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Zusammenfassung. Hintergrund: Menschen mit Demenz (MmD) zu versorgen, fordert Gesundheitssystem und pflegende Angehörige heraus und ist nur durch interprofessionelle medizinische und pflegerische Betreuung zu bewältigen. Fragestellung / Ziel: Die AHeaD-Studie untersuchte Einstellungen von Hausärzt_innen (HÄ) und Pflegefachpersonen (PFP) zur Übertragung bislang hausärztlich ausgeführter Tätigkeiten an PFP in der ambulanten Versorgung von MmD. Methoden: In vier Fokusgruppendiskussionen mit 10 HÄ und 13 PFP wurden Einstellungen zur Übertragung bestimmter Tätigkeiten inhaltsanalytisch untersucht sowie Chancen und Barrieren einer Einführung identifiziert. Ergebnisse: HÄ befürworteten die Übertragung bestimmter Tätigkeiten wie Blutentnahmen, Assessments, deren Monitoring oder Folgeverordnungen für Pflegehilfsmittel. „Klassische“ ärztliche Aufgaben (z. B. Diagnostik von Erkrankungen, Erstverordnung von Medikamenten) wurden weiter in hausärztlicher Hand gesehen. PFP forderten für die Beziehung zwischen PFP und HA mehr Wertschätzung und Anerkennung und bemängelten fehlendes Vertrauen sowie unzureichende Kommunikation. Beide Seiten verwiesen auf knappe Zeitbudgets, die sich kaum am reellen Bedarf der MmD orientierten. Schlussfolgerung: Die Umsetzung einer Aufgabenneuverteilung erfordert die Schaffung eines gesetzlichen und finanziellen Rahmens, zeitlicher Ressourcen, konkreter Aufgabenbeschreibungen sowie die stärkere Zusammenarbeit der involvierten Berufsgruppen. Innovative Konzepte könnten zum sinnvollen Einsatz der Ressourcen beider Berufsgruppen beitragen und die Versorgung von MmD stärken.

Antibody-mediated rejection (AMR) is a major barrier to long-term graft survival following solid organ transplantation (SOT). Major histocompatibility antigens mismatched between donor and recipient are well-recognized targets of humoral alloimmunity in SOT and thought to drive most cases of AMR. In contrast, the implication of minor histocompatibility antigens (mHAs) in AMR has not been fully investigated, and their clinical relevance remains controversial. Recent technological advances, allowing for genome-wide comparisons between donors and recipients, have uncovered novel, polymorphic mHA targets with potential influence on the graft outcome following SOT. Here, we review these latest studies relating to mHAs and discuss their clinical significance.

Purpose of review Many surgical treatment options are available for patients who present with benign prostatic obstruction (BPO). This article reviews the current treatment options available and distinguishes them based on five clinical considerations: antithrombotic therapy, sexual function preservation, ambulatory procedures, anesthesia-related risks and duration of catheterization. Recent findings A comprehensive review of the literature was performed on 10 BPO procedures. Laser enucleation of the prostate (LEP), bipolar plasma transurethral vaporization of the prostate and photoselective vaporization (PVP) of the prostate reduces the risk of bleeding, which is recommended for anticoagulated men. Ejaculatory function is more likely to be preserved following transurethral incision of the prostate, Rezūm, Aquablation, UroLift and iTind. Same-day discharge is possible for LEP, PVP and prostatic arterial embolization (PAE). For patients with high anesthesia-related risks, procedures compatible with local anesthesia (UroLift, Rezūm, iTind and PAE) should be favored. Catheterization duration is shorter with UroLift, PVP and LEP. Summary BPO treatment options are growing rapidly. The optimal procedure for a given patient is based on factors such as associated risks, recovery and expected outcomes. Besides prostate volume, the clinical considerations in the present article can help elucidate the best surgical BPO treatment option for each patient based on their values, preferences, and risk tolerance.

