bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term supplementation with 3200 to 4000 IU of vitamin D daily and adverse events: a systematic review and meta-analysis of randomized controlled trials
Authors: Zittermann Armin , Trummer Christian , Theiler-Schwetz Verena , Pilz Stefan 
Published: March 2023

Abstract
Purpose
The upper tolerable intake level for vitamin D in the general population has been set at 4000 international units (IU) daily, but considerable uncertainty remains. We summarized reported harmful effects of a daily vitamin D supplement of 3200–4000 IU in trials lasting ≥ 6 months.

Methods
We performed a systematic review and meta-analysis of randomized controlled trials in several databases and identified 22 trials reporting safety data. Parameters of calcium metabolism, falls, hospitalization, and mortality were assessed.

Results
The selected trials comprised a total number of 12,952 participants. All trials used supplemental vitamin D3. The relative risk (RR) of hypercalcemia in the vitamin D vs. control arm was 2.21 (95%CI: 1.26–3.87; 10 studies), with a vitamin D-induced frequency of hypercalcemia of 4 cases per 1000 individuals. Subgroup analysis in trials with > 100 and ≤ 100 study participants revealed an RR of 2.63 (95%CI: 1.30–5.30; 7 studies) and 0.80 (95%CI: 0.24–2.62; 3 studies), respectively (Pinteraction = 0.06). Risks of falls and hospitalization were also significantly increased in the vitamin D arm with an RR of 1.25 (95%CI: 1.01–1.55; 4 studies) and 1.16 (95%CI: 1.01–1.33; 7 studies), respectively. Risks of hypercalciuria, kidney stones, and mortality did not differ significantly between study arms. Quality assessment revealed high risk of incomplete reporting of safety-related outcome data.

Conclusion
Supplemental vitamin D doses of 3200–4000 IU/d appear to increase the risk of hypercalcemia and some other adverse events in a small proportion of individuals, indicating that this dose is not completely safe. In future studies, rigorous reporting of safety-related outcomes is needed when using moderately high doses of vitamin D.
Ploidy-stratified single cardiomyocyte transcriptomics map Zinc Finger E-Box Binding Homeobox 1 to underly cardiomyocyte proliferation before birth
Authors: Bak Sara Thornby , Harvald Eva Bang , Ellman Ditte Gry , Mathiesen Sabrina Bech , Chen Ting , Fang Shu , Andersen Kristian Skriver , Fenger Christina Dühring , Burton Mark , Thomassen Mads , Andersen Ditte Caroline 
Published: March 2023

AbstractWhereas cardiomyocytes (CMs) in the fetal heart divide, postnatal CMs fail to undergo karyokinesis and/or cytokinesis and therefore become polyploid or binucleated, a key process in terminal CM differentiation. This switch from a diploid proliferative CM to a terminally differentiated polyploid CM remains an enigma and seems an obstacle for heart regeneration. Here, we set out to identify the transcriptional landscape of CMs around birth using single cell RNA sequencing (scRNA-seq) to predict transcription factors (TFs) involved in CM proliferation and terminal differentiation. To this end, we established an approach combining fluorescence activated cell sorting (FACS) with scRNA-seq of fixed CMs from developing (E16.5, P1, and P5) mouse hearts, and generated high-resolution single-cell transcriptomic maps of in vivo diploid and tetraploid CMs, increasing the CM resolution. We identified TF-networks regulating the G2/M phases of developing CMs around birth. ZEB1 (Zinc Finger E-Box Binding Homeobox 1), a hereto unknown TF in CM cell cycling, was found to regulate the highest number of cell cycle genes in cycling CMs at E16.5 but was downregulated around birth. CM ZEB1-knockdown reduced proliferation of E16.5 CMs, while ZEB1 overexpression at P0 after birth resulted in CM endoreplication. These data thus provide a ploidy stratified transcriptomic map of developing CMs and bring new insight to CM proliferation and endoreplication identifying ZEB1 as a key player in these processes.
Lower limb cutaneous melanoma surgery: location matters
Authors: Piñero-Madrona Antonio , Cerezuela-Fuentes Pablo , Ruiz-Merino Guadalupe , Martínez-Barba Enrique , Ortiz-Reina Sebastián , Martínez-Ortiz María José , López-Ávila Angel , Frías-Iniesta José F. , Viney Alice , Cabezas-Herrera Juan 
Published: March 2023

