Maternal Duplication 15q11-13 Syndrome with Autism Spectrum Disorder: Mood Stabilization by Carbamazepine.

Objectives: Maternal 15q11-13 duplication syndrome (dup15q) is one of the most frequently observed and penetrant genetic abnormalities associated with autism spectrum disorder (ASD), and commonly presents with psychiatric symptoms and seizures. Although carbamazepine has been reported as effective in managing comorbid seizures in dup15q, it has not been reported to be used as a mood stabilizer in this population. Methods: We retrospectively reviewed the charts of five consecutive patients presenting with previously diagnosed dup15q and ASD seeking treatment for psychiatric symptoms and, in four of the patients, seizures. These were the only patients with dup15q treated with carbamazepine in the Neurodevelopmental Psychopharmacology Clinic at the University of Illinois at Chicago during the review period. Results: During treatment, carbamazepine was found to be more effective than other mood stabilizers in all five patients, and in one case a better antiepileptic. Symptoms consistent with bipolar mood disorder such as hyperactivity, impulsivity, irritability, mood lability, intrusiveness, and pressured speech were improved with carbamazepine in combination with other psychotropic medications. This improvement was greater than with other mood stabilizers, including oxcarbazepine, valproate, and lamotrigine. In one case, valproate paradoxically worsened symptoms. In three cases, anxiety was improved with carbamazepine when used in conjunction with other medications targeting anxiety. Conclusions: In treating five patients with dup15q, carbamazepine more effectively stabilized mood-related symptoms than alternative treatments. Prospective randomized controlled trials are necessary to confirm this observation.

Credibility Assessment of a Subject-Specific Mathematical Model of Blood Volume Kinetics for Prediction of Physiological Response to Hemorrhagic Shock and Fluid Resuscitation.

Subject-specific mathematical models for prediction of physiological parameters such as blood volume, cardiac output, and blood pressure in response to hemorrhage have been developed. In silico studies using these models may provide an effective tool to generate pre-clinical safety evidence for medical devices and help reduce the size and scope of animal studies that are performed prior to initiation of human trials. To achieve such a goal, the credibility of the mathematical model must be established for the purpose of pre-clinical in silico testing. In this work, the credibility of a subject-specific mathematical model of blood volume kinetics intended to predict blood volume response to hemorrhage and fluid resuscitation during fluid therapy was evaluated. A workflow was used in which: (i) the foundational properties of the mathematical model such as structural identifiability were evaluated; (ii) practical identifiability was evaluated both pre- and post-calibration, with the pre-calibration results used to determine an optimal splitting of experimental data into calibration and validation datasets; (iii) uncertainty in model parameters and the experimental uncertainty were quantified for each subject; and (iv) the uncertainty was propagated through the blood volume kinetics model and its predictive capability was evaluated via validation tests. The mathematical model was found to be structurally identifiable. Pre-calibration identifiability analysis led to splitting the 180 min of time series data per subject into 50 and 130 min calibration and validation windows, respectively. The average root mean squared error of the mathematical model was 12.6% using the calibration window of (0 min, 50 min). Practical identifiability was established post-calibration after fixing one of the parameters to a nominal value. In the validation tests, 82 and 75% of the subject-specific mathematical models were able to correctly predict blood volume response when predictive capability was evaluated at 180 min and at the time when amount of infused fluid equals fluid loss.

Bioactive Compounds and Their Effect on Blood Pressure-A Review.

Elevated blood pressure affects a great part of the elderly population and is the leading risk factor for cardiovascular disease. New approaches have been taken in the fight against this growing problem, in the form of diets (Mediterranean, Dietary Approaches to Stop Hypertension (DASH) and intermittent fasting). Recent research has shown the promising results regarding diets and their effect on the prevention and improvement of elevated blood pressure. This review attempts to take this a step further, reviewing 26 studies in the search for dietary elements that may be causing this improvement. Although good evidence was found in favor of lycopene, Docosahexaenoic acid (DHA), fiber and anthocyanin, further evidence is needed before any conclusions can be made. In contrast, the evidence shows that licorice increases blood pressure.

Invasive Meningococcal Disease at Fort Ord and San Diego Naval Training Center, 1962-1964.