BACKGROUND AND PURPOSE The aim of this study was to identify the long-term radiological changes, autoantibody specificities, and clinical course in a patient with kelch-like protein 11 (KLHL11)-associated paraneoplastic neurological syndrome (PNS). METHODS Serial brain magnetic resonance images were retrospectively assessed. To test for KLHL11 autoantibodies, longitudinal cerebrospinal fluid (CSF) and serum samples were screened by Phage-display ImmunoPrecipitation and Sequencing (PhIP-Seq). Immunohistochemistry was also performed to assess for the presence of KLHL11 in the patient's seminoma tissue. RESULTS A 42-year-old man presented with progressive ataxia and sensorineural hearing loss. Metastatic seminoma was detected 11 months after the onset of the neurological symptoms. Although immunotherapy was partially effective, his cerebellar ataxia gradually worsened over the next 8 years. Brain magnetic resonance imaging revealed progressive brainstem and cerebellar atrophy with a "hot-cross-bun sign", and low-signal intensity on susceptibility-weighted imaging (SWI) in the substantia nigra, red nucleus and dentate nuclei. PhIP-Seq enriched for KLHL11-derived peptides in all samples. Immunohistochemical staining of mouse brain with the patient CSF showed co-localization with a KLHL11 commercial antibody in the medulla and dentate nucleus. Immunohistochemical analysis of seminoma tissue showed anti-KLHL11 antibody-positive particles in cytoplasm. CONCLUSIONS This study suggests that KLHL11-PNS should be included in the differential diagnosis for patients with brainstem and cerebellar atrophy and signal changes not only on T2-FLAIR but also on SWI, which might otherwise be interpreted as secondary to a neurodegenerative disease such as multiple system atrophy.

ZusammenfassungDie Behandlung orbitaler Verletzungen gehört zum Alltag der medizinischen Akutversorgung. Bei 10 – 25% aller Gesichtsverletzungen ist die Orbita beteiligt. Dieser Beitrag gibt einen Überblick über die möglichen Pathologien nach Orbitatrauma sowie das primärdiagnostische Vorgehen und die therapeutischen Optionen.

Introduction: Genetic obesity is rare and quite challenging for pediatricians in terms of early identification. Src-homology-2 (SH2) B adapter protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway and is found to play an important role in leptin and insulin signaling and therefore in the pathogenesis of obesity and diabetes. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene, are known to be associated with obesity, insulin resistance, hyperphagia, and developmental delay. The aim of our study is to report on a case series of young individuals with 16p11.2 microdeletions, including the SH2B1 gene, and provide detailed information on body mass index (BMI) development and obesity-associated comorbidities. In this way, we want to raise awareness of this syndromic form of obesity as a differential diagnosis of genetic obesity. Methods: We describe the phenotype of 7 children (3 male; age range: 2.8–18.0 years) with 16p11.2 microdeletions, encompassing the SH2B1 gene, and present their BMI trajectories from birth onward. Screening for obesity-associated comorbidities was performed at the time of genetic diagnosis. Results: All children presented with severe, early-onset obesity already at the age of 5 years combined with variable developmental delay. Five patients presented with elevated fasting insulin levels, 1 patient developed diabetes mellitus type 2, 4 patients had dyslipidemia, and 4 developed nonalcoholic fatty-liver disease. Discussion/Conclusion: Chromosomal microdeletions in 16p11.2, including the SH2B1 gene, in children are associated with severe, early-onset obesity and comorbidities associated with insulin resistance. Early genetic testing in suspicious patients and early screening for comorbidities are recommended.

Background Primary graft dysfunction (PGD) is the leading cause of early mortality after heart transplant . Pre-transplant predictors of PGD remain elusive and its etiology remains unclear. Methods Microvesicles were isolated from 88 pre-transplant serum samples and underwent proteomic evaluation using TMT mass spectrometry. Monte Carlo cross validation (MCCV) was used to predict the occurrence of severe PGD after transplant using recipient pre-transplant clinical characteristics and serum microvesicle proteomic data. Putative biological functions and pathways were assessed using gene set enrichment analysis (GSEA) within the MCCV prediction methodology. Results Using our MCCV prediction methodology, decreased levels of plasma kallikrein (KLKB1), a critical regulator of the kinin-kallikrein system, was the most predictive factor identified for PGD (AUROC 0.6444 [0.6293, 0.6655]; odds 0.1959 [0.0592, 0.3663]. Furthermore, a predictive panel combining KLKB1 with inotrope therapy achieved peak performance (AUROC 0.7181 [0.7020, 0.7372]) across and within (AUROCs of 0.66–0.78) each cohort. A classifier utilizing KLKB1 and inotrope therapy outperforms existing composite scores by more than 50 percent. The diagnostic utility of the classifier was validated on 65 consecutive transplant patients, resulting in an AUROC of 0.71 and a negative predictive value of 0.92–0.96. Differential expression analysis revealed a enrichment in inflammatory and immune pathways prior to PGD. Conclusions Pre-transplant level of KLKB1 is a robust predictor of post-transplant PGD. The combination with pre-transplant inotrope therapy enhances the prediction of PGD compared to pre-transplant KLKB1 levels alone and the resulting classifier equation validates within a prospective validation cohort. Inflammation and immune pathway enrichment characterize the pre-transplant proteomic signature predictive of PGD.