AbstractThe anatomical location of cutaneous melanoma is a relevant independent prognostic factor in melanoma. The aim of the study is to know the prognosis of lower limb cutaneous melanoma related to their location within the limb, regardless of the histological type, and if there are any other influencing variables. A real-world data observational study was developed. The lesions were divided depending on the location of the melanoma (thigh, leg and foot). Bivariate and multivariate analysis were performed, and melanoma-specific survival and disease-free survival rates were calculated. When these analysis were done, the results showed that, in melanomas of the lower limb, location on the foot presented a lower melanoma-specific survival rate compared to more proximal locations, and only the anatomical location presents statistical significance to discriminate cases with a higher mortality risk and a lower disease-free survival rate among distal melanomas (mainly on the foot). In conclusion, this study confirms that a more distal location of lower limb cutaneous melanoma is a relevant prognostic factor.Trial registration number NCT04625491 retrospectively registered.
Altered parasympathetic activity during sleep and emotionally arousing wakefulness in frequent nightmare recallers
Authors: Tomacsek Vivien , Blaskovich Borbála , Király Anna , Reichardt Richárd , Simor Péter 
Published: March 2023

AbstractNightmare disorder is characterized by dysfunctional emotion regulation and poor subjective sleep quality reflected in pathophysiological features such as abnormal arousal processes and sympathetic influences. Dysfunctional parasympathetic regulation, especially before and during rapid eye movement (REM) phases, is assumed to alter heart rate (HR) and its variability (HRV) of frequent nightmare recallers (NM). We hypothesized that cardiac variability is attenuated in NMs as opposed to healthy controls (CTL) during sleep, pre-sleep wakefulness and under an emotion-evoking picture-rating task. Based on the polysomnographic recordings of 24 NM and 30 CTL participants, we examined HRV during pre-REM, REM, post-REM and slow wave sleep, separately. Additionally, electrocardiographic recordings of resting state before sleep onset and under an emotionally challenging picture-rating task were also analyzed. Applying repeated measures analysis of variance (rmANOVA), a significant difference was found in the HR of NMs and CTLs during nocturnal segments but not during resting wakefulness, suggesting autonomic dysregulation, specifically during sleep in NMs. As opposed to the HR, the HRV values were not significantly different in the rmANOVA in the two groups, implying that the extent of parasympathetic dysregulation on a trait level might depend on the severeness of dysphoric dreaming. Nonetheless, in the group comparisons, the NM group showed increased HR and reduced HRV during the emotion-evoking picture-rating task, which aimed to model the nightmare experience in the daytime, indicating disrupted emotion regulation in NMs under acute distress. In conclusion, trait-like autonomic changes during sleep and state-like autonomic responses to emotion-evoking pictures indicate parasympathetic dysregulation in NMs.
Understanding the burden of unidentified bodies: a systematic review
Authors: Reid Kate Megan , Martin Lorna J. , Heathfield Laura Jane 
Published: March 2023

AbstractWhile human identification is a crucial aspect of medico-legal investigations, many individuals remain unidentified each year across the world. The burden of unidentified bodies is often referred to when motivating for improved methods of identification, and anatomical teaching, yet the actual burden is somewhat unclear. A systematic literature review was undertaken to identify articles that empirically investigate the number of unidentified bodies experienced. Despite the large number of articles returned, an alarmingly low number (24 articles) provided specific and empirical details on the number of unidentified bodies, demographics and trends thereof. It is possible that this lack of data is due to the variable definition of ‘unidentified’ bodies and the use of alternative terminology such as ‘homelessness’ or ‘unclaimed’ bodies. Nevertheless, the 24 articles provided data for 15 forensic facilities across ten countries of both developed and developing statuses. On average, developing countries experienced more than double (9.56%) the number of unidentified bodies when compared to developed nations (4.40%). While facilities were mandated under different legislations and infrastructures available varied greatly, the most common issue faced is the lack of standardised procedures for forensic human identification. Further to this, the need for investigative databases was highlighted. Through addressing the standardisation of identification procedures and terminology, alongside the appropriate utilisation of existing infrastructure and database creation, the number of unidentified bodies could be significantly reduced globally.
The clinical and genetic spectrum of primary familial brain calcification
Authors: Carecchio Miryam , Mainardi Michele , Bonato Giulia 
Published: March 2023

