Rhinovirus persistence during the COVID-19 pandemic-Impact on pediatric acute wheezing presentations.

Rhinoviruses have persisted throughout the COVID-19 pandemic, despite other seasonal respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, adenoviruses, human metapneumovirus) being mostly suppressed by pandemic restrictions, such as masking and other forms of social distancing, especially during the national lockdown periods. Rhinoviruses, as nonenveloped viruses, are known to transmit effectively via the airborne and fomite route, which has allowed infection among children and adults to continue despite pandemic restrictions. Rhinoviruses are also known to cause and exacerbate acute wheezing episodes in children predisposed to this condition. Noninfectious causes such as air pollutants (PM2.5 , PM10 ) can also play a role. In this retrospective ecological study, we demonstrate the correlation between UK national sentinel rhinovirus surveillance, the level of airborne particulates, and the changing patterns of pediatric emergency department presentations for acute wheezing, before and during the COVID-19 pandemic (2018-2021) in a large UK teaching hospital.

Real-world comorbidities of atopic dermatitis in the US adult ambulatory population.

BACKGROUND: Atopic dermatitis (AD) is a pruritic, inflammatory skin disease associated with various comorbidities. However, comprehensive analyses of real-world comorbidities in adult patients with AD are limited. OBJECTIVE: To characterize the real-world comorbidities associated with adult AD in an ambulatory population. METHODS: We queried the MarketScan Commercial Claims and Encounters database from January 1, 2017 to December 31, 2017. Multivariable logistic regressions were performed to compare comorbidities in adult patients with AD versus age- and sex-matched controls. RESULTS: A total of 39,779 patients with AD and 353,743 controls were identified. Increased odds of psychiatric conditions, including anxiety (odds ratio [OR] 1.44) and mood disorders (OR 1.31), were observed in patients with AD. Patients with AD had higher likelihoods of autoimmune diseases, including vitiligo (OR 4.44) and alopecia areata (OR 6.01). Adult AD was also associated with infections, including impetigo (OR 9.72), methicillin-resistant Staphylococcus aureus (OR 3.92), and cellulitis (OR 2.52). Patients with AD were more likely to have systemic conditions, including lymphoid/hematopoietic malignancy (OR 1.91), atherosclerosis (OR 1.69), and metabolic syndrome (OR 1.47). For all the above, P < .001. LIMITATIONS: Retrospective analysis of health care claims data. CONCLUSION: Adult AD is associated with various psychiatric and systemic comorbidities, emphasizing the systemic nature of AD and the need for the collaborative management of these patients.

Assessing the Variability of Antibiotic Management in Patients With Open Hand Fractures Presenting to the Pediatric Emergency Department.

OBJECTIVES: Open hand fractures may be difficult to recognize and treat. There is variability in management and administration of antibiotics for these types of injuries. Unlike open long bone fractures, there is no standardized protocol for antibiotic administration for open hand fractures in children. The objective of this study is to assess the variability of antibiotic management of open hand fractures in children. METHODS: We performed a retrospective chart review at a tertiary hospital in New York of patients with hand injuries between ages 0 and 18 years presenting to the emergency department during January 2019 and December 2020. Patient encounters were reviewed for open fractures of the hand. Descriptive statistics were included for demographic and physical characteristics. RESULTS: There were 80 encounters with open hand fractures, of which the most common being tuft fractures (77.5%). The mean age was 7.6 years (SD, 4.7 years) with male predominance (58.8%). Crush injuries were the most common mechanism of injury (78.8%). Bedside repair was performed on 62 encounters (77.5%), of which 45 (72.5%) required nail bed repair, 56 (90.3%) required suturing, and 24 (38.7%) required reduction. Antibiotics were given to 62 (77.5%) encounters, most commonly oral cefalexin (45.2%), oral amoxicillin-clavulanic acid (27.4%), and intravenous cefazolin (14.5%). Median time to antibiotics from emergency department registration to administration was 150 minutes (interquartile range, 92-216 minutes). Antibiotic prescriptions were sent for 71 encounters (88.8%). Seventy seven (96.3%) of the encounters were discharged home. CONCLUSIONS: Pediatric open hand fractures have a variability of type and timing to antibiotics. Future initiatives should attempt to create standardized guidelines for management of open hand fractures.

Cost-effectiveness of Argatroban Versus Heparin Anticoagulation in Adult Extracorporeal Membrane Oxygenation Patients.

