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Emotion dysregulation frequently co-occurs with chronic pain, which in turn leads to heightened emotional and physical suffering. This cycle of association has prompted a recommendation for psychological treatment of chronic pain to target mechanisms for emotion regulation. The current trial addressed this need by investigating a new internet-delivered treatment incorporating emotional skills training from dialectical behavioural therapy (DBT). Using a single-case experimental design that is suited to heterogeneous populations and can demonstrate efficacy with a small sample, three participants with chronic pain were recruited. Participants received four weeks of online DBT skills training (iDBT-Pain intervention) which incorporated one-on-one sessions over Zoom and a web app. Results revealed compelling evidence for the intervention on the primary outcome of emotion dysregulation and were promising for the secondary outcome of pain intensity. Improvement was also identified on pre-and post-measures of depression, coping behaviours, sleep problems, wellbeing, and harm avoidance, indicating that the intervention may positively influence other factors related to chronic pain. Overall, the trial provides preliminary efficacy for the intervention to improve chronic pain. However, we recommend further investigation of the iDBT-Pain intervention, either in single case trials, which when conducted with scientific rigour may be aggregated to derive nomothetic conclusions, or in a group-comparison trial to compare with usual modes of treatment. Perspective: This trial advances understanding of emotion-focused treatment for chronic pain and provides evidence for a viable new technological treatment. Importantly, as an internet-delivered approach, the iDBT-Pain intervention is accessible to those with restricted mobility and remote communities where there are often limited psychological services for people with chronic pain. Trial registration: The trial was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12620000604909)

Pacemaker endocarditis is rare and symptoms may be misleading. If missed, it carries significant morbidity and mortality, particularly in the elderly. Advances in multi-modality imaging in recent years have emphasised its role in clinical decision making. This case highlights the ability of multi-modality imaging techniques to individualise diagnosis, management and prognosis in patients with suspected cardiovascular implantable electronic device (CIED) endocarditis.

Objective: A chronic wound fails to progress through the phases of wound healing in an orderly and appropriate process, and poses a major challenge to wound care professionals. Pressure ulcers (PUs) and diabetic foot ulcers (DFUs) are classified as chronic wounds. Antiseptics, such as povidone-iodine (PVP-I), are often used to treat bacterial infections in chronic wounds; however, their efficacy and ability to accelerate wound healing has come into question. As a result, current medical research is now focusing on alternative and natural antiseptic agents, such as honey, for the treatment of chronic wounds. The aim of this study was to analyze the wound healing effects of honey in PU and DFU treatment in comparison to standard antiseptic care. Methods: A systematic literature search of PubMed, ScienceDirect, and ClinicalKey was conducted to identify all published data of clinical trials and narrative reviews that investigated or reported the use of honey and standard antiseptics in the treatment of PUs and DFUs in adults. A keyword search was then performed using the following keywords: “PUs”, “DFUs”, “antiseptics”, “PVP-I”, “honey”, “Manuka honey (MH)”, and “wound healing”. Database restrictions were implemented based on the inclusion and exclusion criteria, notably the report’s availability, completion status and language, the sample populations’ age, as well as, the date of publication. A preferred reporting item for systematic review and meta-analysis (preferred reporting items for systematic reviews and meta-analyzes) diagram was constructed illustrating the study selection process. The eligibility of articles was assessed by the screening of titles, abstracts and full texts. A total of 12 articles were included in this study comprising of 775 patients with PUs, DFUs or a combination of PUs and DFUs. Results: Results indicated that honey reduced bacterial infection, reduced pain and edema experienced by patients, reduced the odor of the wound and promoted wound healing in the treatment of chronic ulcers. Honey was also found to be effective in the process of debridement and exudate removal. Conclusion: Honey was found to be highly effective in the treatment of PUs and DFUs and should be considered as an alternative to standard antiseptic care in the treatment of chronic wounds. However, the literature in this study is limited and so further research into honey and its antiseptic-promoting activity in wound healing is recommended.

Anastomotic leak after colorectal surgery can result in serious morbidity for certain patients. The rate of clinically significant anastomotic leak after colon resection ranges from 1.8% to 11.9%. Risk factors include male sex, steroids, smoking, perioperative blood transfusion, malnutrition, and a low anastomosis. However, the effect of pre-operative chemoradiation therapy (CRT) on rates of anastomotic leak is controversial. Specifically, late leaks, which are defined as those that occur greater than 30 days after surgery, are sparsely described in current literature. Recent evidence suggests that CRT may contribute to the presentation of late anastomotic leaks. In this case series, we report our experience with three patients who received CRT and developed varying presentations of a late anastomotic leak. Therefore, our experience supports the consideration of late anastomotic leaks as a separate entity in colorectal surgery. While pre-operative CRT may increase risk for postoperative anastomotic leak overall, further exploration into the relationship between preoperative CRT and late anastomotic leaks is warranted.

OBJECTIVE To evaluate the effect and safety of topical anti-human vascular endothelial growth factor bevacizumab in dogs with persistent corneal vascularization. ANIMALS STUDIED Prospective case series of 15 adult dogs (20 eyes). PROCEDURES Dogs received 0.25% bevacizumab eye drops BID for 28 days. Follow-ups were scheduled 28 days and 6-7 months after treatment start. Macroscopic findings were scored for conjunctival hyperemia, chemosis, ocular discharge, corneal edema, vascularization, and pigmentation. Vascularized area was assessed by analyzing photographs using an imaging software. RESULTS The treatment response was variable. Some cases showed a marked reduction in vascularized area and edema, while other eyes had subtle signs of improvement. Vascularization score decreased from 1.5 to 1.1 and vascularized area was reduced by 48.8% after 28 days. A thinning of vessels, consolidation of areal bleedings into fine vascular networks, decrease in distal vessel branching, and a change from blurry vascularized beds into demarcated thin vessels were observed. One dog developed a SCCED 6 months after the last bevacizumab administration. Two dogs died 4 and 4.5 months after the last bevacizumab administration, aged 16 and 12 years, respectively. In all events, a causal relationship is unlikely but cannot be ruled out with certainty. CONCLUSIONS Our findings suggest that topical 0.25% bevacizumab may be an effective treatment option for corneal vascularization in dogs. Further long-term placebo-controlled studies with larger patient cohorts are recommended to provide scientific evidence of efficacy and to investigate dosage, safety, possible use as a single treatment, and routes of administration.

Background Little is known about complications after major duodenopancreatic surgery for duodenopancreatic neuroendocrine tumors (dpNETs) in multiple endocrine neoplasia type 1 (MEN1). Therefore, the incidence and severity of complications after major surgery for MEN1-related dpNETs were assessed. Methods Patients were selected from the population-based Dutch MEN1 database if they had undergone a Whipple procedure or total pancreatectomy from 2003 to 2017. Complications were graded according to the Clavien–Dindo classification (grade III or higher complications were considered a severe complication) and definitions from the International Study Group of Pancreatic Surgery. The Cumulative Complication Index (CCI®) was calculated as the sum of all complications weighted for their severity. Univariable logistic regression was performed to assess potential associations between predictor candidates and a severe complication. Results Twenty-seven patients (median age 43 years) underwent a major duodenopancreatic resection, including 14 Whipple procedures and 13 total pancreatectomies. Morbidity and mortality were 100% (27/27) and 4% (1/27), respectively. A severe complication occurred in 17/27 (63%) patients. The median CCI® was 47.8 [range 8.7–100]. Grade B/C pancreatic fistulas, delayed gastric emptying, bile leakage, hemorrhage, and chyle leakage occurred in 7/14 (50%), 10/27 (37%), 1/27 (4%), 7/27 (26%), 3/27 (11%) patients, respectively. Patients with a severe complication had longer operative time and higher blood loss. After Whipple, new-onset endocrine and exocrine insufficiency occurred in 1/13 and 9/14 patients, respectively. Conclusions Major duodenopancreatic surgery in MEN1 is associated with a very high risk of severe complications and cumulative burden of complications and should therefore be reserved for a select subgroup of patients with MEN1-related dpNETs.