Meningococcal epidemics at 2 training facilities were early examples of outbreaks fueled by military demographics and because of lethal drug-resistant bacteria for which there are no vaccines or chemoprophylaxis. Positive outcomes included the elucidation of the natural history of meningococcal colonization and disease and the initiation of vaccine development.

HLA-DRB1 alleles and cervical cancer: A meta-analysis of 36 case-control studies.

BACKGROUND: Human leukocyte antigens (HLA) are encoded by closely linked genetic loci, and are important in cervical carcinogenesis. The association between HLA-DRB1 alleles with cervical cancer has been studied extensively, but results reported thus far have been inconsistent. Hence, we performed a meta-analysis to precisely assess this association. METHODS: A literature search was conducted in various online databases to identify suitable articles. Case-control studies investigating the association between HLA-DRB1 alleles and cervical cancer were included in this study. Fixed and random-effect models were used to calculate the pooled odds ratio (OR) and 95% confidence intervals (CIs). RESULTS: A total of 6645 cases and 9095 controls from 36 case-control studies were included. Of the 13 HLA-DRB1 family alleles, DRB1*09 (OR = 1.30) and DRB1 *15 (OR = 1.60) were associated with cervical cancer risk, whilst DRB1*13 (OR = 0.66) exerted a protective effect. Among the 44 HLA-DRB1 specific alleles, DRB1*04:01 (OR = 1.25), DRB1*10:01 (OR = 1.45), DRB1*11:01 (OR = 1.32), DRB1*15:01 (OR = 1.21) and DRB1*15:02 (OR = 1.55) were associated with an increased risk of cervical cancer. However, DRB1*04:06 (OR = 0.52), DRB1*12:02 (OR = 0.61), DRB1*13:01 (OR = 0.62), DRB1*13:02 (OR = 0.57), and DRB1*14:04 (OR = 0.37) were associated with a decreased risk of cervical cancer. Subgroup analysis also revealed that HLA-DRB1 alleles are associated with cervical cancer in Asian, Caucasian, Hispanic or Latin American and black sub-Saharan Africa populations. CONCLUSION: Our meta-analysis revealed that multiple HLA-DRB1 alleles are associated with cervical cancer in women of diverse ancestry populations.

Pre-positioned Outbreak Research: The Joint Medical Emerging Diseases Intervention Clinical Capability Experience in Uganda.

The West Africa Ebola virus disease outbreak of 2014-2016 demonstrated that responses to viral hemorrhagic fever epidemics must go beyond emergency stopgap measures and should incorporate high-quality medical care and clinical research. Optimal patient management is essential to improving outcomes, and it must be implemented regardless of geographical location or patient socioeconomic status. Coupling clinical research with improved care has a significant added benefit: Improved data quality and management can guide the development of more effective supportive care algorithms and can support regulatory approvals of investigational medical countermeasures (MCMs), which can alter the cycle of emergency response to reemerging pathogens. However, executing clinical research during outbreaks of high-consequence pathogens is complicated and comes with ethical and research regulatory challenges. Aggressive care and excellent quality control must be balanced by the requirements of an appropriate infection prevention and control posture for healthcare workers and by overcoming the resource limitations inherent in many outbreak settings. The Joint Mobile Emerging Disease Intervention Clinical Capability was established in 2015 to develop a high-quality clinical trial capability in Uganda to support rigorous evaluation of MCMs targeting high-consequence pathogens like Ebola virus. This capability assembles clinicians, laboratorians, clinical researchers, logisticians, and regulatory professionals trained in infection prevention and control and in good clinical and good clinical laboratory practices. The resulting team is prepared to provide high-quality medical care and clinical research during high-consequence outbreaks.

Association of TP53 rs1042522 with cervical cancer in the sub-Saharan African population: a meta-analysis.