Purpose: The purpose of this study was to evaluate the cost effectiveness of argatroban compared to heparin during extracorporeal membrane oxygenation (ECMO) therapy. Methods: This was a retrospective study of patients who received argatroban or heparin infusions with ECMO therapy at a community hospital between January 1, 2017 and June 30, 2018. Adult patients who received heparin or argatroban for at least 48 hours while on venovenous (VV) or venoarterial (VA) ECMO were included. Patients with temporary mechanical circulatory assist devices were excluded. Each continuous course of anticoagulant exposure that met the inclusion criteria was evaluated. The primary endpoint was the total cost of anticoagulant therapy for heparin versus argatroban, including all administered study drugs, blood or factor products, and associated laboratory tests. Secondary endpoints included safety and efficacy of anticoagulation with each agent during ECMO. Documentation of bleeding events, circuit clotting, and ischemic events were noted. Partial thromboplastin time (PTT) values were evaluated for time to therapeutic range and percentage of therapeutic PTTs. Results: A total of 11 courses of argatroban and 24 courses of heparin anticoagulation were included in the study. The average cost per course of argatroban was less than the average cost per course of heparin ($7,091.98 vs $15,323.49, respectively; P value = 0.15). Furthermore, argatroban was not associated with an increased incidence of bleeding, thrombotic, or ischemic events. Conclusion: Argatroban may be more cost-effective during ECMO therapy in patients with low antithrombin III levels without increased risk of adverse events.

A novel blood-feeding detoxification pathway in Nippostrongylus brasiliensis L3 reveals a potential checkpoint for arresting hookworm development.

As part of on-going efforts to control hookworm infection, the "human hookworm vaccine initiative" has recognised blood feeding as a feasible therapeutic target for inducing immunity against hookworm infection. To this end, molecular approaches have been used to identify candidate targets, such as Necator americanus (Na) haemoglobinase aspartic protease-1 (APR-1), with immunogenicity profiled in canine and hamster models. We sought to accelerate the immune analysis of these identified therapeutic targets by developing an appropriate mouse model. Here we demonstrate that Nippostrongylus brasiliensis (Nb), a phylogenetically distant strongylid nematode of rodents, begins blood feeding early in its development and that immunisation with Na-APR-1 can block its growth and completion of its life cycle. Furthermore, we identify a new haem detoxification pathway in Nb required for blood feeding that can be blocked by drugs of the quinolone family, reducing both infection burden and the associated anaemia in rodents. Collectively, our findings show that haem metabolism has potential as a checkpoint for interrupting hookworm development in early stages of the hookworm life cycle and that the Nippostrongylus brasiliensis rodent model is relevant for identifying novel therapeutic targets against human hookworm.

Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease.

There is emerging evidence for the role of posaconazole in the management of Aspergillus-related cystic fibrosis (CF) lung disease. The tolerability and efficacy of posaconazole in paediatric CF is not well established. We report a prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3-17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels >1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy. Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.

Collaborative Management Strategies for Drug Shortages in Neurocritical Care.

Drug shortages have become all too familiar in the health care environment, with over 200 drugs currently on shortage. In the wake of Hurricane Maria in September 2017, hospitals across the USA had to quickly and creatively adjust medication preparation and administration techniques in light of decreased availability of intravenous (IV) bags used for compounding a vast amount of medications. Amino acid preparations, essential for compounding parenteral nutrition, were also directly impacted by the hurricane. Upon realization of the impending drug shortages, hospitals resorted to alternative methods of drug administration, such as IV push routes, formulary substitutions, or alternative drug therapies in hopes of preserving the small supply of IV bags available and prioritizing them for them most critical needs. In some cases, alternative drug therapies were required, which increased the risk of medication errors due to the use of less-familiar treatment options. Clinical pharmacists rounding with medical teams provided essential, patient-specific drug regimen alternatives to help preserve a dwindling supply while ensuring use in the most critical cases. Drug shortages also frequently occur in the setting of manufacturing delays or discontinuation and drug recalls, with potential to negatively impact patient care. The seriousness of the drug shortage crisis reached public attention by December 2017, when political and pharmacy organizations called for response to the national drug shortage crisis. In this article, we review institutional mitigation strategies in response to drug shortages and discuss downstream effects of these shortages, focusing on medications commonly prescribed in neurocritical care patients.

Severity of disease and quality of life in parents of children with alopecia areata, totalis, and universalis: A prospective, cross-sectional study.

