lives to better understand the personal impact and develop tailored management plans.

OBJECTIVE: To determine the distribution of Aortic Dissection Detection Risk Score (ADDRS) in undifferentiated chest pain patients. METHODS: Prospective observational study of adult patients presenting to the ED with non-traumatic chest pain. RESULTS: Of 139 patients studied, more than 75% of patients has an ADDRS ≥1, mainly because of the report of severe pain. There were no aortic dissections. In patients with non-specific chest pain, testing driven by the ADDRS protocol would have seen a 280% increase in d-dimer testing and 2200% increase in computed tomography aortogram rates. CONCLUSION: Widespread use of the ADDRS and its investigation protocol cannot be supported.

Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype–phenotype correlations in KS individuals from a registry. Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

Introduction and Objectives: Urinary tract infections (UTI) following ureteroscopy (URS) occur in about 4% of patients. Due to the resistant bacterial strains we encounter in our institution, we retrospectively examined whether a double-drug antibiotic prophylactic treatment (APT) can reduce urosepsis after URS. Materials and Methods: Between February 2015 and March 2016, we performed 344 URS for stone treatment. Starting from September 2015, we changed the APT. Exclusion criteria included procedures involving percutaneous nephrolithotomy, pediatric or pregnant patients, and patients with preoperative clinical UTI. Results: Fifty-seven patients were excluded. Group 1 (n = 106) were the last to receive the conventional APT (oral ciprofloxacin), while the second group (n = 181) were the first to receive the new ­regimen (intravenous gentamycin and ampicillin). A distinct percentage of both groups had a preoperative positive urine culture (29% in group 1 and 19% in group 2). Seven of 9 septic events developed in patients with preoperative positive urine culture (p < 0.001). Patients undergoing retrograde intrarenal surgery were at increased risk for sepsis when treated with conventional APT (p < 0.01). Post-URS sepsis was 7.5% using the conventional APT and 0.5% with the new APT (p < 0.0001). Conclusions: A distinct number of patients undergoing URS stone treatment have positive preoperative urine cultures. “One size fits all” APT is not sufficient according to our data. A regimen tailored to the local antibiotic resistance of the uropathogens can lower the rate of sepsis.

Aim: The aim of this pilot study was to evaluate the therapeutic and safety performance of an intramuscular treatment protocol of multidose of allogeneic adipose stem cells (ASCs) isolated, characterized, and expanded ex vivo from a healthy canine donor. Materials and Methods: Twelve dogs diagnosed with canine atopic dermatitis (CAD) were intramuscularly treated with 0.5×106 of cryopreserved ASCs from a healthy immunized young canine Ehrlichia canis free donor weekly for 6 weeks. Treatment efficacy was evaluated by the pruritus index and the CAD Lesion Index (CADLI) test. Safety and adverse effects were determined by injection site reaction, weight, blood chemistry, liver function, and whole blood count. Results: Canine ASCs obtained from a donor met the minimum qualities required for this type of cells and showed viability of 90% after thawing. The efficacy of the CADLI score and the pruritus index in 12 dogs with atopic dermatitis was statistically significant efficacy. No adverse reactions were observed at the intramuscular application site, or in relation to animal weight, blood cell populations, or liver and renal function. Conclusion: These results suggest that intramuscular administration of cryopreserved ASCs to dogs with atopic dermatitis is a promising cellular therapeutic product for the relief of the symptoms of this disease; however, the duration of the effects obtained with this dose and with other doses should be evaluated, as well as possible immune reactions. As far as we know, this is the first report of the use of multiple intramuscular doses cryopreserved ASCs to treat atopic dermatitis.

OBJECTIVE Impaired awareness of hypoglycemia (IAH) affects one-quarter of adults with type 1 diabetes and significantly increases the risk of severe hypoglycemia. Differences in regional brain responses to hypoglycemia may contribute to the susceptibility of this group to problematic hypoglycemia. This study investigated brain responses to hypoglycemia in hypoglycemia aware (HA) and IAH adults with type 1 diabetes, using three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) functional MRI to measure changes in regional cerebral blood flow (CBF). RESEARCH DESIGN AND METHODS Fifteen HA and 19 IAH individuals underwent 3D pCASL functional MRI during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global, and regional CBF responses to hypoglycemia (47 mg/dL [2.6 mmol/L]) were measured. RESULTS In response to hypoglycemia, total symptom score did not change in those with IAH (P = 0.25) but rose in HA participants (P < 0.001). Epinephrine, cortisol, and growth hormone responses to hypoglycemia were lower in the IAH group (P < 0.05). Hypoglycemia induced a rise in global CBF (HA P = 0.01, IAH P = 0.04) but was not different between groups (P = 0.99). IAH participants showed reduced regional CBF responses within the thalamus (P = 0.002), right lateral orbitofrontal cortex (OFC) (P = 0.002), and right dorsolateral prefrontal cortex (P = 0.036) and a lesser decrease of CBF in the left hippocampus (P = 0.023) compared with the HA group. Thalamic and right lateral OFC differences survived Bonferroni correction. CONCLUSIONS Responses to hypoglycemia of brain regions involved in arousal, decision making, and reward are altered in IAH. Changes in these pathways may disrupt IAH individuals’ ability to recognize hypoglycemia, impairing their capacity to manage hypoglycemia effectively and benefit fully from conventional therapeutic pathways to restore awareness.