PURPOSE Pulmonary rehabilitation (PR) has been shown to be an effective intervention in patients with very severe chronic obstructive pulmonary disease (COPD) awaiting lung transplantation (LTx). The objective of this study was to characterize the prevalence of acute exacerbations (AEs) during PR and their impact on the outcomes of pre-LTx PR. METHODS In this retrospective analysis, 559 patients with COPD awaiting LTx who were referred to a 4-wk inpatient PR program were evaluated. A total of 114 patients (20%) acquired an AE during PR and continued in an adapted fashion. Pulmonary function testing, 6-min walk test (6MWT), and a health-related quality-of-life questionnaire (SF-36) were administered on admission and on discharge of PR. RESULTS Following PR, both groups, patients with and without AE, increased their 6MWT significantly (P < .001) to a clinically relevant amount (58 ± 72 and 52 ± 64 m, respectively). The sum scores of the SF-36 also improved significantly without any between-group differences. No observed changes were different between the two groups. No relevant predictors for PR outcomes could be detected by logistic regression. CONCLUSIONS Our data show that patients with end-stage COPD listed for LTx can achieve clinically relevant improvements in functional exercise capacity and quality of life even if they develop an AE during PR.

Dawn Tladi,1 Lucky Mokgatlhe,2 Theo Nell,3 Sheila Shaibu,4 Ronel Mitchell,5 Comfort Mokgothu,1 Tebogo Gabonthone,1 Omphile Hubona1 1Department of Sport Science, University of Botswana, Gaborone, Botswana; 2Department of Statistics, University of Botswana, Gaborone, Botswana; 3Centre for Cardio-metabolic Research in Africa (CARMA), Integrated Metabolic Research Group, Department of Physiological Sciences, Faculty of Natural Sciences, University of Stellenbosch, Stellenbosch, 7600, South Africa; 4School of Nursing and Midwifery, The Aga Khan University, Nairobi, Kenya; 5Gaborone Biokinetics, Gaborone, BotswanaCorrespondence: Dawn TladiDepartment of Sport Science, Private Bag 00702, Gaborone, BotswanaTel +267 71896028Fax +267 3185096Email tladidm@ub.ac.bwPurpose: The metabolic syndrome (MetS) is on the rise in Sub-Saharan Africa, attributed to increased and uncontrollable urbanization accompanied by its lifestyle changes. Non-communicable diseases, such as hypertension, diabetes, and obesity, which are components of the (MetS) are also on the increase in Botswana. To date, no study has determined the prevalence of the MetS in the apparently healthy Batswana adults. The objective of the study was to determine the prevalence of the MetS among the 25– 65-year-old Batswana residing in urban and neighboring semi-urban areas of Gaborone.Participants and Methods: A cross-sectional study was used to collect data from N=794 participants, n=383 men and n=411 women, residing in Gaborone and two surrounding semi-urban areas. Data collected included demographic, anthropometric measurements, blood pressure (BP), blood glucose, triglycerides, high-density lipoprotein cholesterol (HDL-C) and total cholesterol.Results: A high prevalence of 26.8% was reported, with women mostly afflicted (35.0% vs 18.0%). The MetS risk factors found to be common in women were low HDL-C at (50% vs 48.7%) compared to men, while proportions with elevated BP (50.3% vs 39.4%) were prominent in men. The prevalence increased with age, with the oldest age group showing a higher prevalence in both women and men, respectively (55– 65 years; 38.5% vs 41.2%).Conclusion: An unprecedented high MetS prevalence was revealed among perceived to be healthy Batswana adults, with women at a higher risk. This public health concern creates an opportunity to establish evidence of risk factors, develop guidelines and strategies with appropriate public health measures to prevent and control the MetS.Keywords: abdominal obesity, HDL-C, blood pressure, age, public health

Canine African Trypanosomosis (CAT) is a rarely described disease with frequently lethal outcome. A 5-year-old female mongrel dog weighing 22 kg was presented in Austria due to unilateral uveitis, pancytopenia, and anorexia 4 months after return from a trip through Western Africa. Trypanosoma spp. flagellates were detected in a blood smear and identified as Trypanosoma congolense forest type by PCR. Initial treatment with imidocarb and miltefosine led to clinical improvement but only isometamidium chloride hydrochloride applied intramuscularly led to complete eradication of the pathogen from the dog’s blood 4 months later.

INTRODUCTION: In fighter aircraft, long-duration high-altitude sorties are typically interrupted by refueling excursions to lower altitude. In normoxia, excursions to moderate cabin altitude may increase the occurrence of venous gas emboli (VGE) at high cabin altitude. The aim was to investigate the effect of hyperoxia on VGE and decompression sickness (DCS) during alternating high and moderate altitude exposure.METHODS: In an altitude chamber, 13 healthy men were exposed to three different conditions: A) 90 min at 24,000 ft (7315 m) breathing normoxic gas (54% O2; H-NOR); B) 90 min at 24,000 ft breathing hyperoxic gas (90% O2; H-HYP); and C) three 30-min exposures to 24,000 ft interspersed by two 30-min exposures to 18,000 ft (5486 m) breathing 90% O2 (ALT-HYP). VGE occurrence was evaluated from cardiac ultrasound imaging. DCS symptoms were rated using a scale.RESULTS: DCS occurred in all conditions and altogether in 6 of the 39 exposures. The prevalence of VGE was similar in H-NOR and H-HYP throughout the exposures. During the initial 30 min at 24,000 ft, the prevalence of VGE was similar in ALT-HYP as in the other two conditions, whereas, after the first excursion to 18,000 ft, the VGE score was lower in ALT-HYP than in H-NOR and H-HYP.DISCUSSION: Hyperoxic excursions from 24,000 to 18,000 ft reduces VGE occurrence, presumably by facilitating diffusive gas exchange across the bubble surfaces, increasing the share of bubble content contributed by oxygen. Still, the excursions did not abolish the DCS risk.Ånell R, Grönkvist M, Gennser M, Eiken O. Hyperoxic effects on decompression strain during alternating high and moderate altitude exposures. Aerosp Med Hum Perform. 2021; 92(4):223230.

