Miracle-dz/UniFAR-FTUs huggingface dataset:
High prevalence of cancer‐associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering

The 1,000 genome project, the Exome Aggregation Consortium (ExAC) or the Genome Aggregation database (gnomAD) datasets, were developed to provide large‐scale reference data of genetic variations for various populations to filter out common benign variants and identify rare variants of clinical importance based on their frequency in the human population. Using a TP53 repository of 80,000 cancer variants, as well as TP53 variants from multiple cancer genome projects, we have defined a set of certified oncogenic TP53 variants. This specific set has been independently validated by functional and in silico predictive analysis. Here we show that a significant number of these variants are included in gnomAD and ExAC. Most of them correspond to TP53 hotspot variants occurring as somatic and germline events in human cancer. Similarly, disease‐associated variants for five other tumor suppressor genes, including BRCA1, BRCA2, APC, PTEN, and MLH1, have also been identified. This study demonstrates that germline TP53 variants in the human population are more frequent than previously thought. Furthermore, population databases such as gnomAD or ExAC must be used with caution and need to be annotated for the presence of oncogenic variants to improve their clinical utility.
Testicular apoptosis after dietary zinc deficiency: Ultrastructural and TUNEL studies

The present study was conducted in Wistar rats to determine whether prepubertal dietary zinc deficiency causes apoptotic changes in testes. Prepubertal male Wistar rats (40–50 gm) were divided into 3 groups: zinc control (ZC), pairfed (PF), and zinc deficient (ZD). Control and pairfed groups were given a 100 ppm zinc diet while the deficient groups received 1 ppm zinc diet for 2 and 4 weeks (w), respectively. Ultrastructural studies revealed several apoptotic features such as wavy basement membrane, displaced nuclei, chromatin condensation, plasma membrane blebbing, nuclear membrane dissolution, loss of inter-Sertoli cell junctional complexes, and intercellular bridges and deformed mitochondria. A variable spectrum of sperm defects had also been visualized e.g., acrosomal deformities such as decapitation and a ring of condensed chromatin around the nuclear periphery, deformed sperm heads with a condensed nucleus, tail-elements with superfluous cytoplasm, and damage to the mitochondrial sheath and aggregation of spermatozoa within the membrane. This was further supported by TUNEL studies. Apoptotic index, epididymal sperm concentration, motility, and fertility index also revealed a significant (P < 0.05) decrease in zinc deficient groups (2 and 4 w) when compared with their respective control and pairfed groups. All the above findings are indicative that changes observed in the testes after dietary zinc deficiency are due to the onset of apoptosis. Increased apoptotic degeneration in testes may cause irreversible changes in the germ cells associated with decreased epididymal sperm concentration, motility, and fertility index which contributes to the low efficiency of spermatogenesis thereby indicating a possible role of zinc in fertility.
Towards Understanding the Origin of Cosmic-Ray Positrons and Electrons

Precision measurements of cosmic-ray positron flux by the Alpha Magnetic Spectrometer on the International Space Station are presented based on 1.9 million positrons up to 1 TeV. The positron flux exhibits distinct and complex energy dependence. The positron flux exhibits a significant excess starting from 25.2 ± 1.8GeV followed by a sharp drop-off above 284+91 −64 GeV. In the entire energy range, the positron flux is well described by the sum of a diffuse term associated with low energy secondary positrons produced in the collision of cosmic rays, and a new source term of high energy positrons with a finite energy cutoff. This cutoff energy of the source term is determined to be 810+310 −180 GeV with a significance of more than 4σ. These experimental data show that, at high energies, positrons predominantly originate either from dark matter collisions or from new astrophysical sources.
Integration of a Raman spectroscopy system to a robotic-assisted surgical system for real-time tissue characterization during radical prostatectomy procedures

Abstract. Surgical excision of the whole prostate through a radical prostatectomy procedure is part of the standard of care for prostate cancer. Positive surgical margins (cancer cells having spread into surrounding nonresected tissue) occur in as many as 1 in 5 cases and strongly correlate with disease recurrence and the requirement of adjuvant treatment. Margin assessment is currently only performed by pathologists hours to days following surgery and the integration of a real-time surgical readout would benefit current prostatectomy procedures. Raman spectroscopy is a promising technology to assess surgical margins: its in vivo use during radical prostatectomy could help insure the extent of resected prostate and cancerous tissue is maximized. We thus present the design and development of a dual excitation Raman spectroscopy system (680- and 785-nm excitations) integrated to the robotic da Vinci surgical platform for in vivo use. Following validation in phantoms, spectroscopic data from 20 whole human prostates immediately following radical prostatectomy are obtained using the system. With this dataset, we are able to distinguish prostate from extra prostatic tissue with an accuracy, sensitivity, and specificity of 91%, 90.5%, and 96%, respectively. Finally, the integrated Raman spectroscopy system is used to collect preliminary spectroscopic data at the surgical margin in vivo in four patients.
Initial Diagnosis of Lumbar Disc Herniation Is Associated with a Delay in Diagnosis of Ankylosing Spondylitis