The thymus is a central lymphoid organ primarily responsible for the development of T cells. A small proportion of B cells, however, also reside in the thymus to assist negative selection of self-reactive T cells. Here we show that the thymus of human neonates contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells are part of a larger subset of B cells that share the expression of signature genes defining mouse B1 cells, yet lack the expression of complement receptors CD21 and CD35. Data from single-cell transcriptomic, clonal correspondence and in vitro differentiation assays support the notion of intrathymic CD138+ plasma cell differentiation, alongside other B cell subsets with distinctive molecular phenotypes. Lastly, neonatal thymic plasma cells also include clones reactive to commensal and pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates., The thymus is known as the organ of T lymphocyte development. Here authors show that terminal B cell differentiation also takes place in the thymus of human neonates, leading to antibody production against commensal and pathogenic bacteria.

Equilibrative nucleoside transporters (ENTs) are present at the blood-testis barrier (BTB), where they can facilitate antiviral drug disposition to eliminate a sanctuary site for viruses detectable in semen. The purpose of this study was to investigate ENT-drug interactions with three nucleoside analogs, remdesivir, molnupiravir, and molnupiravir’s active metabolite, β-d-N(4)-hydroxycytidine (EIDD-1931), and four non-nucleoside molecules repurposed as antivirals for coronavirus disease 2019 (COVID-19). The study used three-dimensional pharmacophores for ENT1 and ENT2 substrates and inhibitors and Bayesian machine learning models to identify potential interactions with these transporters. In vitro transport experiments demonstrated that remdesivir was the most potent inhibitor of ENT-mediated [(3)H]uridine uptake (ENT1 IC(50): 39 μM; ENT2 IC(50): 77 μM), followed by EIDD-1931 (ENT1 IC(50): 259 μM; ENT2 IC(50): 467 μM), whereas molnupiravir was a modest inhibitor (ENT1 IC(50): 701 μM; ENT2 IC(50): 851 μM). Other proposed antivirals failed to inhibit ENT-mediated [(3)H]uridine uptake below 1 mM. Remdesivir accumulation decreased in the presence of 6-S-[(4-nitrophenyl)methyl]-6-thioinosine (NBMPR) by 30% in ENT1 cells (P = 0.0248) and 27% in ENT2 cells (P = 0.0054). EIDD-1931 accumulation decreased in the presence of NBMPR by 77% in ENT1 cells (P = 0.0463) and by 64% in ENT2 cells (P = 0.0132), which supported computational predictions that both are ENT substrates that may be important for efficacy against COVID-19. NBMPR failed to decrease molnupiravir uptake, suggesting that ENT interaction is likely inhibitory. Our combined computational and in vitro data can be used to identify additional ENT-drug interactions to improve our understanding of drugs that can circumvent the BTB. SIGNIFICANCE STATEMENT: This study identified remdesivir and EIDD-1931 as substrates of equilibrative nucleoside transporters 1 and 2. This provides a potential mechanism for uptake of these drugs into cells and may be important for antiviral potential in the testes and other tissues expressing these transporters.

Background: Prostate size estimation is a valuable clinical measure widely utilized in urology. This study evaluated the accuracy of preoperative transabdominal ultrasound (TAUS) compared to radica...