Zusammenfassung Hintergrund und Ziele Alpha-2-Makroglobulin (A2 M) ist ein Plasmaprotein mit proteolytischer Wirkung auf viele Proteasen. Bei Patienten mit einem angeborenen Alpha-1-Antitrypsinmangel (AATM) liegt ein funktioneller Protease-Überschuss vor. Ziel dieser Studie war es, die Hypothese zu prüfen, dass bei Patienten mit AATM ein erhöhter A2M-Spiegel nachweisbar ist. Methoden Patienten mit AATM (Genpolymorphismus Pi*ZZ, Pi*SZ, Pi*MZ und seltene Genvarianten) wie auch Probanden mit einem normwertigen AAT-Spiegel (gesunde Probanden, Pi*MM) wurden der A2M- und AAT-Testung unterzogen. Die Serumkonzentrationen der Proteine wurden mittels Nephelometrie bestimmt. Die Polymorphismen Pi*Z und Pi*S wurden durch Polymerase-Kettenreaktion (PCR) nachgewiesen, seltene Genvarianten wurden durch Sequenzierung ermittelt. Ergebnisse In unsere Studie wurden insgesamt 291 Individuen eingeschlossen. Es konnte gezeigt werden, dass es bei Vorliegen eines Genpolymorphismus (Pi*ZZ) und einem Alpha-1-Antitrypsin-Serumspiegel Schlussfolgerungen In dieser Studie konnte eine inverse Korrelation zwischen den Serumspiegeln von AAT und A2M bei Vorliegen eines Genpolymorphismus (Pi*ZZ) nachgewiesen werden. Weitere Studien sind erforderlich, um zu erfassen, welche klinische Bedeutung erhöhte A2M-Serumpiegel bei Patienten mit einem schweren AAT-Mangel Pi*ZZ und seltenen Genvarianten, deren AAT-Serumspiegel unter 50 mg/dl liegt, haben könnten.

Background The Blastomyces antigen concentration in urine (BACU) test is used to diagnose blastomycosis and monitor treatment in dogs. It is unknown if a higher BACU is associated with shorter survival. Objectives To determine if the magnitude of BACU before treatment is associated with survival in dogs with blastomycosis. Animals Fifty‐two dogs with blastomycosis. Methods Retrospective case review. BACU, radiographic lung severity (RLS) score (0‐4 scale), and survival time up to 1 year after diagnosis were obtained through medical record review of dogs with Blastomyces dermatitidis. Results The overall survival was: discharge, 87%; 1 week, 85%; 2 months, 74%; and 6 months, 69%. BACU correlated with RLS score (r s = 0.33, P = .02). BACU and RLS scores were lower in survivors to 2 months than nonsurvivors (average BACU difference of 2.5 ng/mL, 95% confidence interval [CI]: 0.2‐4.8 ng/mL, P = .04; median RLS difference of 2; range, 0‐4, P = .02). Dogs with BACU 5 ng/mL (P = .03) and dogs with severe (3‐4) RLS scores (P = .04). All dogs with a BACU

Background Diphtheria has re-emerged over the past several years. There is a paucity of data on the administration and safety of diphtheria antitoxin (DAT), the standard treatment for diphtheria. The 2017–2018 outbreak among Rohingya refugees in Bangladesh was the largest in decades. We determined the outcomes of DAT-treated patients and describe the occurrence and risk factors associated with adverse reactions to DAT. Methods We conducted a retrospective study at the Médecins Sans Frontières Rubber Garden Diphtheria Treatment Center from December 2017–September 2018. Diphtheria was diagnosed based on the World Health Organization clinical case criteria. High-acuity patients were eligible for DAT. Safety precautions were meticulously maintained. We calculated the presence of adverse events by age, duration of illness, and DAT dosage using bivariate comparisons. Results We treated 709 patients with DAT; 98% (n = 696) recovered and were discharged. One-fourth (n = 170) had at least 1 adverse reaction. Common reactions included cough (n = 115, 16%), rash (n = 66, 9%), and itching (n = 37, 5%). Three percent (n = 18) had severe hypersensitivity reactions. Five patients died during their DAT infusion or soon afterwards, but no deaths were attributed to DAT. Conclusions Outcomes for DAT-treated patients were excellent; mortality was

Background Insulinomas are found in 10–15 per cent of patients with multiple endocrine neoplasia type 1 (MEN1) and lead to life‐threatening hypoglycaemia. Surgical outcome and the optimal surgical strategy for MEN1‐related insulinoma are unknown. Methods Patients with MEN1‐related insulinomas were identified in 46 centres in Europe and North America between 1990 and 2016. Insulinomas were considered localized if the lesion was in the pancreatic head or body/tail. Patients with pancreatic neuroendocrine tumours throughout the pancreas were suspected of having multifocal insulinoma. The primary outcome was postoperative hypoglycaemia, defined as persistent hypoglycaemia, or recurrent hypoglycaemia caused by a new insulinoma or insulin‐producing liver metastases. Hypoglycaemia‐free survival was estimated by the Kaplan–Meier method. Results Ninety‐six patients underwent resection for MEN1‐related insulinoma. Sixty‐three and 33 patients had localized and multifocal insulinomas respectively. After a median follow‐up of 8 (range 1–22) years, one patient (1 per cent) had persistent disease and six (6 per cent) had developed recurrent disease, of whom four had a new insulinoma. The 10‐year hypoglycaemia‐free survival rate was 91 (95 per cent c.i. 80 to 96) per cent. Of those with localized disease, 46 patients underwent pancreatic resection and 17 enucleation. One of these patients had persistent disease and one developed recurrent insulinoma. Among patients with multifocal disease, three developed new insulinomas and two developed insulin‐producing liver metastases. Conclusion Surgery for MEN1‐related insulinoma is more successful than previously thought., In this cohort of 96 patients with resected multiple endocrine neoplasia 1 (MEN1)‐related insulinomas, seven patients (7 per cent) developed postoperative persistent or recurrent hypoglycaemia after a median follow‐up of 8 years. The 10‐year hypoglycaemia‐free survival rate was 91 (95 per cent c.i. 80 to 96) per cent. For patients with localized insulinoma, enucleation seems the preferred procedure. PPPD, pylorus‐preserving pancreatoduodenectomy. Outcomes good

Background: The BenchMarket Medical (BMM) Vertebral Compression Fracture (VCF) Registry, now known as Talosix, is a collaborative effort between Talosix (the authorized registry vendor), Noridian Healthcare Solutions, and clinicians to gather outcomes evidence for cement augmentation treatments in patients with acute painful osteoporotic VCFs. The VCF Registry was designed to provide outcomes evidence to inform the Medicare payer’s “coverage with evidence development” decision to authorize reimbursement for cement augmentation treatments. Objectives: The purpose of this article was to present a pathway for appropriate use of vertebral augmentation based on the findings of the VCF Registry. Study Design: Prospective observational data, including patient characteristics, diagnosis, process of care, and patient-reported outcomes (PROs) for pain and function, were collected from patients undergoing cement augmentation treatment. The PROs were collected at baseline, 1, 3, and 6 months following the procedure. Setting: The VCF Registry is a national ongoing registry with no specified end time or designated sample size. Methods: Primary outcomes were pain improvement measured using the Numeric Rating Scale and function improvement, measured using the Roland Morris Disability Questionnaire (RMDQ). Secondary outcomes included cement leakage, new neurologic deficits, adverse events, readmissions, and death. Results: The VCF Registry delivered outcomes data to support Noridian’s “coverage with evidence development” decision. A total of 732 patients were included in this study. Registry outcomes confirmed postmarket evidence of highly significant pain relief with mean pain score improvement of 6.5/10 points at 6 months. Function also improved significantly with mean RMDQ score change of 11.4/24 points 6 months after surgery. Results also showed the safety and reliability of cement augmentation. Limitations: The nature of the registry data is that it contains nonrandomized, nonplacebo controlled data and should not be perceived as such. The real-world setting and the large number of patients within the dataset should increase the external validity of the findings. Conclusions: Cement augmentation treatments of patients with acute painful VCFs reliably results in highly significant benefits of pain decrease and functional improvement for this Medicare population. Key words: Vertebral compression fractures, osteoporosis, kyphoplasty, back pain, registry

