Miracle-dz/UniFAR-FTUs huggingface dataset:
Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.
Effects of High Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) on Delay Discounting in Major Depressive Disorder: An Open-Label Uncontrolled Pilot Study

Background: Delay discounting (DD) refers to the decrease of a present subjective value of a future reward as the delay of its delivery increases. Major depressive disorder (MDD), besides core emotional and physical symptoms, involves difficulties in reward processing. Depressed patients often display greater temporal discounting rates than healthy subjects. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique applied in several countries to adult patients with treatment resistant depression. Studies suggest that this technique can be used to modulate DD, but no trial has assessed its effects on depressed patients. Methods: In this open-label uncontrolled trial, 20 patients diagnosed with MDD and at least stage II treatment resistance criteria underwent 20 HF-rTMS sessions over the dorsolateral prefrontal cortex (dlPFC; 10 Hz, 110% MT, 20 min). Pre-post treatment DD rates were compared. Effects on impulsivity, personality factors, and depressive symptoms were also evaluated. Results: No significant effect of HF-rTMS over the left dlPFC on DD of depressed individuals was observed, although rates seemed to increase after sessions. However, treatment resulted in significant improvement on cognitive impulsivity and depressive symptoms, and was well-tolerated. Conclusion: Despite the limitations involved, this pilot study allows preliminary evaluation of HF-rTMS effects on DD in MDD, providing substrate for further research.
Pain after laparoscopic surgery: Focus on shoulder-tip pain after gynecological laparoscopic surgery.

Laparoscopy, one of minimally invasive procedures, is a commonly used procedure in diagnosis and management of various kinds of clinical problems, including gynecologic organ-related diseases. Compared with conventional exploratory laparotomy, the benefits of laparoscopic surgery include reduction of surgical wound, decreasing in postoperative pain, shortening hospital stay, rapid recovery and a better cosmetic result. However, there are still up to 80% of patients after laparoscopic surgery complaining of high levels of pain and needing pain relief. Post-laparoscopic pain can be separated into distinct causes, such as surgical trauma- or incision wound-associated inflammatory change, and pneumoperitoneum (carbon dioxide)-related morphological and biochemical changes of peritoneum and diaphragm. The latter is secondary to irritation, stretching, and foreign body stimulation, leading to phrenic neuropraxia and subsequent shoulder-tip pain (STP). STP is the most typical unpleasant experience of patients after laparoscopic surgery. There are at least eleven strategies available to attempt to decrease post-laparoscopic STP, including (1) the use of an alternative insufflating gas in place of CO2, (2) the use of low-pressure pneumoperitoneum in place of standard-pressure pneumoperitoneum, (3) the use of warmed or warmed and humidified CO2, (4) gasless laparoscopy, (5) subdiaphragmatic intraperitoneal anesthesia, (6) local intraperitoneal anesthesia, (7) actively expelling out of gas, (8) intraperitoneal drainage, (9) fluid instillation, (10) pulmonary recruitment maneuvers, (11) others and combination. The present article is limited in discussing post-laparoscopic STP. We extensively review published articles to provide a better strategy to reduce post-laparoscopic STP.
Scale‐up of a Type I secretion system in E. coli using a defined mineral medium

Secretion of heterologous proteins into the culture supernatant in laboratory strains of Escherichia coli is possible by utilizing a Type I secretion system (T1SS). One prominent example for a T1SS is based on the hemolysin A toxin. With this system, heterologous protein secretion has already been achieved. However, no cultivations in a defined mineral medium and in stirred tank bioreactors have been described in literature up to now, hampering the broad applicability of the system. In this study, a mineral medium was developed for cultivation under defined conditions. With this medium, the full potential and advantage of a secretion system in E. coli (low secretion of host proteins, no contamination with proteins from complex media compounds) can now be exploited. Additionally, quantification of the protein amount in the supernatant was demonstrated by application of the Bradford assay. In this work, host cell behavior was described in small scale by online monitoring of the oxygen transfer rate. Scalability was demonstrated by stirred tank fermentation yielding 540 mg/L HlyA1 in the supernatant. This work enhances the applicability of a protein secretion system in E. coli and paves the way for an industrial application.
Joint Deployment and Task Scheduling Optimization for Large-Scale Mobile Users in Multi-UAV-Enabled Mobile Edge Computing