Outcomes following administration of very-low-dose recombinant activated factor VIIa (vld-rFVIIa) for cardiac surgical bleeding remain debatable. We sought to determine the association of vld-rFVIIa and adverse surgical outcomes. Retrospective, cohort matching of patients undergoing cardiac surgery who received vld-rFVIIa (median 13.02 μg/kg) for perioperative bleeding were matched to cardiac surgical patients who had bleeding and received standard of care for bleeding without Factor VIIa administration. Of the 362 matched patients (182 in each group), patients who received rFVIIa required significantly less red blood cell transfusions [median 3 units (range 0--60, IQR = 4 units) versus 4 units (range 2-34, IQR = 4 units); P = 0.0004], decreased length of hospital stay (median 8 versus 9 days; P = 0.0158) and decreased renal risk (P

Introduction: The growing number of surgical options available to treat benign prostatic hyperplasia (BPH), may overwhelm patients and urologists when deciding on an optimal treatment. Therefore, we developed an online patient decision aid (PtDA) that includes all guideline-approved surgical modalities. The objective of this study was to assess the acceptability of the PtDA among former BPH surgery patients and urologists that treat BPH surgically. Methods: The International Patient Decision Aids Standards were used to develop a PtDA that includes monopolar transurethral resection of the prostate (TURP), bipolar TURP, GreenLight photovaporization, endoscopic enucleation of the prostate, Rezum, Urolift, Aquablation, open retropubic prostatectomy, and robotic simple prostatectomy as management options. Eleven urologists that regularly treat BPH and 19 patients who received BPH surgery were recruited. Alpha-testing was performed using a validated acceptability scoring system. Results: For all sections of the PtDA, most urologists agreed that the language used was easy to follow (91.9%), that the amount of information provided was adequate (63.6%), that the length of the PtDA was appropriate (63.6%), and that the outcomes reported were correct (81.8%). All 19 patient participants agreed that the language used was easy to follow, and most found that the amount of information provided was adequate (84.2%), that the length of the PtDA was appropriate (84.2%), and that the outcomes reported were well-explained (89.5%). Conclusions: Our PtDA was found to be acceptable among urologists and patients. These results demonstrate that most of the participants either recommend the use of this tool or plan to incorporate it in their clinical practice.

Background: Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit-safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods: A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings: Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit-safety balances remain better than those of the noncannabinoid drugs. Interpretation: The benefit-safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P, Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

In the wake of the COVID-19 pandemic, drug repurposing has been highlighted for rapid introduction of therapeutics. Proposed drugs with activity against SARS-CoV-2 include compounds with positive charges at physiologic pH, making them potential targets for the organic cation secretory transporters of kidney and liver, i.e., the basolateral organic cation transporters, OCT1 and OCT2; and the apical multidrug and toxin extruders, MATE1 and MATE2-K. We selected several compounds proposed to have in vitro activity against SARS-CoV-2 (chloroquine, hydroxychloroquine, quinacrine, tilorone, pyronaridine, cetylpyridinium, and miramistin) to test their interaction with OCT and MATE transporters. We used Bayesian machine learning models to generate predictions for each molecule with each transporter and also experimentally determined IC(50) values for each compound against labeled substrate transport into CHO cells that stably expressed OCT2, MATE1, or MATE2-K using three structurally distinct substrates (atenolol, metformin and 1-methyl-4-phenylpyridinium) to assess the impact of substrate structure on inhibitory efficacy. For the OCTs substrate identity influenced IC(50) values, although the effect was larger and more systematic for OCT2. In contrast, inhibition of MATE1-mediated transport was largely insensitive to substrate identity. Unlike MATE1, inhibition of MATE2-K was influenced, albeit modestly, by substrate identity. Maximum unbound plasma concentration/IC(50) ratios were used to identify potential clinical DDI recommendations; all the compounds interacted with the OCT/MATE secretory pathway, most with sufficient avidity to represent potential DDI issues for secretion of cationic drugs. This should be considered when proposing cationic agents as repurposed antivirals. SIGNIFICANCE STATEMENT: Drugs proposed as potential COVID-19 therapeutics based on in vitro activity data against SARS-CoV-2 include compounds with positive charges at physiological pH, making them potential interactors with the OCT/MATE renal secretory pathway. We tested seven such molecules as inhibitors of OCT1/2 and MATE1/2-K. All the compounds blocked transport activity regardless of substrate used to monitor activity. Suggesting that plasma concentrations achieved by normal clinical application of the test agents could be expected to influence the pharmacokinetics of selected cationic drugs.