AbstractPrimary familial brain calcification (PFBC), formerly known as Fahr’s disease, is a rare neurodegenerative disease characterized by bilateral progressive calcification of the microvessels of the basal ganglia and other cerebral and cerebellar structures. PFBC is thought to be due to an altered function of the Neurovascular Unit (NVU), where abnormal calcium-phosphorus metabolism, functional and microanatomical alterations of pericytes and mitochondrial alterations cause a dysfunction of the blood–brain barrier (BBB) and the generation of an osteogenic environment with surrounding astrocyte activation and progressive neurodegeneration. Seven causative genes have been discovered so far, of which four with dominant (SLC20A2, PDGFB, PDGFRB, XPR1) and three with recessive inheritance (MYORG, JAM2, CMPK2). Clinical presentation ranges from asymptomatic subjects to movement disorders, cognitive decline and psychiatric disturbances alone or in various combinations. Radiological patterns of calcium deposition are similar in all known genetic forms, but central pontine calcification and cerebellar atrophy are highly suggestive of MYORG mutations and extensive cortical calcification has been associated with JAM2 mutations. Currently, no disease-modifying drugs or calcium-chelating agents are available and only symptomatic treatments can be offered.
Application of optical coherence tomography and keratograph in the measurements of lower lid margin thickness
Authors: Wang Da-Hu , Tang Jian-Cen , Hao Xiao-Jun , Zhang Yin-Jian , Liu Xin-Quan 
Published: March 2023

Abstract
Purpose
This study aims to investigate the applicability of lower lid margin thickness (LLMT) measurements in adults with and without meibomian gland dysfunction (MGD) by optical coherence tomography (OCT) and keratograph.

Methods
This is a cross-sectional, observational study. A hundred and eight volunteers aged 20 to 79, including 68 MGD patients and 40 normal subjects, were recruited. Using OCT and keratograph to measure the LLMT from the posterior lash line to anterior edge or outer edge of the tear meniscus was separately performed two times by the same person.

Results
The mean age of normal and MGD subjects was 50.5 ± 14.2 years and 55.8 ± 15.5 years, respectively. The LLMT with OCT and keratograph in MGD patients was significantly greater than that in normal subjects (1.06 ± 0.27 and 1.03 ± 0.25 mm vs. 0.90 ± 0.20 and 0.86 ± 0.16 mm, respectively). In both normal and MGD subjects, the tear meniscus height and LLMT with OCT were both greater than that with keratograph (P < 0.05), and intraclass correlation coefficient (ICC) demonstrated a good agreement in the LLMT measurements between two devices (ICC = 0.83 and 0.79, respectively). Additionally, the LLMT in MGD patients was appeared to be positively correlated with meiboscore (rs = 0.37, P = 0.002).

Conclusions
The OCT and keratograph were two reliable tools in the LLMT measurements, which may have potential applications for diagnosis and evaluation of MGD. Furthermore, we found that the LLMT measured by OCT was greater than that measured by keratograph.
The relation between clinically diagnosed and parent-reported feeding difficulties in children with and without clefts
Authors: de Vries Iris A. C. , Guillaume Camille H. A. L. , Penris Wouter M. , Eligh Anne Merijn , Eijkemans Rene M. J. C. , Kon Moshe , Breugem Corstiaan C. , van Dijk Marijn W. G. 
Published: March 2023