Author(s): Gianella, Sara; Moser, Carlee; Vitomirov, Andrej; McKhann, Ashley; Layman, Laura; Scott, Brianna; Caballero, Gemma; Lada, Steven; Bosch, Ronald J; Hoenigl, Martin; Lurain, Nell; Landay, Alan; Lederman, Michael M; Hunt, Peter W; Smith, Davey | Abstract: BACKGROUND:Even with antiretroviral therapy (ART), persons with HIV (PWH) experience increased morbidity/mortality. Cytomegalovirus (CMV) and Epstein-Barr-Virus (EBV) co-infections likely exacerbate inflammatory-related diseases. OBJECTIVE:To determine if presence of detectable CMV or EBV DNA in peripheral blood mononuclear cells (PBMC) is associated with non-AIDS events among PWH receiving modern ART. DESIGN:We performed a case-control study of PWH starting ART and HIV-suppressed at year 1 and thereafter, 140 cases who experienced non-AIDS events and 305 matched controls. Events included myocardial infarction, stroke, malignancy, serious bacterial infection or death. METHODS:Blood samples were studied pre-ART, 1-year post-ART and pre-event. Controls had an event-free follow-up equal or greater than cases. CMV and EBV levels were measured in PBMC. Conditional logistic regression analysis assessed associations and adjusted for relevant covariates; Spearman's correlations compared CMV and EBV levels with other biomarkers. RESULTS:CMV was detected in PBMC of 25% of participants, EBV was detected in g 90%. Higher EBV levels were associated with increased risk of events at all time points (odds ratio (OR) per one IQR = 1.5-1.7, all p l 0.009). At year 1, detectable CMV was associated with increased risk of events in most adjusted models (OR = 1.4-1.8, p-values ranging 0.03-0.17). Higher levels of CMV and EBV correlated with multiple inflammatory markers and lower CD4/CD8 ratio. CONCLUSIONS:In PWH starting ART, CMV and EBV in PBMC were associated with development of non-AIDS events. Clinical trials will be needed to understand causal mechanisms and ways to interrupt them.

Non-healing corneal ulcers (NHCU) are a common problem in equine practice and several treatment options are available with different success and healing times. The aim of this retrospective study was to evaluate and to compare treatment protocols, clinical courses, corneal healing time and outcomes of NHCU.From December 2001 to December 2017, a total of 57 horses with NHCU were presented at the Vetmeduni Vienna. Recorded data included affected eye, signalment, clinical symptoms, season of diagnosis, treatment protocols, complications and corneal healing rate.Sixty-three eyes were diagnosed with a NHCU. Follow-up information was available for 48/63 eyes. For those treated medically mean corneal healing time was 15.7 days (± SD 12.0). Medical treatment included topical antibiotics, antimycotics, cycloplegics, and systemic anti-inflammatory drugs. Twelve eyes received treatment with a poly-carboxymethylglucose-sulfate regenerating agent (CacicolResults correlated with those previously described and thus demonstrated the difficulty and complexity of this disease. Further research is needed to determine an optimal treatment protocol for non-healing ulcers in horses.Since NHCUs are a commonly encountered problem in equine practice a reliable treatment protocol is required. This study reflects the problems with those ulcers and provides several protocols for possible treatments.Nicht oder schwer heilende Hornhautdefekte (NHHD) sind ein häufig auftretendes Problem in der Pferdepraxis. Es gibt dafür verschiedenste Behandlungsmethoden mit unterschiedlichem Erfolg und variierenden Heilungszeiträumen. Ziel dieser retrospektiven Studie war, Behandlungsmethoden, klinische Verläufe, korneale Heilungsdauer und Erfolgsraten bei NHHD zu untersuchen und zu vergleichen.eb Von Dezember 2001 bis Dezember 2017 wurden 57 Pferde mit einem NHHD an der Vetmeduni Vienna vorgestellt. Die aufgenommenen Patientendaten umfassten das betroffene Auge, Signalement, klinische Symptome, die Jahreszeit zum Zeitpunkt der Diagnose, Behandlungsprotokolle, Komplikationen und die korneale Heilungsdauer.Bei 63 Augen wurde die Diagnose NHHD gestellt. Verlaufskontrollen lagen bei 48/63 Augen vor. Medikamentös behandelte Augen wiesen eine Heilungsdauer von 15,7 Tagen (± SD 12,0) auf. Diese Behandlung beinhaltete die topische Gabe von Antibiotika, Antimykotika und Zykloplegika sowie systemisch verabreichte Antiphlogistika. Zwölf Augen wurden mit einem Poly-Carboxymethylglukose-Sulfat-Regenerationsmittel (CacicolDie Ergebnisse korrelieren mit den Daten publizierter Studien und demonstrieren dennoch die Problematik und Komplexität dieser Erkrankung. Weitere Forschung ist notwendig, um ein optimales Behandlungsschema für nicht heilende Hornhautdefekte bei Pferden zu entwickeln.Da NHHD ein häufig auftretendes Problem in der Pferdepraxis darstellen, ist ein verlässliches Behandlungsprotokoll dringend notwendig. Diese Studie zeigt die Probleme und Komplikationen mit diesen Ulzerationen auf und beschreibt zusätzlich verschiedene Behandlungsmethoden.

Middle aortic syndrome (MAS) is a rare vascular disease occurring in pediatric patients. MAS describes narrowing of the abdominal aorta, often referred to as abdominal coarctation. Extra-aortic vessels are commonly involved, including the renal and mesenteric arteries. Pediatric patients with MAS frequently present with severe hypertension, and medical management often is insufficient. Many of these patients require endovascular or open surgical intervention. This review article discusses the etiology, symptoms, and management of pediatric MAS. It highlights the preoperative, intraoperative, and postoperative anesthetic management of these patients. It is important that anesthesiologists be aware of this rare disease and its special anesthetic considerations when caring for children with MAS because of its high morbidity.

Many countries in sub-Saharan Africa have experienced lower COVID-19 caseloads and fewer deaths than countries in other regions worldwide. Under-reporting of cases and a younger population could partly account for these differences, but pre-existing immunity to coronaviruses is another potential factor. Blood samples from Sierra Leonean Lassa fever and Ebola survivors and their contacts collected before the first reported COVID-19 cases were assessed using enzyme-linked immunosorbent assays for the presence of antibodies binding to proteins of coronaviruses that infect humans. Results were compared to COVID-19 subjects and healthy blood donors from the United States. Prior to the pandemic, Sierra Leoneans had more frequent exposures than Americans to coronaviruses with epitopes that cross-react with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), SARS-CoV, and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). The percentage of Sierra Leoneans with antibodies reacting to seasonal coronaviruses was also higher than for American blood donors. Serological responses to coronaviruses by Sierra Leoneans did not differ by age or sex. Approximately a quarter of Sierra Leonian pre-pandemic blood samples had neutralizing antibodies against SARS-CoV-2 pseudovirus, while about a third neutralized MERS-CoV pseudovirus. Prior exposures to coronaviruses that induce cross-protective immunity may contribute to reduced COVID-19 cases and deaths in Sierra Leone.