OBJECTIVE: TP53 plays a crucial role in preventing cancer development. Previous studies in sub-Saharan Africa (SSA) reported inconclusive findings for the association of the TP53 rs1042522 C > G variant with cervical cancer. We therefore performed a meta-analysis to summarise this association in the SSA population. METHODS: Online databases were searched to identify suitable articles according to the PRISMA guidelines. We included studies published in English or French that provided the sample sizes and genotype counts for both cases and controls and evaluated the association between TP53 rs1042522 and cervical cancer in the SSA population. A fixed-effect model was used to calculate the pooled odds ratio (OR) and 95% confidence intervals (95% CIs). RESULTS: A total of 699 cervical cancer cases and 1008 controls from eight studies in SSA were included in this meta-analysis. Women harbouring the variant G allele of the TP53 rs1042522 were at increased risk of cervical cancer in allelic (G vs. C; OR = 1.30, 95% Cl = 1.12-1.50), homozygous (GG vs. CC; OR = 1.62, 95% CI = 1.20-2.19) and recessive (GG vs. CG + GG; OR = 1.74, 95% CI = 1.34-2.25) genetic models. However, the dominant genetic model (CG + GG vs. CC; OR = 1.20, 95% CI = 0.96-1.48) was not significantly associated with cervical cancer. CONCLUSIONS: Our meta-analysis revealed that harbouring variant G allele of TP53 rs1042522 is associated with cervical cancer risk in the SSA population.

OBJECTIF: Le TP53 joue un rôle crucial dans la prévention du développement du cancer. Des études antérieures en Afrique subsaharienne (ASS) ont rapporté des résultats non concluants pour l'association de la variante TP53 rs1042522 C>G avec le cancer du col de l'utérus. Nous avons donc réalisé une méta-analyse pour résumer cette association dans la population SSA. MÉTHODES: Les bases de données en ligne ont été recherchées pour identifier les articles appropriés selon les directives PRISMA. Nous avons inclus des études publiées en anglais ou en français qui ont fourni la taille des échantillons et le nombre de génotypes pour les cas et les témoins et évalué l'association entre TP53 rs1042522 et le cancer du col de l'utérus dans la population SSA. Un modèle à effet fixe a été utilisé pour calculer le rapport de cotes combiné (OR) et les intervalles de confiance à 95% (IC95%). RÉSULTATS: Un total de 699 cas de cancer du col utérin et 1008 témoins de huit études en ASS ont été inclus dans cette méta-analyse. Les femmes hébergeant l'allèle variant G du TP53 rs1042522 présentaient un risque accru de cancer du col de l'utérus chez les modèles génétiques alléliques (G vs C; OR = 1,30, IC95%: 1,12-1,50), homozygotes (GG vs CC; OR = 1,62, IC95%: 1,20-2,19) et récessifs (GG vs.CG + GG; OR = 1,74, IC95%: 1,34-2,25). Cependant, le modèle génétique dominant (CG + GG vs CC; OR = 1,20, IC95%: 0,96-1,48) n'était pas significativement associé au cancer du col utérin. CONCLUSIONS: Notre méta-analyse a révélé que l'hébergement de l'allèle variant G de TP53 rs1042522 est associé au risque de cancer du col de l'utérus dans la population SSA.

Microfluidic device for expedited tumor growth towards drug evaluation.

Patient derived organoids have emerged as robust preclinical models for screening anti-cancer therapeutics. Current 2D culturing methods do not provide physiological responses to therapeutics, therefore 3D models are being developed to better reproduce physiological responses. 3D culturing however often requires large initial cell populations and one week to one month to grow tumors ready for therapeutic testing. As a solution a 3D culturing system has been developed capable of producing physiologically relevant tumors in an expedited fashion while only requiring a small number of initial cancer cells. A bi-layer microfluidic system capable of facilitating active convective nutrient supply to populations of cancer cells facilitates expedited growth of cancer cells when starting with populations as small as 8 cells. The system has been shown to function well with adherent and non-adherent cell types by expediting cell growth by a factor ranging from 1.27 to 4.76 greater than growth under static conditions. Utilizing such an approach has enable to formation of tumors ready for therapeutic screening within 3 days and the ability to perform therapeutic screening within the microfluidic system is demonstrated. A mathematical model has been developed which allows for adjustments to be made to the dynamic delivery of nutrients in order to efficiently use culture media without excessive waste. We believe this work to be the first attempt to grow cancers in an expedited fashion utilizing only a convective nutrient supply within a microfluidic system which also facilitates on-device therapeutic screening. The developed microfluidic system and cancer growth method have the potential to offer improved drug screening for patients in clinical settings.