Objective. There is often a considerable delay in diagnosis of ankylosing spondylitis (AS). In this multicenter study, we analyzed the delay and possible associated factors, including an initial diagnosis of lumbar disc herniation (LDH), which we frequently encounter in daily clinical practice. Methods. The study included 393 consecutive patients [258 men (65.6%), mean age 39.3 ± 10.8 yrs] with AS according to the modified New York criteria. Face-to-face interviews were done using a structured questionnaire, addressing all the potentially relevant factors. Results. The mean diagnostic delay was 8.1 ± 8.6 years in the whole study population. The shortest delay was observed when rheumatologists were the first physicians consulted (2.9 ± 5.3 yrs). An initial diagnosis of LDH was reported by 33% of the patients. The diagnostic delays in patients with an initial diagnosis of LDH and those without were 9.1 ± 8.5 years and 6.2 ± 7.4 years, respectively (p = 0.002). In a regression model, predictive factors for delay in diagnosis were age at onset of spondyloarthritic symptoms, back pain, education level, prior diagnosis of LDH, and surgical history for LDH. Conclusion. These results indicate the need to increase awareness of the concept of axial spondyloarthritis among specialists who might be the first physicians consulted by patients with AS for their back pain. There is also a need to develop strategies for early referral of such patients to rheumatologists.
Liver Microvascular Injury and Thrombocytopenia of Antibody–Calicheamicin Conjugates in Cynomolgus Monkeys—Mechanism and Monitoring

Purpose: Adverse reactions reported in patients treated with antibody–calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers. Experimental Design: Cynomolgus monkeys were dosed intravenously at 6 mg/m2/dose once every 3 weeks with a nonbinding antibody–calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day 63). Results: PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury. Conclusions: These data support the conclusion that target-independent damage to liver SECs may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS. Clin Cancer Res; 23(7); 1760–70. ©2016 AACR.
The implementation and first insights of the French-speaking Swiss programme for monitoring self-harm.

AIMS OF THE STUDY Self-harm is a major risk factor for suicide but remains poorly documented. No data on self-harm in French-speaking Switzerland exist. To address this deficiency, the Swiss Federal Office of Public Health commissioned a specific self-harm monitoring programme. We present and discuss its implementation and first findings. METHODS Every patient aged 18–65 years presenting for self-harm to the emergency departments of the Lausanne and Neuchâtel general hospitals were included in the monitoring programme over a 10-month period (December 2016 to September 2017). Clinicians collected anonymous sociodemographic and clinical data. RESULTS The sample included 490 patients (54.9% female and 45.1% male) for 554 episodes of self-harm, showing a higher proportion of patients aged 18–34 (49.2%) than older age groups (35–49, 33.7% and 50–65, 17.1%). Patients were mostly single (56.1%) and in problematic socioeconomic situations (65.7%). Self-poisoning was the most commonly used method (58.2%) and was preferred by women (71% of females and 42.5% of males, Fisher’s exact test, p <0.001) and the majority of patients (53.3%) had experienced at least one previous episode of self-harm. The self-harm rate was 220 per 100,000 inhabitants in Lausanne and 140 in Neuchâtel. Suicidal intent was clear for 50.6% of the overall sample, unclear for 25.1% and absent for 24.3%. It differed significantly between sites (χ2(2) = 9.068, p = 0.011) as Lausanne reported more incidents of unclear intent (27.7% versus 17.4% in Neuchâtel) and Neuchâtel more incidents with absence of intent (33.1% versus 21.3% in Lausanne). In Lausanne, patients more frequently resorted to methods such as jumping from a height (11.4%) and hanging (9%) than in Neuchâtel (1.6% and 4.9%, Fisher’s exact test, p = 0.006). CONCLUSIONS Our results are globally consistent with previous research on self-harm. We found significant inter-site differences in methods, suicidal intent and self-harm rates. Our findings highlight the importance of implementing local self-harm monitoring to identify specific at-risk groups and develop targeted preventive intervention.
Determining a Resting Metabolic Rate Prediction Equation for Collegiate Female Athletes.