BACKGROUND: Caregiver-oriented quality of life (QoL) research in alopecia areata is limited. No study has used a parent-tailored survey to examine the relationship between QoL and severity of alopecia as measured by Severity of Alopecia Tool (SALT) scores. OBJECTIVES: This is a prospective study that describes QoL in parents of pediatric patients with all subtypes of alopecia areata and investigates the relationship between QoL and severity of disease, duration of disease, and age of patients. METHODS: Pediatric patients and their parents were invited to participate during clinic visits. Participating parents completed the Quality of Life in a Child's Chronic Disease Questionnaire (QLCCDQ) and the Family Dermatology Life Quality Index (FDLQI). A subset of children completed the Children's Dermatologic Life Quality Index (CDLQI). SALT scores at time of survey completion were recorded. RESULTS: In total, 153 patients were included. Significant mild-to-moderate negative correlations were found between SALT scores and FDLQI scores, QLCCDQ scores, and QLCCDQ emotional domain scores. Age of child correlated negatively with QLCCDQ scores but not FDLQI scores. No significant correlation was found between duration of disease and FDLQI scores, QLCCDQ scores, or QLCCDQ emotional domain scores. LIMITATIONS: This study is limited by its small sample size and cross-sectional design. CONCLUSIONS: Impaired parent QoL might be associated with increasing severity of disease and age of affected child but not duration of disease. Providers should tailor counseling accordingly and help parents set realistic expectations for long-term experience with the disease.

Treatment of severe pediatric atopic dermatitis with methotrexate: A retrospective review.

BACKGROUND/OBJECTIVES: Severe atopic dermatitis (AD) may require systemic immunomodulatory agents to control symptoms. A lack of evidence and guidelines for systemic AD therapy in children has led to variability in agents selected and uncertainty in their comparative efficacy and safety. Evaluation of the efficacy of methotrexate in children with severe AD was performed. METHODS: We performed a retrospective chart review of 55 pediatric patients seen at Children's Hospital of Philadelphia that measured improvement using the Investigator's Global Assessment (IGA), a scale that rates AD symptoms from 0 to 5. RESULTS: About 76% of patients showed improvement with methotrexate. Mean baseline IGA of all patients was 4.18. After 6-9 months of treatment, this improved to 2.94. There was additional improvement to a mean IGA score of 2.39 after 12-15 months of treatment. At the final visit before each patient stopped methotrexate, the mean IGA score was 2.71. Approximately 50% of patients experienced minor side effects with gastrointestinal side effects the most common. CONCLUSIONS: In a diverse patient population, safety and efficacy of methotrexate was demonstrated. Significant improvement in IGA was noted for the majority after 6-9 months of therapy with further improvement when continuing treatment to 12-15 months. Methotrexate remains an important option for long-term symptom control with a favorable side effect profile and low cost.

Safety and efficacy of parenteral iron in children with inflammatory bowel disease.

AIMS: Iron deficiency anaemia frequently complicates inflammatory bowel disease (IBD) in children and adults. Oral iron may exacerbate gastrointestinal symptoms and absorption may be insufficient in intestinal inflammation. Even where oral iron is successful, repletion of iron stores can be unacceptably slow. Intravenous iron compounds were in the past associated with serious adverse reactions and historically were considered a last resort in children. New generation preparations have a safer profile in adults, although reluctance to use them in children may persist, where safety data are lacking. We investigate the safety and efficacy of ferric carboxymaltose and iron sucrose in children. METHODS: We retrospectively identified all children with IBD who received parenteral iron over a 38-month period in a single regional referral centre. Safety, tolerability and adverse events were established by case note review. Efficacy was assessed by change in haematinic indices pre- and post-treatment. RESULTS: Forty-one children (18 male; median age 14 years, range 3-17) received a total of 104 iron infusions. Of these, 44% (18) had Crohn's disease; 56% (23) ulcerative colitis. Thirty-five received ferric carboxymaltose, seven iron sucrose and one both. Three children developed mild rash post infusion which resolved quickly with chlorphenamine. Mean increase in haemoglobin was 2.5 g dl-1 (0.3-5.8). Iron levels increased by a mean of 8.4 g dl-1 (1-25), transferrin saturation by 16.2% (2-47). Transferrin decreased by 0.84 g dl-1 (0.3-3.4). CONCLUSIONS: New generation parenteral iron preparations are safe, well tolerated and efficacious in children with iron deficiency anaemia and IBD.

Aplasia cutis congenita: Evaluation of signs suggesting extracutaneous involvement.