Equilibrativenucleoside transporters (ENTs) participate in the pharmacokinetics and disposition of nucleoside analog drugs. Understanding drug interactions with the ENTs may inform and facilitate the development of new drugs, including chemotherapeutics and antivirals that require access to sanctuary sites such as the male genital tract. This study created three-dimensional pharmacophores for ENT1 and ENT2 substrates and inhibitors using K(t) and IC(50) data curated from the literature. Substrate pharmacophores for ENT1 and ENT2 are distinct, with partial overlap of hydrogen bond donors, whereas the inhibitor pharmacophores predominantly feature hydrogen bond acceptors. Mizoribine and ribavirin mapped to the ENT1 substrate pharmacophore and proved to be substrates of the ENTs. The presence of the ENT-specific inhibitor 6-S-[(4-nitrophenyl)methyl]-6-thioinosine (NBMPR) decreased mizoribine accumulation in ENT1 and ENT2 cells (ENT1, ∼70% decrease, P = 0.0046; ENT2, ∼50% decrease, P = 0.0012). NBMPR also decreased ribavirin accumulation in ENT1 and ENT2 cells (ENT1: ∼50% decrease, P = 0.0498; ENT2: ∼30% decrease, P = 0.0125). Darunavir mapped to the ENT1 inhibitor pharmacophore and NBMPR did not significantly influence darunavir accumulation in either ENT1 or ENT2 cells (ENT1: P = 0.28; ENT2: P = 0.53), indicating that darunavir’s interaction with the ENTs is limited to inhibition. These computational and in vitro models can inform compound selection in the drug discovery and development process, thereby reducing time and expense of identification and optimization of ENT-interacting compounds. SIGNIFICANCE STATEMENT: This study developed computational models of human equilibrative nucleoside transporters (ENTs) to predict drug interactions and validated these models with two compounds in vitro. Identification and prediction of ENT1 and ENT2 substrates allows for the determination of drugs that can penetrate tissues expressing these transporters.

Introduction To evaluate the long-term effect on intraocular pressure (IOP) and glaucoma medication of selective laser trabeculoplasty (SLT) compared to minimally invasive glaucoma surgery (MIGS) in primary open-angle glaucoma (POAG) and its potential in clinical practice. Methods A total of 342 consecutive patients (stand-alone procedures) were included. One hundred and five patients underwent SLT treatment (360° SLT, 95–105 spots, Trabeculas SLT ARCLaser, Nürnberg, DE), 107 patients had an ab interno-derived trabeculotomy (Trabectome®, NeoMedix, Tustin, USA), and 130 patients received iStent inject® implantation (2 implants-Glaukos, CA, USA). IOP and glaucoma therapy were evaluated preoperatively, 1 day, 6 weeks, 3 months, 6 months, and 1, 2, and 3 years postoperatively. Statistical analysis was performed using a regression model and propensity matching score (reduced cohort number) using SPSS v20.0. Kaplan–Meier analysis was included using the following six criteria: criterion A (IOP ≤ 21 mmHg with or without medication, qualified success), criterion B (IOP ≤ 18 mmHg with or without medication, qualified success), criterion C (IOP ≤ 21 mmHg without medication, complete success), criterion D (IOP ≤ 18 mmHg without medication, complete success), criterion E (IOP ≤ 21 mmHg and IOP reduction > 20% after therapy), and criterion F (IOP ≤ 18 mmHg and IOP reduction > 20% after therapy). Results In the matched cohort, the SLT cohort showed an IOP reduction of 31.2% from 19.9 ± 2.3 to 13.7 ± 2.7 mmHg (p

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1β and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1+ pathological fibroblasts3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand–receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development. Lung samples collected soon after death from COVID-19 are used to provide a single-cell atlas of SARS-CoV-2 infection and the ensuing molecular changes.

BackgroundLow-middle-income countries experience among the highest rates of traumatic brain injury in the world. Much of this burden may be preventable with faster intervention, including reducing the time to definitive care. This study examines the relationship between traumatic brain injury severity and time to definitive care in major trauma hospitals in three low-middle-income countries.MethodsA prospective traumatic brain injury registry was implemented in six trauma hospitals in Armenia, Georgia and the Republic of Moldova for 6 months in 2019. Brain injury severity was measured using the Glasgow Coma Scale (GCS) at admission. Time to definitive care was the time from injury until arrival at the hospital. Cox proportionate hazards models predicted time to care by severity, controlling for age, sex, mechanism, mode of transportation, location of injury and country.ResultsAmong 1135 patients, 749 (66.0%) were paediatric and 386 (34.0%) were adults. Falls and road traffic were the most common mechanisms. A higher proportion of adult (23.6%) than paediatric (5.4%) patients had GCS scores indicating moderate (GCS 9–11) or severe injury (GCS 0–8) (pConclusionsImplementation of standard triage and transport protocols may reduce mortality and improve outcomes from traumatic brain injury, and trauma systems should focus on the most severe injuries.