Watson, AD, Zabriskie, HA, Witherbee, KE, Sulavik, A, Gieske, BT, and Kerksick, CM. Determining a resting metabolic rate prediction equation for collegiate female athletes. J Strength Cond Res XX(X): 000-000, 2018-A lack of evidence exists regarding the accuracy of common resting metabolic rate (RMR) prediction equations in athletic female populations. The purpose of this research was to measure RMR in a large cohort of NCAA Division II female athletes and use regression techniques to develop new prediction equations. Sixty-six female athletes from 11 different sports completed this protocol, which included skinfold measurements followed by an RMR assessment using indirect calorimetry. The average RMR was 1,466 ± 150 kcal·d. Many between-sport differences in body composition were identified, with gymnastics athletes having the lowest body fat percentage (p < 0.05) and basketball athletes having the greatest absolute fat-free mass (p < 0.05). Resting metabolic rate was moderately correlated (p < 0.05) with height (r = 0.52), total mass (r = 0.59), and fat-free mass (r = 0.54). Two equations were developed, both of which were more accurate for this population than other RMR prediction equations. One of the new equations, which used height and body mass as covariates (equation 1), was slightly more accurate than the equation using body composition parameters (equation 2). The new equations were cross-validated using a randomly selected subset (n = 22) of the original sample. The subset did not show statistically different results from the remainder of the sample (n = 44) between equation 1 (p = 0.083) and equation 2 (p = 0.22). Equation 1, which had more easily measurable parameters, exhibited heightened accuracy, which has important implications for implementation among athletes, coaches, and athletic support staff.
A Randomized Controlled Trial Comparing a Human Acellular Dermal Matrix Versus Conventional Care for the Treatment of Venous Leg Ulcers.

INTRODUCTION Venous leg ulcers (VLUs) are often chronic and difficult to treat, which makes alternative options to conventional care necessary to improve ulcer healing rates. While human acellular dermal matrices (ADMs) have shown promise in treating diabetic foot ulcers, no comparative studies have been published regarding VLU treatment. Decellularized ADMs (D-ADMs) have been used successfully in the treatment of a wide variety of wound repairs and may be effective in treating VLUs. OBJECTIVE This study is a multicenter, randomized, controlled, open-label trial designed to evaluate the safety and efficacy of D-ADM compared with conventional wound care management in patients with chronic ulcers of the lower extremity. MATERIALS AND METHODS Patients were randomly assigned to receive either D-ADM or standard of care (control) in a 2:1 ratio. Treatment began at week 0 and wounds were evaluated on a weekly basis until wound closure was observed or the patient completed 24 weekly follow-up visits. RESULTS Eighteen patients were included in the D-ADM arm and 10 patients in the control arm. There was a strong trend of reduction in percent wound area for D-ADM patients with an average reduction of 59.6% at 24 weeks versus 8.1% at 24 weeks for control patients. In addition, healed ulcers in the D-ADM arm remained closed at a substantially higher rate after termination than healed ulcers in the control. CONCLUSIONS In this report, the authors note the successful increase in healing rates and rate of percent wound closure as compared with conventional care options.
Endoscopic endonasal surgery for Clival Chordomas – a single institution experience and short term outcomes

Abstract Purpose: Clival Chordomas are locally aggressive tumours which pose a significant treatment challenge. Endoscopic endonasal approach for clival chordomas is correlated with higher resection rates and lower morbidity rates in comparison to open approaches. We present our initial single institution experience and short-term patient outcomes following endoscopic endonasal approach for resection of clival chordomas. Materials and methods: This is a retrospective analysis of ten patients undergoing endoscopic endonasal approach for clival chordomas in our neurosurgical unit over a 6 year period between August 2010 and September 2016. The procedures were performed using two surgeons, four hands, binostril endoscopic endonasal approach with a Karl Storz® endoscope and intraoperative BrainLab® image guidance. Results: Overall 15 endoscopic endonasal approach resections of clival chordoma were performed in 10 patients with median follow up period of 39.5 months (range 9–76). Gross total resection was achieved in 4 cases (40%), near total resection in 4 cases (40%) and subtotal resection in 2 cases (20%). 5 cases (50%) required revision resections. Cerebrospinal fluid leak occurred in 2 patients. 1 case of meningitis occurred in a patient with revision surgery. There were no new neurological deficits post operatively with 3 patients demonstrating resolution of diplopia post operatively. No recurrence occurred following gross total resection. 1 out of 4 cases of near total resection showed evidence of progression during the follow up period. Both cases of subtotal resection demonstrated evidence of progression with one dying of unrelated cause during the follow up period. Conclusion: Endoscopic endonasal approach represents a safe technique for debulking and resection of clival chordomas. Due to the rarity of clival chordomas, it is important that patients with this pathology are managed in high volume skull base centres where a multi-disciplinary team approach is available.
Debate: CON Position. Should Hemoglobin Targets for Anemic Patients with Chronic Kidney Disease Be Changed?