Background: More than 90% of the global 400 000 annual malaria deaths occur in Africa. The current SARS-CoV-2 pandemic has resulted in more than 830 000 deaths in its first 10 months. Case presentation: This case describes a patient who had travelled from Mozambique to Cape Town, presented with a mild febrile illness, and was diagnosed with both COVID-19 and uncomplicated Plasmodium falciparum malaria infection. She responded well to malaria treatment and had an uneventful COVID-19 admission. Her blood smear showed a low malaria parasitaemia and a relatively high gametocyte load. Conclusion: We postulate that her clinical course and abnormal smear could well be due to reciprocal disease-modifying effects of the infections. The presenting symptoms of COVID-19 may mimic endemic infectious diseases including malaria, tuberculosis, pneumocystis pneumonia and influenza thus there is a need for clinical vigilance to identify and treat such co-infections. The full article is available at https://doi.org/10.36303/JMLSTSA.2020.2.2.57

Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer’s disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

Here, we discuss the presence and roles of heterogeneity in the development of uveal melanoma. Both genetic and cellular heterogeneity are considered, as their presence became undeniable due to single cell approaches that have recently been used in uveal melanoma analysis. However, the presence of precursor clones and immune infiltrate in uveal melanoma have been described as being part of the tumour already decades ago. Since uveal melanoma grow in the corpus vitreous, they present a unique tumour model because every cell present in the tumour tissue is actually part of the tumour and possibly plays a role. For an effective treatment of uveal melanoma metastasis, it should be clear whether precursor clones and normal cells play an active role in progression and metastasis. We propagate analysis of bulk tissue that allows analysis of tumour heterogeneity in a clinical setting.

STUDY DESIGN: Population-based cohort studyObjective. We examined associations between common lumbar degenerative changes observed on MRI and present or future low back pain (LBP). SUMMARY OF BACKGROUND DATA: The association between lumbar MRI degenerative findings and LBP is unclear. Longitudinal studies are sparse. METHODS: Participants (n = 3,369) from a population-based cohort study were imaged at study entry, with LBP status measured at baseline and 6-year follow-up. MRI scans were reported on for the presence of a range of MRI findings. LBP status was measured on a 0-10 scale. Regression models were used to estimate the cross-sectional and longitudinal associations between individual and multiple MRI findings and LBP severity. Separate longitudinal analyses were conducted for participants with and without baseline pain. RESULTS: MRI findings were present in persons with and without back pain at baseline. Higher proportions were found in older age groups. 76.4% of participants had a least one MRI finding and 8.3% had 5 or more different MRI findings. Cross-sectionally, most MRI findings were slightly more common in those with LBP and pain severity was slightly higher in those with MRI findings (ranging from 0.06 for high intensity zone to 0.83 for spondylolisthesis). In the longitudinal analyses we found most MRI findings were not associated with future LBP-severity regardless of the presence or absence of baseline pain. Compared to zero MRI findings, having multiple MRI findings (≥5) was associated with mildly greater pain-severity at baseline (0.84; 0.50 to 1.17) and greater increase in pain-severity over 6 years in those pain free at baseline (1.21; 0.04 to 2.37), but not in those with baseline pain (-0.30; -0.99 to 0.38). CONCLUSION: Our study shows that the MRI degenerative findings we examined, individually or in combination, do not have clinically important associations with LBP, with almost all effects less than one unit on a 0-10 pain scale.Level of Evidence: 3.

Uveal melanoma (UM) metastasize haematogeneously, and tumor blood vessel density is an important prognostic factor. We hypothesized that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, might play a role in tumor development and metastatic behavior. mRNA levels of ANG-1 and ANG-2 were determined in 64 tumors using an Illumina HT-12 v4 mRNA chip and compared to clinical, pathologic, and genetic tumor parameters. Tissue expression was also determined by immunohistochemistry (IHC). Samples of aqueous humor were collected from 83 UM-containing enucleated eyes and protein levels that were determined in a multiplex proximity extension assay. High tissue gene expression of ANG-2, but not of ANG-1, was associated with high tumor thickness, high largest basal diameter, involvement of the ciliary body, and with UM-related death (ANG-2 mRNA p &lt, 0.001, ANG-2 aqueous protein p &lt, 0.001). The presence of the ANG-2 protein in aqueous humor correlated with its mRNA expression in the tumor (r = 0.309, p = 0.03). IHC showed that ANG-2 was expressed in macrophages as well as tumor cells. The presence of ANG-2 in the tumor and in aqueous humor, especially in high-risk tumors, make ANG-2 a potential targetable cytokine in uveal melanoma.

The FMR1 gene in its premutation (PM) state has been linked to a range of clinical and subclinical phenotypes among FMR1 PM carriers, including some subclinical traits associated with autism spectrum disorder (ASD). This study attempted to further characterize the phenotypic profile associated with the FMR1 PM by studying a battery of assessments examining clinical-behavioral traits, social-cognitive, and executive abilities in women carrying the FMR1 PM, and associations with FMR1-related variability. Participants included 152 female FMR1 PM carriers and 75 female controls who were similar in age and IQ, and screened for neuromotor impairments or signs of fragile X-associated tremor/ataxia syndrome. The phenotypic battery included assessments of ASD-related personality and language (i.e., pragmatic) traits, symptoms of anxiety and depression, four different social-cognitive tasks that tapped the ability to read internal states and emotions based on different cues (e.g., facial expressions, biological motion, and complex social scenes), and a measure of executive function. Results revealed a complex phenotypic profile among the PM carrier group, where subtle differences were observed in pragmatic language, executive function, and social-cognitive tasks that involved evaluating basic emotions and trustworthiness. The PM carrier group also showed elevated rates of ASD-related personality traits. In contrast, PM carriers performed similarly to controls on social-cognitive tasks that involved reliance on faces and biological motion. The PM group did not differ from controls on self-reported depression or anxiety symptoms. Using latent profile analysis, we observed three distinct subgroups of PM carriers who varied considerably in their performance across tasks. Among PM carriers, CGG repeat length was a significant predictor of pragmatic language violations. Results suggest a nuanced phenotypic profile characterized by subtle differences in select clinical-behavioral, social-cognitive, and executive abilities associated with the FMR1 PM in women.

Background: Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor size is still regarded as the main prognostic factor and therefore used for surgical decision-making. We assessed reliability and agreement of radiological and pathological tumor size in a population-based cohort of patients with MEN1-related pNETs. Methods: Patients were selected from the Dutch MEN1 database if they had undergone a resection for a pNET between 2003 and 2018. Radiological (MRI, CT, and endoscopic ultrasonography [EUS]) and pathological tumor size were collected from patient records. Measures of agreement (Bland-Altman plots with limits of agreement [LoA] and absolute agreement) and reliability (intraclass correlation coefficients [ICC] and unweighted kappa) were calculated for continuous and categorized (< or ≥2 cm) pNET size. Results: In 73 included patients, the median radiological and pathological tumor sizes measured were 22 (3–160) and 21 (4–200) mm, respectively. Mean bias between radiological and pathological tumor size was −0.2 mm and LoA ranged from −12.9 to 12.6 mm. For the subgroups of MRI, CT, and EUS, LoA of radiological and pathological tumor size ranged from −9.6 to 10.9, −15.9 to 15.8, and −13.9 to 11.0, respectively. ICCs for the overall cohort, MRI, CT, and EUS were 0.80, 0.86, 0.75, and 0.76, respectively. Based on the 2 cm criterion, agreement was 81.5%; hence, 12 patients (18.5%) were classified differently between imaging and pathology. Absolute agreement and kappa values of MRI, CT, and EUS were 88.6, 85.7, and 75.0%, and 0.77, 0.71, and 0.50, respectively. Conclusion: Within a population-based cohort, MEN1-related pNET size was not systematically over- or underestimated on preoperative imaging. Based on agreement and reliability measures, MRI is the preferred imaging modality.