Specific clinical features of aplasia cutis congenita may indicate the presence of underlying cranial or cerebrovascular defects, allowing for early recognition and intervention. Most information about aplasia cutis congenita exists as individual case reports, with few large-scale studies. We conducted a 7-year retrospective chart review of 90 cases of aplasia cutis congenita and identified clinical characteristics including morphology, number of lesions, anatomic location, presence of hair collar sign, associated cutaneous features, histology, and imaging results. The anatomic location of the lesion (vertex, midline) (P = .01), presence of hair collar sign (P < .001), vascular stains (P < .001), and nodules (P = .007) were found to be strong clinical indicators of skull or cerebrovascular involvement.

The patient-centered acne severity scale study.

Acne is one of the most common skin conditions seen by dermatologists. As with many other cutaneous diseases, due to its visibility, acne often produces a large psychosocial impact on patients who suffer from the disease. Such psychosocial burdens are exacerbated by the variation in acne presentation that can lead to the usage of multiple different treatments before visible improvements are appreciated. Although many scales have been established to determine severity from the clinician standpoint, patient-oriented scales are lacking. Clinicians use these severity tools to guide management and judge patient improvement from visit to visit. Creation of such a severity scale from a patient's perspective would allow patients to not only assess their perception of their acne independent of a physician but could also be used to determine patient satisfaction with treatment that would then help to more effectively guide management. Therefore the goal of this study is to create and validate a patient-centered acne severity scale using a visual analogue scale format.

Following Natures Lead: On the Construction of Membrane-Inserted Toxins in Lipid Bilayer Nanodiscs.

Bacterial toxin or viral entry into the cell often requires cell surface binding and endocytosis. The endosomal acidification induces a limited unfolding/refolding and membrane insertion reaction of the soluble toxins or viral proteins into their translocation competent or membrane inserted states. At the molecular level, the specific orientation and immobilization of the pre-transitioned toxin on the cell surface is often an important prerequisite prior to cell entry. We propose that structures of some toxin membrane insertion complexes may be observed through procedures where one rationally immobilizes the soluble toxin so that potential unfolding â†” refolding transitions that occur prior to membrane insertion orientate away from the immobilization surface in the presence of lipid micelle pre-nanodisc structures. As a specific example, the immobilized prepore form of the anthrax toxin pore translocon or protective antigen can be transitioned, inserted into a model lipid membrane (nanodiscs), and released from the immobilized support in its membrane solubilized form. This particular strategy, although unconventional, is a useful procedure for generating pure membrane-inserted toxins in nanodiscs for electron microscopy structural analysis. In addition, generating a similar immobilized platform on label-free biosensor surfaces allows one to observe the kinetics of these acid-induced membrane insertion transitions. These platforms can facilitate the rational design of inhibitors that specifically target the toxin membrane insertion transitions that occur during endosomal acidification. This approach may lead to a new class of direct anti-toxin inhibitors.

Characterisation of radicals formed by the triazine 1,4-dioxide hypoxia-activated prodrug, SN30000.

The radical species underlying the activity of the bioreductive anticancer prodrug, SN30000, have been identified by electron paramagnetic resonance and pulse radiolysis techniques. Spin-trapping experiments indicate both an aryl-type radical and an oxidising radical, trapped as a carbon-centred radical, are formed from the protonated radical anion of SN30000. The carbon-centred radical, produced upon the one-electron oxidation of the 2-electron reduced metabolite of SN30000, oxidises 2-deoxyribose, a model for the site of damage on DNA which leads to double strand breaks. Calculations using density functional theory support the assignments made.

Bevacizumab and Glioblastoma Multiforme: A Thrombosis and Bleeding Dilemma (A Case Report and a Brief Review of the Literature).

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor in adults. It is a highly vascularized tumor, and the advent of angiogenic inhibitors, in particular bevacizumab, is thought to be promising for the treatment of these tumors. However, bevacizumab has been associated with an increased risk of arterial and venous thromboembolism and hemorrhage. We report a case of superior vena cava syndrome developing in a glioblastoma patient treated with bevacizumab. Superior vena cava thrombosis in the setting of treatment with vascular endothelial growth factor has not been well-described. The issue arises as how to best manage the hemostatic complications of antiangiogenic agents in patients who have an established risk of bleeding and thrombosis with their GBM. This report discusses the individual risk of bleeding and thrombosis associated with GBM and the use of bevacizumab. Studies suggest that GBM patients who require therapeutic anticoagulation for venous thromboembolic complications while on bevacizumab therapy can be anticoagulated with the risk of bleeding being comparable to that expected from therapeutic anticoagulation alone. However, the potential risks and benefits should be thoroughly discussed with each patient before starting anticoagulation therapy for thrombotic complications.