want to see CKD patients suffering that way anymore in the name of over-interpretation of ‘evidence-based medicine’ or of ‘p values’ used in a wrong way. The association between anemia and negative outcome is consistent but overemphasized. Analysis of registry data found an inverse relationship between Hb levels and mortality. This was confirmed by data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a large prospective observational study involving patients randomly selected from representative dialysis facilities worldwide [2] . From these findings, the hypothesis was generated that complete anemia correction with ESAs could improve patient outcome. However, these studies included a small percentage of subjects with high Hb/hematocrit levels. Data that is more recent indicates that the relationship between anemia and mortality may be not linear, but U-shaped. Anyways, data coming from observational studies should only be considered as hypothesis-generating. This is also so because they only considered achieved Hb levels, while paying little attention, if any, to the ESA doses. Additionally, partial anemia correction improves or prevents left ventricular hypertrophy. Small, mainly uncontrolled studies showed partial regression of left ventricular hypertrophy after anemia correction. According to a very recent meta-analysis, anemia correction with The results of the TREAT study have been warmly awaited from the nephrological community as the last most important piece of the puzzle in defining optimal hemoglobin (Hb) target to aim for with erythropoiesisstimulating agents (ESAs). In support of this, the next global clinical practice guidelines on anemia in CKD patients, under the aegis of Kidney Disease Improving Global Outcomes (KDIGO), have been planned after the evidence coming from this study [1] . Do we believe that the findings of the TREAT study will substantially change the way we correct anemia in CKD patients? In our opinion, not substantially, and there are several reasons for this. The first reason is that we should never forget where we come from. Medicine is a fast evolving branch: what seems obvious today was completely different two decades ago. Younger doctors did not experience the era preceding the introduction of recombinant human erythropoietin and have no idea how CKD patients felt those days. Despite being younger and having much less comorbidities, the majority of uremic patients were only ‘survivors’, experiencing shortness of breath even after short walking. Anemia was only slightly and temporary improved by giving iron, frequent blood transfusions (with the risk of infections and iron overload) or even high-risk androgen hormones. The availability of ESAs has completely revolutionized the management of anemia. Doctors living those days do not Published online: May 21, 2010 Nephrology American Journal of
Interethnic Bias in Willingness to Engage in Casual Sex Versus Committed Relationships

Interethnic romantic relationships are widely seen as a strong indicator of a well-integrated society. However, racial bias may still be evident in the tendency to engage in casual sex versus committed relationships. Using a large, age-diverse sample of 3,453 White British participants, this study found a general preference for White partners over racial minority partners. Furthermore, in line with social structural theory, participants reported a relative preference for marriage (versus casual sex) with White partners, but a relative preference for casual sex (versus marriage) with racial minorities. This pattern was further modified by sex: Men reported a general preference for casual sex (versus marriage) with all racial groups except White partners. Women, however, reported a general preference for marriage (versus casual sex) with all groups, but this preference was strongest for White partners. The pattern was not further modified by sexual orientation. Implications for contemporary interethnic romantic relationships are discussed.
Multi‐dimensional models for functional testing of keloid scars: In silico, in vitro, organoid, organotypic, ex vivo organ culture, and in vivo models

Keloid scars are described as benign fibro‐proliferative dermal outgrowths that commonly occur in pigmented skin post cutaneous injury, and continue to grow beyond the boundary of the original wound margin. There is a lack of thorough understanding of keloid pathogenesis and thus keloid therapeutic options remain ill‐defined. In view of the poor response to current therapy and high recurrence rates, there is an unmet need in improving our knowledge and therefore in identifying targeted and effective treatment strategies in management of keloids. Keloid research however, is hampered by a lack of relevant animal models as keloids do not spontaneously occur in animals and are unique to human skin. Therefore, developing novel animal models and nonanimal models for functional evaluation of keloid cells and tissue for better understanding their pathobiology and response to putative candidate therapies are essential. Here, we present the key concepts and relevant emerging research on two‐dimensional and three‐dimensional cell and tissue models for functional testing of keloid scars. We will describe in detail current models including in vitro mono‐ and co‐cultures, multi‐cellular spheroids (organoids) and organotyopic cultures, ex vivo whole skin keloid tissue organ culture models as well as in vivo human patient models. Finally, we discuss the role played by time as the fourth dimension in a novel model that involves sequential temporal biopsies of human patients with keloids (a so called 4D in vivo human model). The use of these unique models will no doubt prove pivotal in identification of new drug targets as well as biomarkers, in functional testing of emerging novel therapeutics, and in enhancing our understanding of keloid disease biology.