Infected chronic sinus secondary to a retained fragment of radial artery introducer sheath following percutaneous coronary intervention (PCI).

Coronary angiography and percutaneous coronary intervention (PCI) are frequently performed procedures in the UK and the developed world, with the radial artery becoming the preferred route of access. A chronically retained macroscopic fragment of radial artery introducer sheath is a very rare complication that has not, to our knowledge, been reported. We report the case of a 62-year-old woman who underwent PCI and developed a persisting infected sinus and abscess at the cannulation site despite multiple courses of antibiotics. Surgical exploration of the forearm recovered a foreign body that was found in the brachioradialis muscle and resembled a fragment of hydrophilic sheath. In conclusion, this case highlights that it is possible to leave macroscopic fragments of hydrophilic sheaths in situ. This is likely to be encountered during difficult access, especially during arterial spasm, and it is advised that the sheath and any other vascular access device is thoroughly inspected following removal.

Ebola Virus Causes Intestinal Tract Architectural Disruption and Bacterial Invasion in Non-Human Primates.

In the 2014⁻2016 West Africa Ebola Virus (EBOV) outbreak, there was a significant concern raised about the potential for secondary bacterial infection originating from the gastrointestinal tract, which led to the empiric treatment of many patients with antibiotics. This retrospective pathology case series summarizes the gastrointestinal pathology observed in control animals in the rhesus EBOV-Kikwit intramuscular 1000 plaque forming unit infection model. All 31 Non-human primates (NHPs) exhibited lymphoid depletion of gut-associated lymphoid tissue (GALT) but the severity and the specific location of the depletion varied. Mesenteric lymphoid depletion and necrosis were present in 87% (27/31) of NHPs. There was mucosal barrier disruption of the intestinal tract with mucosal necrosis and/or ulceration most notably in the duodenum (16%), cecum (16%), and colon (29%). In the intestinal tract, hemorrhage was noted most frequently in the duodenum (52%) and colon (45%). There were focal areas of bacterial submucosal invasion in the gastrointestinal (GI) tract in 9/31 (29%) of NHPs. Only 2/31 (6%) had evidence of pancreatic necrosis. One NHP (3%) experienced jejunal intussusception which may have been directly related to EBOV. Immunofluorescence assays demonstrated EBOV antigen in CD68+ macrophage/monocytes and endothelial cells in areas of GI vascular injury or necrosis.

Cellular and Vascular Components of Tertiary Lymphoid Structures.

Inflammatory immune cells recruited at the site of chronic inflammation form structures that resemble secondary lymphoid organs (SLO). These are characterized by segregated areas of prevalent T- or B-cell aggregation, differentiation of high endothelial venules, and local activation of resident stromal cells, including lymphatic endothelial cells. B-cell proliferation and affinity maturation toward locally displayed autoantigens have been demonstrated at these sites, known as tertiary lymphoid structures (TLS). TLS formation during chronic inflammation has been associated with local disease persistence and progression, as well as increased systemic manifestations. While bearing a similar histological structure to SLO, the signals that regulate TLS and SLO formation can diverge and a series of pro-inflammatory cytokines have been ascribed as responsible for TLS formation at different anatomical sites. Moreover, for a long time the structural compartment that regulates TLS homeostasis, including survival and recirculation of leucocytes has been neglected. In this chapter, we summarize the novel data available on TLS formation, structural organization, and the functional and anatomical links connecting TLS and SLOs.

Biomimetic microfluidic platform for the quantification of transient endothelial monolayer permeability and therapeutic transport under mimicked cancerous conditions.