Abstract
A cleft lip and/or palate (CL/P) is one of the most common craniofacial malformations, occurring worldwide in about one in 600–1000 newborn infants. CL/P is known to influence the feeding process negatively, causing feeding difficulties in 25–73% of all children with CL/P. Because there is a risk for serious complications in these children regarding feeding difficulties, there is often a need for intensive medical counseling and treatment. At this moment, adequate diagnosis and measurement remain a challenge and often lead to a delayed referral for professional help. Since parents play a big part in reporting feeding difficulties, it is important to help objectify parents’ experiences, as well as the use of a frontline screening instrument for routine check-ups during medical appointments. The aim of this study is to investigate the relationship between parent perspective and standardized observation by medical professionals on feeding difficulties in 60 children with and without clefts at the age of 17 months. We focus on the information from parents and health professionals by comparing the Observation List Spoon Feeding and the Schedule for Oral Motor Assessment with the validated Dutch translation of the Montreal Children’s Hospital Feeding Scale. Conclusion: There is a need for timely and adequate diagnosis and referral when it comes to feeding difficulties in children with CL/P. This study underscores the importance of combining both parental observations and measurements of oral motor skills by healthcare professionals to enable this.

What is Known:

• Early identification of feeding difficulties can prevent adversely affected growth and development.

• Clefts increase the probability of feeding difficulties; however, the diagnostic trajectory is unclear.

• The Observation List Spoon Feeding (OSF) and Schedule for Oral Motor Assessment (SOMA) are validated to measure oral motor skills. The Montreal Children’s Hospital Feeding Scale Dutch version (MCH-FSD) has been validated for the parental perception of infant feeding difficulties.

What is New:

• Parents of children with CL/P experience relatively few feeding problems in their child on average.

• Oral motor skills for spoon feeding are associated with oral motor skills for solid foods in children with CL/P.

• The extent of the cleft is associated with experiencing more feeding difficulties in children with CL/P.
Managing severe hypertension in children
Authors: Coulthard Malcolm G. 
Published: March 2023

AbstractSevere childhood hypertension is uncommon and frequently not recognised and is best defined as a systolic blood pressure (SBP) above the stage 2 threshold of the 95th centile + 12 mmHg. If no signs of end-organ damage are present, this is urgent hypertension which can be managed by the slow introduction of oral or sublingual medication, but if signs are present, the child has emergency hypertension (or hypertensive encephalopathy if they include irritability, visual impairment, fits, coma, or facial palsy), and treatment must be started promptly to prevent progression to permanent neurological damage or death. However, detailed evidence from case series shows that the SBP must be lowered in a controlled manner over about 2 days by infusing short-acting intravenous hypotensive agents, with saline boluses ready in case of overshoot, unless the child had documented normotension within the last day. This is because sustained hypertension may increase pressure thresholds of cerebrovascular autoregulation which take time to reverse. A recent PICU study that suggested otherwise was significantly flawed. The target is to reduce the admission SBP by its excess, to just above the 95th centile, in three equal steps lasting about ≥ 6 h, 12 h, and finally ≥ 24 h, before introducing oral therapy. Few of the current clinical guidelines are comprehensive, and some advise reducing the SBP by a fixed percentage, which may be dangerous and has no evidence base. This review suggests criteria for future guidelines and argues that these should be evaluated by establishing prospective national or international databases.
Early skeletal muscle mass decline is a prognostic factor in patients receiving gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer: a retrospective observational study
Authors: Suzuki Yukari , Saito Kei , Nakai Yousuke , Oyama Hiroki , Kanai Sachiko , Suzuki Tatsunori , Sato Tatsuya , Hakuta Ryunosuke , Ishigaki Kazunaga , Saito Tomotaka , Hamada Tsuyoshi , Takahara Naminatsu , Tateishi Ryosuke , Fujishiro Mitsuhiro 
Published: March 2023

Abstract
Purpose
Patients with pancreatic cancer often have cancer cachexia at diagnosis. Recent studies suggested that loss of skeletal muscle mass was related to cancer cachexia, which hindered continuance of chemotherapy and could be one of prognostic factors in pancreatic cancer, however the association remains unclear in patients receiving gemcitabine and nab-paclitaxel (GnP).

Methods
We retrospectively studied 138 patients with unresectable pancreatic cancer receiving first-line GnP at the University of Tokyo from January 2015 to September 2020. We calculated body composition in CT images before chemotherapy and at initial evaluation, and evaluated the association of both body composition before chemotherapy and its changes at initial evaluation.