This article establishes a new multiunmanned aerial vehicle (multi-UAV)-enabled mobile edge computing (MEC) system, where a number of unmanned aerial vehicles (UAVs) are deployed as flying edge clouds for large-scale mobile users. In this system, we need to optimize the deployment of UAVs, by considering their number and locations. At the same time, to provide good services for all mobile users, it is necessary to optimize task scheduling. Specifically, for each mobile user, we need to determine whether its task is executed locally or on a UAV (i.e., offloading decision), and how many resources should be allocated (i.e., resource allocation). This article presents a two-layer optimization method for jointly optimizing the deployment of UAVs and task scheduling, with the aim of minimizing system energy consumption. By analyzing this system, we obtain the following property: the number of UAVs should be as small as possible under the condition that all tasks can be completed. Based on this property, in the upper layer, we propose a differential evolution algorithm with an elimination operator to optimize the deployment of UAVs, in which each individual represents a UAV’s location and the entire population represents an entire deployment of UAVs. During the evolution, we first determine the maximum number of UAVs. Subsequently, the elimination operator gradually reduces the number of UAVs until at least one task cannot be executed under delay constraints. This process achieves an adaptive adjustment of the number of UAVs. In the lower layer, based on the given deployment of UAVs, we transform the task scheduling into a 0-1 integer programming problem. Due to the large-scale characteristic of this 0-1 integer programming problem, we propose an efficient greedy algorithm to obtain the near-optimal solution with much less time. The effectiveness of the proposed two-layer optimization method and the established multi-UAV-enabled MEC system is demonstrated on ten instances with up to 1000 mobile users.
Identification of a Glass Substrate to Study Cells Using Fourier Transform Infrared Spectroscopy: Are We Closer to Spectral Pathology?

The rising incidence of cancer worldwide is causing an increase in the workload in pathology departments. This, coupled with advanced analysis methodologies, supports a developing need for techniques that could identify the presence of cancer cells in cytology and tissue samples in an objective, fast, and automated way. Fourier transform infrared (FT-IR) microspectroscopy can identify cancer cells in such samples objectively. Thus, it has the potential to become another tool to help pathologists in their daily work. However, one of the main drawbacks is the use of glass substrates by pathologists. Glass absorbs IR radiation, removing important mid-IR spectral data in the fingerprint region (1800 cm−1 to 900 cm−1). In this work, we hypothesized that, using glass coverslips of differing compositions, some regions within the fingerprint area could still be analyzed. We studied three different types of cells (peripheral blood mononuclear cells, a leukemia cell line, and a lung cancer cell line) and lymph node tissue placed on four different types of glass coverslips. The data presented here show that depending of the type of glass substrate used, information within the fingerprint region down to 1350 cm−1 can be obtained. Furthermore, using principal component analysis, separation between the different cell lines was possible using both the lipid region and the fingerprint region between 1800 cm−1 and 1350 cm−1. This work represents a further step towards the application of FT-IR microspectroscopy in histopathology departments.
Drug-responsive versus drug-refractory mesial temporal lobe epilepsy: a single-center prospective outcome study

ABSTRACT Objectives: To evaluate clinical, electrophysiological, and neuroradiological factors which correlate with the prognosis in patients with mesial temporal lobe epilepsy (MTLE). Methods: This was a single-center prospective outcome study in patients with MTLE. The patients’ family history, clinical characteristics, neurophysiological data (electroencephalography – EEG), neuroimaging, antiepileptic therapy, and outcome were collected and analyzed. The population was divided into four groups depending on the frequency of the seizures when they attended their last follow up. All variables and outcome measures were compared between the four groups. Results: In total 83 consecutive patients were included within the four groups. Group 1 (seizure-free) consisted of 7 patients, (9%), Group 2 (rare seizures) consisted of 15 patients (18%), Group 3 (often seizures) consisted of 30 patients (36%), and Group 4 (very often seizures) consisted of 31 patients (37%). The groups did not differ significantly in demographic characteristics. There was a strong positive correlation between resistance to therapy and sleep activation on EEG (p = 0.005), occurrence of focal to bilateral seizures (p = 0.007), automatisms (p = 0.004), and the number of previously used antiepileptic drugs (AEDs) (p = 0.002). There was no association between febrile convulsions (FC), hippocampal sclerosis (HS), and the outcome that was found. Conclusion: MTLE is a heterogeneous syndrome. Establishing the factors responsible for, and associated with, drug resistance is important for optimal management and treatment, as early identification of drug resistance should then ensure a timely referral for surgical treatment is made. This prospective study shows that sleep activation on EEG, ictal automatisms, occurrence of focal to bilateral tonic-clonic seizures, and increased number of tried AEDs are negative prognostic factors.
The molecular basis of LST-1 self-renewal activity and its control of stem cell pool size