We review the disease, biology and biochemistry of kinetoplastids, as well as the new drugs and drug candidates that have entered the clinic in the last decade. We also describe examples of the pre-clinical exploration of small molecules against various protein targets, (e.g., cysteine proteases, the proteasome and tubulin), as well as cutting-edge molecular and computational strategies, and technologies being brought to bear to discover and develop new anti-trypanosomal drugs. For comprehensive descriptions of the disease, biology and drug therapies prior to 2011, the reader is encouraged to review the chapter by P. M. Woster that appeared in 2010 in the seventh edition of Burger’s Medicinal Chemistry, Drug Discovery, and Development, with the title Antiprotozoal/Antiparasitic Agents.

Greenlight photo-selective vaporization of the prostate (GL-PVP) has gained international acceptance as a safe and effective alternative procedure for the treatment of benign prostatic hyperplasia (BPH), especially in anticoagulated men. This descriptive analysis aims to characterize the current state of GL-PVP, pooling data from international centers. Data from 3627 patients who underwent GL-PVP with the XPS-180 W system in seven international centers performed by eight expert surgeons between 2011 and 2019 were retrospectively analyzed. Demographic, perioperative, and postoperative data were collected, including IPSS, QoL, Qmax, PVR, and PSA, and complications. At baseline, median age, prostate volume, PSA, and IPSS were 70 years (interquartile range 64–77), 64 (47–90), 3.1 ng/mL (1.8–6), and 22 (19–27), respectively. Median lasing and operative time were 34 (23–48) and 62 min (46–85), respectively. Median energy use was 250.0 kJ (168.4–367.9), with 92.6% of procedures being completed with one laser fiber. In 60.1% of cases, catheter was removed on postoperative day 1 with median length of 2 days. All-cause mortality within 30 days was 0.3%. Median PSA reduction at 3 months and 60 months compared to baseline was 43.9 and 46.4%, respectively (p

Supplemental Digital Content is available in the text., Background: Cardiac involvement among hospitalized patients with severe coronavirus disease 2019 (COVID-19) is common and associated with adverse outcomes. This study aimed to determine the prevalence and clinical implications of COVID-19 cardiac involvement in young competitive athletes. Methods: In this prospective, multicenter, observational cohort study with data from 42 colleges and universities, we assessed the prevalence, clinical characteristics, and outcomes of COVID-19 cardiac involvement among collegiate athletes in the United States. Data were collected from September 1, 2020, to December 31, 2020. The primary outcome was the prevalence of definite, probable, or possible COVID-19 cardiac involvement based on imaging definitions adapted from the Updated Lake Louise Imaging Criteria. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for cardiac involvement, and adverse cardiovascular events or hospitalizations. Results: Among 19 378 athletes tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 3018 (mean age, 20 years [SD, 1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least 1 element of cardiac triad testing (12-lead ECG, troponin, transthoracic echocardiography) followed by cardiac magnetic resonance imaging (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21 of 2999 [0.7%]), cardiac troponin (24 of 2719 [0.9%]), and transthoracic echocardiography (24 of 2556 [0.9%]). Definite, probable, or possible SARS-CoV-2 cardiac involvement was identified in 21 of 3018 (0.7%) athletes, including 15 of 2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6 of 198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-CoV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15 of 119 [12.6%]) versus a primary screening CMR (6 of 198 [3.0%]). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (odds ratio, 3.1 [95% CI, 1.2, 7.7]) or at least 1 abnormal triad test result (odds ratio, 37.4 [95% CI, 13.3, 105.3]). Five (0.2%) athletes required hospitalization for noncardiac complications of COVID-19. During clinical surveillance (median follow-up, 113 days [interquartile range=90 146]), there was 1 (0.03%) adverse cardiac event, likely unrelated to SARS-CoV-2 infection. Conclusions: SARS-CoV-2 infection among young competitive athletes is associated with a low prevalence of cardiac involvement and a low risk of clinical events in short-term follow-up.