The lack of effective treatments for autism spectrum disorder (ASD) and congenital hydrocephalus (CH) reflects the limited understanding of the biology underlying these common neurodevelopmental disorders. Although ASD and CH have been extensively studied as independent entities, recent human genomic and pre-clinical animal studies have uncovered shared molecular pathophysiology. Here, we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for individuals with ASD and CH.

Objectives: To assess the feasibility of a multi-site randomised controlled trial to evaluate the effect of functional electrical stimulation on bradykinesia in people with Parkinson’s disease. Design: A two-arm assessor blinded randomised controlled trial with an 18 weeks intervention period and 4 weeks post-intervention follow-up. Setting: Two UK hospitals; a therapy outpatient department in a district general hospital and a specialist neuroscience centre. Participants: A total of 64 participants with idiopathic Parkinson’s disease and slow gait −1. Interventions: Functional electrical stimulation delivered to the common peroneal nerve while walking in addition to standard care compared with standard care alone. Main measures: Feasibility aims included the determination of sample size, recruitment and retention rates, acceptability of the protocol and confirmation of the primary outcome measure. The outcome measures were 10 m walking speed, Unified Parkinson’s Disease Rating Scale (UPDRS), Mini Balance Evaluation Systems Test, Parkinson’s Disease Questionnaire-39, EuroQol 5-dimension 5-level, New Freezing of Gait questionnaire, Falls Efficacy Score International and falls diary. Participants opinion on the study design and relevance of outcome measures were evaluated using an embedded qualitative study. Results: There was a mean difference between groups of 0.14 ms−1 (CI 0.03, 0.26) at week 18 in favour of the treatment group, which was maintained at week 22, 0.10 ms−1 (CI –0.05, 0.25). There was a mean difference in UPDRS motor examination score of –3.65 (CI –4.35, 0.54) at week 18 which was lost at week 22 –0.91 (CI –2.19, 2.26). Conclusion: The study design and intervention were feasible and supportive for a definitive trial. While both the study protocol and intervention were acceptable, recommendations for modifications are made.

Contains fulltext : 245221.pdf (Publisher’s version ) (Open Access) BACKGROUND: Metastasized pancreatic neuroendocrine tumors are the leading cause of death in patients with multiple endocrine neoplasia type 1. Aside from tumor size, prognostic factors of pancreatic neuroendocrine tumors are largely unknown. The present study aimed to assess whether the prognosis of patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors differs from those with resected multiple endocrine neoplasia type 1-related insulinomas and assessed factors associated with prognosis. METHODS: Patients who underwent resection of a multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors between 1990 and 2016 were identified in 2 databases: the DutchMEN Study Group and the International MEN1 Insulinoma Study Group databases. Cox regression was performed to compare liver metastases-free survival of patients with a nonfunctioning pancreatic neuroendocrine tumors versus those with an insulinoma and to identify factors associated with liver metastases-free survival. RESULTS: Out of 153 patients with multiple endocrine neoplasia type 1, 61 underwent resection for a nonfunctioning pancreatic neuroendocrine tumor and 92 for an insulinoma. Of the patients with resected lymph nodes, 56% (18/32) of nonfunctioning pancreatic neuroendocrine tumors had lymph node metastases compared to 10% (4/41) of insulinomas (P = .001). Estimated 10-year liver metastases-free survival was 63% (95% confidence interval 42%-76%) for nonfunctioning pancreatic neuroendocrine tumors and 87% (72%-91%) for insulinomas. After adjustment for size, World Health Organization tumor grade, and age, nonfunctioning pancreatic neuroendocrine tumors had an increased risk for liver metastases or death (hazard ratio 3.04 [1.47-6.30]). In pancreatic neuroendocrine tumors ≥2 cm, nonfunctioning pancreatic neuroendocrine tumors (2.99 [1.22-7.33]) and World Health Organization grade 2 (2.95 [1.02-8.50]) were associated with liver metastases-free survival. CONCLUSION: Patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors had a significantly lower liver metastases-free survival than patients with insulinomas. Postoperative counseling and follow-up regimens should be tumor type specific and at least consider size and World Health Organization grade.

IntroductionDifficulties in emotional regulation are key to the development and maintenance of chronic pain. Recent evidence shows internet-delivered dialectic behaviour therapy (iDBT) skills training can reduce emotional dysregulation and pain intensity. However, further studies are needed to provide more definitive evidence regarding the efficacy of iDBT skills training in the chronic pain population.Methods and analysisA single-case experimental design (SCED) with multiple baselines will be used to examine the efficacy of a 4-week iDBT-Pain skills training intervention (iDBT-Pain intervention) to reduce emotional dysregulation and pain intensity in individuals with chronic pain. The iDBT-Pain intervention encompasses two components: (1) iDBT-Pain skills training sessions (iDBT-Pain sessions) and (2) the iDBT-Pain skills training web application (iDBT-Pain app). Three individuals with chronic pain will be recruited and randomly allocated to different baseline phases (5, 9 or 12 days). Following the baseline phase, participants will receive six 60–90 min iDBT-Pain sessions approximately 4 or 5 days apart, delivered by a psychologist via Zoom. To reinforce learnings from the iDBT-Pain sessions, participants will have unlimited use of the iDBT-Pain app. A 7-day follow-up phase (maintenance) will follow the intervention, whereby the iDBT-Pain sessions cease but the iDBT-Pain app is accessible. Emotional regulation, as the primary outcome measure, will be assessed using the Difficulties in Emotion Regulation Scale. Pain intensity, as the secondary outcome measure, will be assessed using a visual analogue scale. Generalisation measures will assess psychological state factors (depression, anxiety and coping behaviour), alongside sleep quality, well-being and harm avoidance. SCEDs are increasingly considered effective designs for internet-delivered psychological interventions because SCED enables the investigation of interindividual variability in a heterogeneous population such as chronic pain.Ethics and disseminationThis trial was approved by the University of New South Wales (HC200199). Results will be published in peer-reviewed journals.Trial registration numberACTRN12620000604909.

International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Autism spectrum disorder (ASD) and fragile X syndrome (FXS) are neurodevelopmental disorders with overlapping pragmatic language impairments. Prior work suggests pragmatic language differences may run in families. This study examined specific pragmatic difficulties (i.e., linguistic mazes and perseverations) in boys (9–18 years) with idiopathic ASD (n = 26) and FXS+ASD (n = 29), and relationships with maternal maze use. Language samples were obtained separately for boys and mothers. Nonparametric analyses suggested that boys largely did not differ in their rates of mazes, but that boys with FXS+ASD exhibited more perseverations. Mazes were correlated between fragile X dyads. Maternal mazes were correlated with child perseverations among idiopathic ASD dyads. These findings have implications for the etiological significance of ASD-related language phenotypes.

SummaryThe potential mid-term and long-term consequences after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are as yet unknown. This is the first report of bronchoscopically verified organizing pneumonia as a complication of coronavirus disease 2019 (Covid19). It caused persisting dyspnea, impaired pulmonary function, and radiological abnormalities over 5 weeks after onset of symptoms. While organizing pneumonia frequently requires treatment with systemic corticosteroids, in this case it resolved spontaneously without treatment after 6 weeks. Healthcare professionals should consider organizing pneumonia in patients with persisting respiratory symptoms after Covid19.