Therapeutic delivery from microvasculature to cancerous sites is influenced by many factors including endothelial permeability, vascular flow rates/pressures, cancer secretion of cytokines and permeabilizing agents, and characteristics of the chosen therapeutics. This work uses bi-layer microfluidics capable of studying dye and therapeutic transport from a simulated vessel to a cancerous region while allowing for direct visualization and quantification of endothelial permeability. 2.5 to 13 times greater dye transport was observed when utilizing small dye sizes (FITC) when compared to larger molecules (FITC-Dextran 4 kDa and FITC-Dextran 70 kDa), respectively. The use of lower flow rates/pressures is shown to improve dye transport by factors ranging from 2.5 to 5 times, which result from increased dye diffusion times within the system. Furthermore, subjecting confluent endothelial monolayers to cancerous cells resulted in increased levels of vascular permeability. Situations of cancer induced increases in vascular permeability are shown to facilitate enhanced dye transport when compared to non-diseased endothelial monolayers. Subsequent introduction of paclitaxel or doxorubicin into the system was shown to kill cancerous cells resulting in the recovery of endothelial confluency overtime. The response of endothelial cells to paclitaxel and doxorubicin is quantified to understand the direct influence of anti-cancer therapeutics on endothelial growth and permeability. Introduction of therapeutics into the system showed the recovery of endothelial confluency and dye transport back to conditions experienced prior to cancer cell introduction after 120 h of continuous treatment. Overall, the system has been utilized to show that therapeutic transport to cancerous sites depends on the size of the chosen therapeutic, the flow rate/pressure established within the vasculature, and the degree of cancer induced endothelial permeability. In addition, treatment of the cancerous region has been demonstrated with anti-cancer therapeutics, which are shown to influence vascular permeability in direct (therapeutics themselves) and indirect (death of cancer cells) manners. Lastly, the system presented in this work is believed to function as a versatile testing platform for future anti-cancer therapeutic testing and development.

Treatment-focused Ebola trials, supportive care and future of filovirus care.

INTRODUCTION: During the 2014-2016 Ebolavirus (EBOV) outbreak, several candidate therapeutics were used in EBOV-infected patients in clinical trials and under expanded access for emergency use. This review will focus briefly on medications used during the outbreak. We will discuss current therapeutic candidates and their status and will then turn to a related and essential topic: supportive care and the standard of care for filovirus infected patients. Potential benefits and pitfalls of combination therapies for filoviruses will be discussed. Areas covered: Clinical trials of therapeutics targeting EBOV; clinical usage of therapeutics during recent EBOV outbreak; potential need for combination therapy; role of supportive care in treatment of Ebola virus disease (EVD). Expert commentary: In the absence of another large scale EBOV outbreak, the path to therapeutic product licensure in the United States of America (USA) would need to be via the FDA Animal Rule. However, human data may be needed to supplement animal data. The future of filovirus therapeutics may therefore benefit by establishing the ability to implement clinical trials in an outbreak setting in a timely fashion. Supportive care guidelines for filovirus infection should be defined and established as standard of care for treatment of EVD.

Primary Bacterial Gluteal Pyomyositis: A Rare Disease in Temperate Climates Presenting as Suspected Septic Arthritis of the Hip.

BACKGROUND: In nations with temperate climates, primary polymyositis is a rare, life-threatening bacterial infection that can mimic various clinical diseases depending on the area involved, leading to delayed diagnosis and management. CASE REPORT: We describe a young postpartum woman who presented to the emergency department with hip pain that was initially suspected to be caused by septic arthritis. However, hip arthrocentesis was negative, and a magnetic resonance imaging scan revealed extensive pyomyositis of the gluteal muscles. She underwent surgical debridement and was given parenteral antibiotics with good clinical recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We emphasize that cases of pyomyositis in temperate countries are often diagnosed late and therefore delay life- and potentially limb-saving treatment. For patients who present with hip and thigh pain and clinical features of sepsis, pyomyositis should be considered in the differential diagnosis and an early magnetic resonance imaging scan should be performed to confirm the diagnosis and reduce the high morbidity and mortality associated with this emerging disease.

Popliteal Artery Pseudoaneurysm with Secondary Chronic Common Peroneal Nerve Neuropathy and Foot Drop after Total Knee Replacement.

Total knee replacements (TKRs) are performed to treat debilitating arthritis and are one of the most routinely performed surgical procedures in the United Kingdom. Complications of infection and deep vein thrombosis are well recognized and managed, whereas neurovascular injuries are rarely reported although should not be disregarded. We report on the case of a 72-year-old man who presented 5 weeks after a TKR with symptoms of a progressively worsening ipsilateral foot drop. A diagnosis of common peroneal nerve neuropathy secondary to the compressive effects of a popliteal pseudoaneurysm was made, and he underwent uneventful patch repair of the pseudoaneurysm. Unique to the literature is the chronicity of the foot drop, which still persisted at follow-up 6 weeks later.