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and recurrent severe hypoglycemia (RSH) remain problematic for people with type 1 diabetes (T1D), despite major therapeutic advances. We explored beliefs around hypo- and hyperglycemia in adults with T1D with, and without, IAH and RSH. RESEARCH DESIGN AND METHODS A cross-sectional U.S. multicenter survey included Attitudes to Awareness of Hypoglycemia (A2A; a 19-item questionnaire concerning beliefs about hypoglycemia), the Gold score (single item: awareness of hypoglycemia), and a question about severe hypoglycemia over the preceding year. The survey was emailed to 6,200 adult participants of the annual T1D Exchange clinic registry data collection. A2A data were subjected to principal component analysis with varimax rotation. RESULTS Among 1,978 respondents (response rate 32%), 61.7% were women, mean ± SD age was 39.6 ± 16.3 years, and T1D duration was 23.1 ± 13.8 years. Thirty-seven percent reported IAH, 16% RSH, and 9% both. A2A items segregated into three factors, differently distributed by hypoglycemia experience. Respondents with IAH or RSH expressed appropriate concern about hypoglycemia, but those with IAH were more likely to prioritize hyperglycemia concerns than those with intact awareness (P = 0.002). Those with RSH showed greater normalization of asymptomatic hypoglycemia than those without (P = 0.019) and trended toward prioritizing hyperglycemia concerns (P = 0.097), driven by those with both IAH and RSH. CONCLUSIONS Adults with T1D with IAH and RSH report specific cognitions about hypoglycemia and hyperglycemia, which may act as barriers to hypoglycemia avoidance and recovery of awareness. These may be modifiable and present a target for enhancing engagement of vulnerable people with strategies to avoid future hypoglycemia.

BackgroundThe aim of this study was to validate a point-of-care C-reactive protein (CRP) test (QuikRead, wide-range [wr] CRP) against standard laboratory testing in neonates with suspected sepsis.MethodsThis was a single-centre prospective cohort study of neonates (n = 91). The main outcome measure was the paired evaluation of the wr-CRP point-of-care test and automated laboratory CRP tests in neonates with suspected sepsis.ResultsThere were 126 measured CRP-sample pairs. The mean difference between the laboratory CRP and the wr-CRP point-of-care test values was 0.19 (95% confidence interval [CI]:‒1.0–0.65). Pearson’s correlation coefficient was 0.94. The area under the receiver operating characteristic (ROC) curve was 0.99 (95% CI: 0.98–1.00). At a QuikRead CRP cut-off of ≥6.2, the sensitivity and specificity were 77% and 100%, respectively.ConclusionsPoint-of-care wr-CRP testing can be used as a screening test in neonates with suspected sepsis. Rapid bed-side diagnostics and minimal blood volume requirements present an attractive alternative to common laboratory CRP testing.

Intrahepatic lipid (IHL) is linked with reduced hepatic insulin sensitivity and insulin clearance. Despite their high risk for type 2 diabetes (T2D), there have been limited investigations of these relationships in black populations. We investigated these relationships in 18 white European (WE) and 18 black West African (BWA) men with T2D

IF 2.164 (2017); International audience; Pai syndrome was originally described as the association of a midline cleft lip, midline facial polyps, and lipoma of the central nervous system. However, only a few patients present with the full triad, and most exhibit a wide spectrum of phenotypic variability. The aim of this study was to phenotypically delineate Pai syndrome and to propose new criteria to facilitate a clinical diagnosis in the future. The study cohort consisted of seven case patients and an additional 60 cases diagnosed with Pai syndrome identified in a literature review. Only 23 of 67 patients presented the full triad as historically described by Pai et al. (1987). A congenital facial midline skin mass was always encountered, particularly affecting the nasal structures (60/67). A midline facial cleft was reported in 45 of 67 patients and a pericallosal lipoma in 42 of 67 patients. The proposed definition of Pai syndrome is the association of (1) a congenital nasal and/or mediofrontal skin mass and/or a mid-anterior alveolar process polyp as a mandatory criterion, and at least one of the following criteria: (2) midline cleft lip and/or midline alveolar cleft, and/or (3) a pericallosal lipoma or interhemispheric lipoma in the case of corpus callosum dysgenesis.

Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Telomeres are a specific base sequence of DNA, responsible for chromosome stability and DNA protection. We aimed to investigate the association between telomere systems and IVF outcomes according to patients' BMI. For all telomere characteristics, there was a distinct trend towards shorter telomeres and activation of telomere shortening compensatory mechanisms in the BMI group >25 kg/m2, reaching statistical significance for senescence only (r = 0.7, p value

The need for alternative treatments for multiple sclerosis (MS) has triggered copious amounts of research into microbial therapies focused on manipulating the microbiota–gut–brain axis. This comprehensive review was intended to present and systematically evaluate the current clinical and preclinical evidence for various probiotic and commensal gut microbial therapies as treatments for MS, using the Bradford Hill criteria (BHC) as a multi-parameter assessment rubric. Literature searches were performed to identify a total of 37 relevant studies (6 human, 31 animal), including 28 probiotic therapy and 9 commensal therapy studies. In addition to presenting qualitative summaries of these findings, therapeutic evidence for each bacterial formulation was assessed using the BHC to generate summative scores. These scores, which encompassed study quality, replication, and other considerations, were used to rank the most promising therapies and highlight deficiencies. Several therapeutic formulations, including VSL#3, Lactobacillus paracasei, Bifidobacterium animalis, E. coli Nissle 1917, and Prevotella histicola, emerged as the most promising. In contrast, a number of other therapies were hindered by limited evidence of replicable findings and other criteria, which need to be addressed by future studies in order to harness gut microbial therapies to ultimately provide cheaper, safer, and more durable treatments for MS.

Objectives Preeclampsia (PE) is a pregnancy-related syndrome characterized by the onset of hypertension and proteinuria that can lead to end-organ dysfunction. Galectin-3 (Gal-3) is involved in cell growth, differentiation, inflammation and fibrosis. Thioredoxin (TXN) acts as antioxidant enzyme in several cellular processes, regulating inflammation and inhibiting apoptosis. TXNIP is an endogenous inhibitor of TXN. We evaluated changes in the inflammatory response of Gal-3, TXN, and TXNIP at the level of maternal blood, placenta, and umbilical cord blood of women with PE. Study design Ten women with PE and 20 with normal pregnancy (NP) were recruited during admission for delivery. Blood samples were obtained from parturients and umbilical cords, and placental tissue for analysis. Results Gal-3 and TXNIP mRNA expression were higher in maternal plasma in PE group compared to NP and were lower in cord blood plasma and placentas in the PE group. In the PE group, TXN/TXNIP mRNA ratio was higher in cord blood plasma (2.07) compared to maternal plasma (1.09). TXN/TXNIP placental protein ratio was similar between PE (0.89) and NP (0.79). ELISA demonstrated that Gal-3 levels in maternal serum were significantly higher in the PE vs. the NP group. Conclusions Pro-inflammatory changes were expressed by high Gal-3 and TXNIP mRNA in maternal blood of PE women, but not in their placental and cord blood samples. These findings may imply that the placenta has a role in protecting the fetus from the damages of inflammatory response, which is more common in PE than in NP.

Objective Studies have demonstrated a potential correlation between low vitamin D status and both an increased risk of infection with SARS-CoV-2 and poorer clinical outcomes. This retrospective study examines if, and to what degree, a relationship exists between pre-infection serum 25-hydroxyvitamin D (25(OH)D) level and disease severity and mortality due to SARS-CoV-2. Participants The records of individuals admitted between April 7th, 2020 and February 4th, 2021 to the Galilee Medical Center (GMC) in Nahariya, Israel, with positive polymerase chain reaction (PCR) tests for SARS-CoV-2 (COVID-19) were searched for historical 25(OH)D levels measured 14 to 730 days prior to the positive PCR test. Design Patients admitted to GMC with COVID-19 were categorized according to disease severity and level of 25(OH)D. An association between pre-infection 25(OH)D levels, divided between four categories (deficient, insufficient, adequate, and high-normal), and COVID-19 severity was ascertained utilizing a multivariable regression analysis. To isolate the possible influence of the sinusoidal pattern of seasonal 25(OH)D changes throughout the year, a cosinor model was used. Results Of 1176 patients admitted, 253 had records of a 25(OH)D level prior to COVID-19 infection. A lower vitamin D status was more common in patients with the severe or critical disease (p < 0.001). Patients with vitamin D deficiency (p < 0.001). Conclusions Among hospitalized COVID-19 patients, pre-infection deficiency of vitamin D was associated with increased disease severity and mortality.