Atypical visual attention patterns have been observed among carriers of the fragile X mental retardation gene (FMR1) premutation (PM), with some similarities to visual attention patterns observed in autism spectrum disorder (ASD) and among clinically unaffected relatives of individuals with ASD. Patterns of visual attention could constitute biomarkers that can help to inform the neurocognitive profile of the PM, and that potentially span diagnostic boundaries. This study examined patterns of eye movement across an array of fixation measurements from three distinct eye-tracking tasks in order to investigate potentially overlapping profiles of visual attention among PM carriers, ASD parents, and parent controls. Logistic regression analyses were conducted to examine whether variables constituting a PM-specific looking profile were able to effectively predict group membership. Participants included 65PM female carriers, 188 ASD parents, and 84 parent controls. Analyses of fixations across the eye-tracking tasks, and their corresponding areas of interest, revealed a distinct visual attention pattern in carriers of the FMR1 PM, characterized by increased fixations on the mouth when viewing faces, more intense focus on bodies in socially complex scenes, and decreased fixations on salient characters and faces while narrating a wordless picture book. This set of variables was able to successfully differentiate individuals with the PM from controls (Sensitivity = 0.76, Specificity = 0.85, Accuracy = 0.77) as well as from ASD parents (Sensitivity = 0.70, Specificity = 0.80, Accuracy = 0.72), but did not show a strong distinction between ASD parents and controls (Accuracy = 0.62), indicating that this set of variables comprises a profile that is unique to PM carriers. Regarding predictive power, fixations toward the mouth when viewing faces was able to differentiate PM carriers from both ASD parents and controls, whereas fixations toward other social stimuli did not differentiate PM carriers from ASD parents, highlighting some overlap in visual attention patterns that could point toward shared neurobiological mechanisms. Results demonstrate a profile of visual attention that appears strongly associated with the FMR1 PM in women, and may constitute a meaningful biomarker.

Lassa fever (LF) is a viral hemorrhagic disease found in Sub-Saharan Africa and is responsible for up to 300,000 cases and 5000 deaths annually. LF is highly endemic in Sierra Leone, particularly in its Eastern Province. Kenema Government Hospital (KGH) maintains one of only a few LF isolation facilities in the world with year-round diagnostic testing. Here we focus on space-time trends for LF occurring in Sierra Leone between 2012 and 2019 to provide a current account of LF in the wake of the 2014–2016 Ebola epidemic. Data were analyzed for 3277 suspected LF cases and classified as acute, recent, and non-LF or prior LF exposure using enzyme-linked immunosorbent assays (ELISAs). Presentation rates for acute, recent, and non-LF or prior LF exposure were 6.0% (195/3277), 25.6% (838/3277), and 68.4% (2244/3277), respectively. Among 2051 non-LF or prior LF exposures, 33.2% (682/2051) tested positive for convalescent LF exposure. The overall LF case-fatality rate (CFR) was 78.5% (106/135). Both clinical presentations and confirmed LF cases declined following the Ebola epidemic. These declines coincided with an increased duration between illness onset and clinical presentation, perhaps suggesting more severe disease or presentation at later stages of illness. Acute LF cases and their corresponding CFRs peaked during the dry season (November to April). Subjects with recent (but not acute) LF exposure were more likely to present during the rainy season (May to October) than the dry season (p &lt, 0.001). The findings here suggest that LF remains endemic in Sierra Leone and that caseloads are likely to resume at levels observed prior to the Ebola epidemic. The results provide insight on the current epidemiological profile of LF in Sierra Leone to facilitate LF vaccine studies and accentuate the need for LF cohort studies and continued advancements in LF diagnostics.

CA extern - Weitere Nicht-UDE-Autoren sind nicht genannt. Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiology

Background: Bone marrow examination is a useful diagnostic tool in human immunodeficiency virus (HIV)-positive patients presenting with cytopenias and fever. However, its role in the afebrile and asymptomatic patient presenting with an isolated cytopenia is not well established. This study was conducted to determine the indications for bone marrow examination and its diagnostic yield, in HIV-positive patients at Tygerberg Hospital.Methods: A retrospective, cross-sectional descriptive study was performed over a 3-year period from 01 September 2015 to 31 August 2018. The bone marrow examination reports for the HIV-positive patients who had a bone marrow examination during the study period were retrieved. Clinical and laboratory information was captured.Results: Altogether 374 bone marrow reports for HIV-positive patients were found. The indication of the bone marrow examination included investigation of unexplained cytopenias, suspected haematological malignancies, follow-up examination for patients with known haematological diseases, staging of haematological or non-haematological malignancies and investigation of suspected disseminated infection. The patients’ median age was 43 years and the interquartile range was 27–60 years. There was a slight female predominance with females 51% and males 49%. The diagnostic yield was 33.7%. Acute leukaemia and lymphoma were the most common diagnoses. Haematinic deficiency and pure red cell aplasia were found in the majority of cases with isolated anaemia. All cases with isolated thrombocytopenia were due to immune thrombocytopenia.Conclusion: Bone marrow examination is a useful investigation for HIV-positive patients with cytopenias, suspected haematological malignancy and lymphoma staging. However, its early use in patients with isolated anaemia and isolated thrombocytopenia is questionable.

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here, we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuroinflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, and gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby bacterial inflammagens may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that iron chelation, pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments, which may relieve the characteristic motor and nonmotor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuro-inflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby lipopolysaccharides may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments which may relieve the characteristic non-motor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

The purpose of this study was to describe the ocular findings, structural ocular complications, and vision impairment in a cohort of Lassa fever survivors in Kenema, Sierra Leone. A retrospective, uncontrolled, cross-sectional study of 31 Lassa fever survivors (62 eyes) who underwent an ophthalmic evaluation in January 2018 at the Kenema Government Hospital in Kenema, Sierra Leone was performed. Data collection included demographic information, ocular/systemic symptoms, visual acuity (VA), and ophthalmic examination findings. Main outcome measures included anterior and posterior segment ophthalmic manifestations and level of VA impairment in Lassa fever survivors. Anterior segment findings included cataract (18%) and pterygium (2%), while posterior segment manifestations consisted of glaucoma (6%), preretinal hemorrhage (2%), and lattice degeneration (2%). Findings suggestive of prior sequelae of uveitis included chorioretinal scarring (5%), retinal fibrosis (3%), and vitreous opacity (2%). Visual acuity was normal/mildly impaired in 53 eyes (85%), moderately impaired in 6 eyes (10%), and 3 eyes (5%) were considered blind by the World Health Organization (WHO) criteria. Median VA was worse in Lassa fever survivors with ophthalmic disease findings (p

Many clinical trials are beginning to assess the effectiveness of compounds known to regulate autophagy in patients receiving anti-cancer chemotherapy. However, autophagy inhibition, through exogenous inhibitors, or activation, through starvation, has revealed conflicting roles in cancer management and chemotherapeutic outcome. This study aimed to assess the effect of amino acid starvation on doxorubicin-treated breast cancer cells by assessing the roles of autophagy and apoptosis. An in vitro breast cancer model consisting of the normal breast epithelial MCF12A and the metastatic breast cancer MDAMB231 cells was used. Apoptotic and autophagic parameters were assessed following doxorubicin treatments, alone or in combination with bafilomycin, ATG5 siRNA or amino acid starvation. Inhibition of autophagy, through ATG5 siRNA or bafilomycin treatment, increased caspase activity and intracellular doxorubicin concentrations in MCF12A and MDAMB231 cells during doxorubicin treatment. While amino acid starvation increased autophagic activity and decreased caspase activity and intracellular doxorubicin concentrations in MCF12A cells, no changes in autophagic parameters or caspase activity were observed in MDAMB231 cells. Our in vivo data showed that 24 h protein starvation during high dose doxorubicin treatment resulted in increased survival of tumor-bearing GFP-LC3 mice. Results from this study suggest that short term starvation during doxorubicin chemotherapy may be a realistic avenue for adjuvant therapy, especially with regards to the protection of non-cancerous cells. More research is however, needed to fully understand the regulation of autophagic flux during starvation.