ABSTRACT PUF RNA-binding proteins have diverse roles in animal development, with a broadly conserved role in stem cells. Two paradigmatic PUF proteins, FBF-1 and FBF-2, promote both self-renewal and differentiation in the C. elegans germline. The LST-1 protein is a pivotal regulator of self-renewal and is oncogenic when mis-expressed. Here, we demonstrate that LST-1 self-renewal activity resides within a predicted disordered region that harbors two KXXL motifs. We find that the KXXL motifs mediate the binding of LST-1 to FBF, and that point mutations of these motifs abrogate LST-1 self-renewal activity. The LST-1-FBF partnership is therefore crucial to stem cell maintenance and is a key element in the FBF regulatory network. A distinct region within LST-1 determines its spatial expression and size of the GSC pool. Most importantly, the molecular understanding of how an IDR-rich protein works in an essential partnership with a conserved stem cell regulator and RNA-binding protein suggests broad new avenues for combinatorial control. Summary: Two short motifs in a disordered C. elegans protein are central to its self-renewal activity and to its partnership with a conserved PUF RNA-binding protein.
Emergence of Polymyxin Resistance in Clinical Klebsiella pneumoniae Through Diverse Genetic Adaptations: A Genomic, Retrospective Cohort Study.

BACKGROUND Polymyxins are antimicrobials of last resort for the treatment of carbapenem-resistant Enterobacteriaceae, but resistance in 5% to >40% isolates has been reported. We conducted a genomic survey of clinical polymyxin-resistant (PR) Klebsiella pneumoniae to determine the molecular mechanisms of PR and the role of polymyxin exposure versus transmission in PR emergence. METHODS We included 88 patients with PR K. pneumoniae from 2011-2018 and collected demographic, antimicrobial exposure, and infection data. Whole-genome sequencing was performed on 388 isolates, including 164 PR isolates. Variant calling and insertion sequence detection were performed, focusing on key genes associated with PR (mgrB, crrAB, phoPQ, and pmrAB). We conducted phylogenetic analyses of key K. pneumoniae multi-locus sequence types (ST258, ST17, ST307, and ST392). RESULTS Polymyxin exposure was documented in 53/88 (60%) patients prior to PR detection. Through an analysis of key PR genes, we detected 129 individual variants and 72 unique variant combinations in PR isolates. This included multiple, distinct changes in 36% of patients with serial PR isolates. Insertion sequence disruption was limited to mgrB (P < .001). Polymyxin minimum inhibitory concentrations showed stepwise increases with the number of PR genes affected (P < .001). When clusters containing PR isolates in ≥2 patients were analyzed, 10/14 had multiple genetic events leading to PR. CONCLUSIONS Molecular mechanisms leading to PR in clinical K. pneumoniae isolates are remarkably heterogenous, even within clusters or individual patients. Polymyxin exposure with de novo PR emergence led to PR in the majority of patients, rather than transmission. Optimizing polymyxin use should be a key strategy in stopping the spread of PR.
Long-term dynamics of measles in London: Titrating the impact of wars, the 1918 pandemic, and vaccination

A key question in ecology is the relative impact of internal nonlinear dynamics and external perturbations on the long-term trajectories of natural systems. Measles has been analyzed extensively as a paradigm for consumer-resource dynamics due to the oscillatory nature of the host-pathogen life cycle, the abundance of rich data to test theory, and public health relevance. The dynamics of measles in London, in particular, has acted as a prototypical test bed for such analysis using incidence data from the pre-vaccination era (1944–1967). However, during this timeframe there were few external large-scale perturbations, limiting an assessment of the relative impact of internal and extra demographic perturbations to the host population. Here, we extended the previous London analyses to include nearly a century of data that also contains four major demographic changes: the First and Second World Wars, the 1918 influenza pandemic, and the start of a measles mass vaccination program. By combining mortality and incidence data using particle filtering methods, we show that a simple stochastic epidemic model, with minimal historical specifications, can capture the nearly 100 years of dynamics including changes caused by each of the major perturbations. We show that the majority of dynamic changes are explainable by the internal nonlinear dynamics of the system, tuned by demographic changes. In addition, the 1918 influenza pandemic and World War II acted as extra perturbations to this basic epidemic oscillator. Our analysis underlines that long-term ecological and epidemiological dynamics can follow very simple rules, even in a non-stationary population subject to significant perturbations and major secular changes.
Beyond the Ligand: Extracellular and Transcellular G Protein–Coupled Receptor Complexes in Physiology and Pharmacology