Results
Compared by skeletal muscle mass index (SMI) change rate between pre-chemotherapy and initial evaluation, there were statistically significantly differences in the median OS: 16.3 months (95%CI 12.3–22.7) and 10.3 months (95%CI 8.3–18.1) between SMI change rate ≥ -3.5% and < -3.5% groups (P = 0.01). By multivariate analysis for OS, CA19-9 (HR 3.34, 95%CI 2.00–5.57, P < 0.01), PLR (HR 1.68, 95%CI 1.01–2.78, P = 0.04), mGPS (HR 2.32, 95%CI 1.47–3.65, P < 0.01) and relative dose intensity (HR 2.21, 95%CI 1.42–3.46, P < 0.01) were significantly poor prognostic factors. SMI change rate (HR 1.47, 95%CI 0.95–2.28, P = 0.08) showed a trend to poor prognosis. Sarcopenia before chemotherapy was not significantly associated with PFS or OS.

Conclusion
Early skeletal muscle mass decline was associated with poor OS. Further investigation is warranted whether the maintenance of skeletal muscle mass by nutritional support would improve prognosis.
A Hybrid Methodology of Rock Support Design for Poor Ground Conditions in Hard Rock Tunnelling
Authors: Terron-Almenara Jorge , Holter Karl Gunnar , Høien Are Håvard 
Published: March 2023

AbstractThe design of rock support in hard rock tunnelling is often assisted by the use of empirical engineering rock mass classification systems. This has involved support design in a wide variety of geological- and rock mechanical-conditions, including poor ground conditions like fault zones and weak rocks. For most of the encountered situations, the empirical support designs have performed well. However, the empirical classification systems pose several limitations to describe ground behavior and derive optimal rock support design in poor ground conditions as discussed in several publications during the last decades. In the present study, an analysis of 118 case records, mostly from monitored Norwegian tunnel sites, has been undertaken to investigate the performance of the current empirical design practice with the Q-system when exposed to poor ground conditions. The results have revealed significant improvement possibilities which relate to a wide variety of ground conditions. Among others, weak rocks, anisotropic rock, and rock mass conditions in the transition from self-bearing rock masses to rock masses requiring load-bearing support in the tunnel, and typically with rock mass quality Q < 1. As a result, a set of improvements and design recommendations have been developed and an integrated or hybrid design methodology specific for poor ground conditions proposed. The hybrid approach combines the main components and advantages of different design methodologies and provides guidance for design optimization where the empirical approach presents limitations.
Personalized surgical informed consent with stereoscopic visualization in neurosurgery—real benefit for the patient or unnecessary gimmick?
Authors: Hertzsprung Nicolas , Krantchev Kiril , Picht Thomas , Roethe Anna L. , Rubarth Kerstin , Fuellhase Josch , Vajkoczy Peter , Acker Güliz 
Published: March 2023

Abstract
Background
Informed consent of the patient prior to surgical procedures is obligatory. A good and informative communication improves patients’ understanding and confidence, thus may strengthen the patient-doctor relationship. The aim of our study was to investigate the usefulness of additional stereoscopic visualization of patient-specific imaging during informed consent conversation.

Methods
Patients scheduled for a brain tumor surgery were screened for this study prospectively. The primary exclusion criteria were cognitive or visual impairments. The participants were randomized into two groups. The first group underwent a conventional surgical informed consent performed by a neurosurgeon including a demonstration of the individual MRI on a 2D computer screen. The second group received an additional stereoscopic visualization of the same imaging to explain the pathology more in-depth. The patients were then asked to fill in a questionnaire after each part. This questionnaire was designed to assess the potential information gained from the patients with details on the anatomical location of the tumor as well as the surgical procedure and possible complications. Patients’ subjective impression about the informed consent was assessed using a 5-point Likert scale.

Results
A total of 27 patients were included in this study. After additional stereoscopic visualization, no significant increase in patient understanding was found for either objective criteria or subjective assessment. Participants’ anxiety was not increased by stereoscopic visualization. Overall, patients perceived stereoscopic imaging as helpful from a subjective perspective. Confidence in the department was high in both groups.

Conclusion
Stereoscopic visualization of MRI images within informed consent conversation did not improve the objective understanding of the patients in our series. Although no objective anatomical knowledge gain was noted in this series, patients felt that the addition of stereoscopic visualization improved their overall understanding. It therefore potentially increases patient confidence in treatment decisions.