Background Surgical options are limited when treating large (>80 cm3) prostates for lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). Open simple prostatectomy remains the most common procedure performed for large prostates. There is a need for novel surgical approaches with shorter learning curves and effective treatment. Aquablation could be this novel tool. Objective To compare the outcome of Aquablation for 30–80-cm3 prostates with the outcome for 80–150-cm3 prostates at 2-yr follow-up. Design, setting, and participants We used data from two trials. WATER is a prospective, double-blind, multicenter, international clinical trial comparing the safety and efficacy of Aquablation and transurethral resection of the prostate in the treatment of LUTS/BPH in men aged 45–80 yr with a prostate of 30–80 cm3. WATER II is a prospective, multicenter, single-arm international clinical trial of Aquablation in men with a prostate of 80–150 cm3. Intervention Aquablation, an ultrasound-guided, robotically executed waterjet ablative procedure. Outcome measurements and statistical analysis We compared 24-mo outcomes between 116 WATER and 101 WATER II study subjects. Student’s t test or a Wilcoxon test was used to compare continuous variables and Fisher’s test for categorical variables. Results and limitations The International Prostate Symptom Score (IPSS) reductions at 24 mo was 14.5 points for WATER and 17.4 points for WATER II (p = 0.31). At baseline, the maximum urinary flow rate (Qmax) was 9.4 and 8.7 cm3/s in WATER and WATER II, improving to 20.5 and 18.2 cm3/s, respectively (p = 0.60) at 24 mo. Improvements in both IPSS and Qmax were immediate and sustained throughout follow-up. At 2 yr, the surgical retreatment rate was 4% in WATER and 2% in WATER II. Conclusions Aquablation is effective in patients with a prostate of 30–80 cm3 and patients with a prostate of 80–150 cm3 treated for LUTS/BPH, with comparable outcomes in both groups. It has low complication and retreatment rates at 2 yr of follow-up, with durable improvements in functional outcome. Patient summary Outcomes of Aquablation for both small-to-moderately-sized and large prostates are similar and sustainable at 2 yr of follow-up.

The Popeye domain-containing protein 1 (POPDC1), a tight junction-associated transmembrane protein with a unique binding site for cAMP, has been shown to act as a tumour suppressor in cancer cells. Through interaction with many downstream effectors and signalling pathways, POPDC1 promotes cell adhesion and inhibits uncontrolled cell proliferation, epithelial-to-mesenchymal transition and metastasis. However, POPDC1 expression is down-regulated in many types of cancer, thereby reducing its tumour-suppressive actions. This review discusses the role of POPDC1 in the progression of the malignant phenotype and highlights the broad range of benefits POPDC1 stabilisation may achieve therapeutically. Cancer stem cells (CSCs) are a key hallmark of malignancies and commonly promote treatment resistance. This article provides a comprehensive overview of CSC signalling mechanisms, many of which have been shown to be regulated by POPDC1 in other cell types, thus suggesting an additional therapeutic benefit for POPDC1-stabilising anti-cancer drugs. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.

Purpose Several roles are attributed to the myometrium including sperm and embryo transport, menstrual discharge, control of uterine blood flow, and labor. Although being a target of diabetes complications, the influence of high glucose on this compartment has been poorly investigated. Both miRNAs and IGF1R are associated with diabetic complications in different tissues. Herein, we examined the effects of high glucose on the expression of miRNAs and IGF1R signaling pathway in the human myometrium. Methods Human myometrial explants were cultivated for 48 h under either high or low glucose conditions. Thereafter, the conditioned medium was collected for biochemical analyses and the myometrial samples were processed for histological examination as well as miRNA and mRNA expression profiling by qPCR. Results Myometrial structure and morphology were well preserved after 48 h of cultivation in both high and low glucose conditions. Levels of lactate, creatinine, LDH and estrogen in the supernatant were similar between groups. An explorative screening by qPCR arrays revealed that 6 out of 754 investigated miRNAs were differentially expressed in the high glucose group. Data validation by single qPCR assays confirmed diminished expression of miR-215-5p and miR-296-5p, and also revealed reduced miR-497-3p levels. Accordingly, mRNA levels of IGF1R and its downstream mediators FOXO3 and PDCD4, which are potentially targeted by miR-497-3p, were elevated under high glucose conditions. In contrast, mRNA expression of IGF1, PTEN, and GLUT1 was unchanged. Conclusions The human myometrium responds to short-term exposure (48 h) to high glucose concentrations by regulating the expression of miRNAs, IGF1R and its downstream targets.