BackgroundActivating Gαq signalling mutations are considered an early event in the development of uveal melanoma. Whereas most tumours harbour a mutation in GNAQ or GNA11, CYSLTR2 (encoding G-protein coupled receptor CysLT2R) forms a rare alternative. The role of wild-type CysLT2R in uveal melanoma remains unknown.MethodsWe performed a digital PCR-based molecular analysis of benign choroidal nevi and primary uveal melanomas. Publicly available bulk and single cell sequencing data were mined to further study wild-type and mutant CYSLTR2.Results1/16 nevi and 2/120 melanomas carried the CYSLTR2 mutation. The mutation was subclonal in the nevus, while being clonal in both melanomas. In the melanomas, secondary, subclonal CYSLTR2 alterations shifted the allelic balance towards the mutant. The resulting genetic heterogeneity was confirmed in distinct areas of both tumours. At the RNA level, further silencing of wild-type and preferential expression of mutant CYSLTR2 was identified, which was also observed in 2/3 CYSLTR2 mutant melanomas from the TCGA cohort. In CYSLTR2 wild-type melanomas, high expression of CYSLTR2 originated from melanoma cells and correlated to tumour inflammation.ConclusionsOur findings suggest that CYSLTR2 is involved in both early and late development of uveal melanoma. Whereas the CYSLTR2 p.L129Q mutation is likely to be the initiating oncogenic event, various mechanisms further increase the mutant allele abundance during tumour progression. This makes mutant CysLT2R an attractive therapeutic target in uveal melanoma. In GNAQ, GNA11 and PLCB4 mutant melanomas, expression of wild-type CYSLTR2 possibly facilitates an interaction with immune cells in the microenvironment and may also have therapeutic potential.

About 30% of adults with autism are minimally verbal. Past research suggested that after age five, few gain verbal fluency, but studies have rarely investigated whether family environmental factors contribute to the acquisition of verbal fluency. The present study utilized data from the Autism Diagnostic Interview-Revised to compare changes in verbal fluency for 404 individuals with autism from childhood to adolescence and adulthood. Socioeconomic factors were examined across fluency groups (i.e., those who did/did not achieve verbal fluency). Findings indicated that fully 60% of those who were minimally verbal in early childhood acquired verbal fluency in adolescence and adulthood. Parent socioeconomic status differed across fluency groups, suggesting the importance of environmental factors for individual development.

Abstract Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung disease with limited therapeutic options. We retrospectively analyzed the effects of a comprehensive 4-week inpatient pulmonary rehabilitation (PR) program in 58 patients with advanced LAM (FEV1: 45 ± 34%predicted, 6-min walk distance (6MWD): 338 ± 167 m). Exercise performance (6MWD: + 49 ± 50 m; p p = 0.049 and mental component: + 5.2 ± 12.1 points; p Trial registration Clinical-Trials registration number: NCT04184193; date of registration: December 3, 2019.

Background Following the 2013–2016 West African Ebola outbreak, distinct, persistent health complaints were recognized in Ebola virus disease (EVD) survivors. Here we provide an in-depth characterization of post-Ebola syndrome >2.5 years after resolution of disease. Additionally, we report subphenotypes of post-Ebola syndrome with overlapping symptom clusters in survivors from Eastern Sierra Leone. Methods Participants in Eastern Sierra Leone were identified by the Sierra Leone Association of Ebola survivors. Survivors and their contacts were administered a questionnaire assessing self-reported symptoms and a physical examination. Comparisons between survivors and contacts were conducted using conditional logistic regression. Symptom groupings were identified using hierarchical clustering approaches. Simplified presentation of incredibly complex evaluations (SPICE), correlation analysis, logistic regression, and principal component analysis (PCA) were performed to explore the relationships between symptom clusters. Results Three hundred seventy-five EVD survivors and 1040 contacts were enrolled into the study. At enrollment, EVD survivors reported significantly more symptoms than their contacts in all categories (P 2.5 years after disease. The interrelationship between symptom clusters indicates that post-Ebola syndrome is a heterogeneous disease. The distinct musculoskeletal and non-musculoskeletal phenotypes identified likely require targeted therapies to optimize long-term treatment for EVD survivors., This study explored the relationship between groups of symptoms in post-Ebola syndrome. We found that the presentation of post-Ebola syndrome is heterogeneous with distinct subphenotypes that likely require targeted interventions.

This study examined narrative ability in ASD and parents across two contexts differing in structure and emotional content, and explored gaze patterns that may underlie narrative differences by presenting narrative tasks on an eye tracker. Participants included 37 individuals with ASD and 38 controls, 151 parents of individuals with ASD and 63 parent controls. The ASD and ASD parent groups demonstrated lower narrative quality than controls in the less structured narrative task only. Subtler, context-dependent differences emerged in gaze and showed some associations with narrative quality. Results indicate a narrative ability profile that may reflect genetic liability to ASD, and subtle links between visual attention and complex language skills that may be influenced by ASD genetic risk.

As the United States prepares to return to work and open up the economy in the midst of the COVID-19 pandemic without an available vaccine or effective therapy, testing and contact tracing are essential to contain and limit the spread of the COVID-19 virus. In response to the urgent public health need for accurate, effective, low-cost, and scalable COVID-19 testing technology, we evaluated and identified diagnostic solutions with potential for use as an at-home product. We conducted a deep horizon scan for antigen and serology-based diagnostics and down-selected to the most promising technologies. A total of 303 candidate products (138 antibody and 44 antigen tests) were identified. Product evaluations were based entirely on company-provided data. 73 serology-based antibody tests passing an initial scoring algorithm based on specificity and sensitivity data were then further evaluated using a second scoring algorithm. This second algorithm included a review of additional technical specifications of the devices, an analysis of supply chain, manufacturing, and distribution capacity of each vendor. 24 potential antibody products met the selection criteria for further direct laboratory evaluation. The performance metrics for selection of these 24 products are currently being evaluated in a Mass General Brigham laboratory. Testing alone might not be sufficient to prevent the spread of a highly contagious disease like COVID-19. Manual contact tracing could complement testing, but it is likely to fail in identifying many individuals who were in contact with a given COVID patient. The proliferation of smartphones in the population has enabled the development of solutions that can provide public health officials with valuable information for rapid and accurate contact tracing. Besides, electronic-based contact tracing solutions can be augmented by symptom self-reports gathered using electronic patient reported outcome (ePRO) platforms and by physiological data collected using wearable sensors. We performed a detailed assessment of 12 ePRO solutions, 27 wearable sensors, and 44 electronic-based contact tracing solutions. These technologies were evaluated using criteria developed to assess their suitability to address the COVID-19 pandemic. We identified a number of solutions that could augment if not provide a more effective alternative to manual contact tracing. Finally, we propose a theoretical framework in which ePRO platforms, wearable sensors, and electronic-based contact tracing solutions would be utilized in combination with molecular and serological tests to identify and isolate COVID-19 cases rapidly.