"There's No Sewing Classes, There's No Bedazzling Seminars": The Impact of Masculinity on Social Connectedness and Mental Health for Men Living in Inner-Regional Australia.

Regional Australian masculinities are typified by 'traditional' values (e.g., stoicism, self-reliance) known to restrict social connectedness. Thus, these masculinities have been implicated in worsening men's mental health. What remains unclear, however, is how men living in inner-regional communities (i.e., townships on the fringes of major cities) might uniquely experience masculinity, social connectedness, and mental health. We interviewed 29 boys/men and one non-binary participant (M age = 43.77 years) living in the Macedon Ranges (an inner-regional Australian community). Using reflexive thematic analysis, we generated three themes. Participants described inner-regional masculinities as traditional and rigid, and attributed the Macedon Ranges' comparatively high suicide rate to these masculinities. Conversely, migration from the neighbouring city of Melbourne was implicated in introducing more inclusive masculinities to the area that conflicted with existing masculine norms. Thus, Macedon Ranges men were framed as ultimately lacking a cohesive community identity. Proximity to Melbourne was described as encouraging local men to commute daily for work instead of working locally, thereby further weakening community identity. Overall, these phenomena were implicated in damaging the psychosocial wellbeing of local men via reducing social connectedness. Because men's mental illness is so pervasive within regional Australian communities, these findings have direct implications for policymakers. Namely, policies need to acknowledge that masculinities directly influence mental health and that inner-regional masculinities are impacted by unique place-based considerations distinct from men living in other regional communities.

Specificity of staphylococcal superantigen-like protein 10 toward the human IgG1 Fc domain.

Staphylococcal superantigen-like protein 10 (SSL10) is a highly conserved member of the SSL family secreted by Staphylococcus aureus that displays structural but not functional similarity to superantigens. SSL10 bound to fibrinogen and fibronectin from plasma and in addition displayed striking specificity toward the gamma-1 subclass of human Igs. SSL10 also bound strongly to primate IgG but not to any other species tested, including rabbit, pig, guinea pig, cow, sheep, or mouse. A soluble form of the 12-kDa beta-grasp C-terminal domain of SSL10 (SSL10(95-197)) retained fibrinogen and fibronectin binding but lost the ability to bind IgG1, indicating that SSL10 bound to IgG1 primarily through its N-terminal oligonucleotide binding fold domain. SSL10 blocked the binding of IgG1 to FcgammaRs on monocytes and neutrophil phagocytosis of IgG1-opsonized bacteria. Mutagenesis of human IgG1 at key sites significantly reduced SSL10 binding including Lys(322) that is important for C1q binding, a combination of Leu(234) and Leu(235) that are important for FcgammaR binding, and a combination of Lys(274) and Asp(276) that together are unique to IgG1. These mutations suggest that the most likely site bound by SSL10 is the outer face of the Cgamma2 domain in close proximity to both the FcgammaR and C1q binding sites. SSL10 is a potential virulence factor for S. aureus targeting IgG1-mediated immunity.

In vitro mechanistic study of cell death and in vivo performance evaluation of RGD grafted PEGylated docetaxel liposomes in breast cancer.

Objectives of the investigations were to prepare RGD grafted docetaxel liposomes (RGD-PEG-LP-DC) using supercritical fluid technology and evaluate it in vitro for cytotoxicity, DNA content analysis, mechanism of cell death, and in vivo for pharmacokinetic and biodistribution studies in BALB/c mice. The RGD-PEG-LP-DCs were found to be most cytotoxic in BT-20 and MDA-MB-231 cell lines. The flowcytometry results shows at 48 hours, 96% G2 phase arrest for RGD-PEG-LP-DC at 5 nM drug concentration. The mode of cell death was found to be mainly by necrosis at low drug equivalent concentration (1 nM) and by apoptosis at high drug equivalent concentration (10 nM). With increase in time and concentration the mode of cell death by apoptosis was found to be increasing. Biodistribution demonstrated that site specific drug distribution, t(1/2), and MRT improved significantly for RGD-PEG-LP-DC. From the studies site specific and sustained intracellular drug delivery from RGD-PEG-LP-DCs may provide promising strategy in enhancing embattled against breast cancer treatment. FROM