G protein–coupled receptors (GPCRs) remain one of the most successful targets of U.S. Food and Drug Administration–approved drugs. GPCR research has predominantly focused on the characterization of the intracellular interactome’s contribution to GPCR function and pharmacology. However, emerging evidence uncovers a new dimension in the biology of GPCRs involving their extracellular and transcellular interactions that critically impact GPCR function and pharmacology. The seminal examples include a variety of adhesion GPCRs, such as ADGRLs/latrophilins, ADGRBs/brain angiogenesis inhibitors, ADGRG1/GPR56, ADGRG6/GPR126, ADGRE5/CD97, and ADGRC3/CELSR3. However, recent advances have indicated that class C GPCRs that contain large extracellular domains, including group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8), γ-aminobutyric acid receptors, and orphans GPR158 and GPR179, can also participate in this form of transcellular regulation. In this review, we will focus on a variety of identified extracellular and transcellular GPCR-interacting partners, including teneurins, neurexins, integrins, fibronectin leucine-rich transmembranes, contactin-6, neuroligin, laminins, collagens, major prion protein, amyloid precursor protein, complement C1q-likes, stabilin-2, pikachurin, dystroglycan, complement decay-accelerating factor CD55, cluster of differentiation CD36 and CD90, extracellular leucine-rich repeat and fibronectin type III domain containing 1, and leucine-rich repeat, immunoglobulin-like domain and transmembrane domains. We provide an account on the diversity of extracellular and transcellular GPCR complexes and their contribution to key cellular and physiologic processes, including cell migration, axon guidance, cellular and synaptic adhesion, and synaptogenesis. Furthermore, we discuss models and mechanisms by which extracellular GPCR assemblies may regulate communication at cellular junctions. SIGNIFICANCE STATEMENT G protein–coupled receptors (GPCRs) continue to be the prominent focus of pharmacological intervention for a variety of human pathologies. Although the majority of GPCR research has focused on the intracellular interactome, recent advancements have identified an extracellular dimension of GPCR modulation that alters accepted pharmacological principles of GPCRs. Herein, we describe known endogenous allosteric modulators acting on GPCRs both in cis and in trans.
Online Health Information Seeking Among US Adults: Measuring Progress Toward a Healthy People 2020 Objective

Objective: During the past decade, the availability of health information online has increased dramatically. We assessed progress toward the Healthy People 2020 (HP2020) health communication and health information technology objective of increasing the proportion of health information seekers who easily access health information online. Methods: We used data from 4 administrations of the Health Information National Trends Survey (HINTS 2008-2017) (N = 18 103). We conducted multivariable logistic regression analysis to evaluate trends over time in experiences with accessing health information and to examine differences by sociodemographic variables (sex, age, race/ethnicity, education, income, metropolitan status) separately for those who used the internet (vs other information sources) during their most recent search for health information. Results: Among US adults who looked for health information and used the internet for their most recent search, the percentage who reported accessing health information without frustration was stable during the study period (from 37.2% in 2008 to 38.5% in 2017). Accessing information online without frustration was significantly and independently associated with age 35-49 (vs age 18-34) (odds ratio [OR] = 1.34; 95% confidence interval [CI], 1.03 -1.73), non-Hispanic black (vs non-Hispanic white) race/ethnicity (OR = 2.15; 95% CI, 1.55-2.97), and annual household income <$20 000 (vs >$75 000) (OR = 0.66; 95% CI, 0.47-0.93). The percentage of adults who used an information source other than the internet and reported accessing health information online without frustration ranged from 31.3% in 2008 to 42.7% in 2017. Survey year 2017 (vs 2008) (OR = 1.61; 95% CI, 1.09-2.35) and high school graduate education (vs college graduate) (OR = 0.69; 95% CI, 0.49-0.97) were significantly and independently associated with accessing health information without frustration from sources other than the internet. Conclusions: The percentage of online health information seekers reporting easily accessing health information did not meet the HP2020 objective. Continued efforts are needed to enable easy access to online health information among diverse populations.
The built environment and health: fostering interprofessional collaboration for better policy recommendations

ABSTRACT This paper describes the initiation and proceedings of a national consultation organized to appraise issues in the local built environment affecting public health, using an interprofessional and intersectoral approach. The consultation was hosted as a part of the onsite session of an international fellowship program in interprofessional education and practice, organized by the Manipal FAIMER Institute for Leadership in Interprofessional Education, India. One hundred and eight delegates from across academic disciplines including the health professions, management, public health, architecture, and engineering, participated in this event. Plenary lectures and case studies highlighted the theoretical basics of built environment. Participants were also introduced to fundamental parameters for evaluating health-related aspects of the built environment. Delegates were then grouped into 18 teams and assigned to visit predetermined locations which they appraised and provided recommendations for. These were then thematically coded and synthesized for communication to relevant local municipal authorities. The consultation scope was limited by involving only academics in the appraisal process, and next steps include the engagement of local citizens and policy-makers to ensure the implementation of recommendations. This event illustrates how engaging interprofessional stakeholders can facilitate knowledge-driven development for promoting health equity, through action on the social determinants of health.