Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.

Whole genome and exome sequencing are reporting on hundreds of thousands of missense mutations. Taking a pan-disease approach, we explored how mutations in intrinsically disordered regions (IDRs) break or generate protein interactions mediated by short linear motifs. We created a peptide-phage display library tiling ~57,000 peptides from the IDRs of the human proteome overlapping 12,301 single nucleotide variants associated with diverse phenotypes including cancer, metabolic diseases and neurological diseases. By screening 80 human proteins, we identified 366 mutation-modulated interactions, with half of the mutations diminishing binding, and half enhancing binding or creating novel interaction interfaces. The effects of the mutations were confirmed by affinity measurements. In cellular assays, the effects of motif-disruptive mutations were validated, including loss of a nuclear localisation signal in the cell division control protein CDC45 by a mutation associated with Meier-Gorlin syndrome. The study provides insights into how disease-associated mutations may perturb and rewire the motif-based interactome.

FaSTPACE: a fast and scalable tool for peptide alignment and consensus extraction.

Several novel high-throughput experimental techniques have been developed in recent years that generate large datasets of putative biologically functional peptides. However, many of the computational tools required to process these datasets have not yet been created. In this study, we introduce FaSTPACE, a fast and scalable computational tool to rapidly align short peptides and extract enriched specificity determinants. The tool aligns peptides in a pairwise manner to produce a position-specific global similarity matrix for each peptide. Peptides are realigned in an iterative manner scoring the updated alignment based on the global similarity matrices of the peptides and updating the global similarity matrices based on the new alignment. The method then iterates until the global similarity matrices converge. Finally, an alignment and consensus motif are extracted from the resulting global similarity matrices. The tool is the first to support custom weighting for the input peptides to satisfy the pressing need to include experimental attributes encoding peptide confidence in specificity determinant extraction. FaSTPACE exhibited state-of-the-art performance and accuracy when benchmarked against similar tools on motif datasets generated using curated peptides and high-throughput data from proteomic peptide phage display. FaSTPACE is available as an open-source Python package and a web server.

Obesity management in the pediatric patient.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The purpose of this review is to discuss treatment modalities for obesity in children and adolescents, including nonpharmacological, pharmacological, and surgical interventions. SUMMARY: The prevalence of pediatric obesity has dramatically risen, with rates of 20.7% and 22.2% among children and adolescents, respectively. Obesity is a complex medical condition with multifactorial risk factors, including diet and exercise, social determinants of health, and environmental and genetic factors. The management approach among children and adolescents with obesity includes nutrition counseling, increased physical activity, and readiness for behavioral change. Pharmacotherapy may be recommended, yet the literature has not elucidated the most appropriate first-line treatment. Metformin and orlistat have been studied and may be considered in pediatric patients with comorbid complications, including type 2 diabetes and nonalcoholic fatty liver disease. Phentermine and topiramate in combination, as well as glucagon-like peptide-1 receptor agonists, have provided modest benefits in weight reduction among youth. Setmelanotide has a unique mechanism of action and may be considered for those with obesity due to genetic disorders. Bariatric surgery should be reserved for adolescents meeting criteria for severe obesity. CONCLUSION: Treatment for obesity in children and adolescents includes a comprehensive approach with structured lifestyle programs, mental health support, and mitigation of social determinants of health. Pharmacotherapy may also be considered, yet no medication is recommended over another, giving flexibility for shared decision-making with the patient and family regarding comorbidities and potential drug interactions. Adolescents with severe obesity who meet specified criteria may also be referred for surgical evaluation.

Updates in the treatment of asthma in pediatrics: A review for pharmacists.

PURPOSE: The purpose of this review is to summarize the management of asthma in children and to highlight different guideline-based approaches. This review also discusses literature regarding the use of corticosteroids, both inhaled and systemic, as well as biologic agents, in asthma management. SUMMARY: Asthma is a common chronic respiratory condition in the pediatric population and has evolved into a highly patient-specific disease. Of the 2 main asthma guidelines, one developed by the National Asthma Education and Prevention Program was recently published as a focused update in 2020. The other, from the Global Initiative for Asthma, focuses on a global strategy for management and prevention, with the most recent update in 2023. Both reports discuss diagnosis, assessment, and treatment of asthma in adults and children. Treatment is designed as a stepwise approach in both reports, although there are key differences. This article focuses on gaps in these guidelines, including the use of bronchodilators and inhaled corticosteroids with single maintenance and reliever therapy and long-acting muscarinic antagonists in children. It also reviews treatment in children under 5 years of age, although recommendations are limited due to a lack of evidence in this age group. Finally, this review discusses considerations for emerging treatments, including biologics, for patients who are difficult to treat. CONCLUSION: New treatment strategies and agents have emerged in the treatment of pediatric asthma. Pharmacists play a key role in providing education about, dispensing, and recommending the newest evidence-based treatment options for children.

Influence of Seasonality and Public-Health Interventions on the COVID-19 Pandemic in Northern Europe.

BACKGROUND: Most government efforts to control the COVID-19 pandemic revolved around non-pharmaceutical interventions (NPIs) and vaccination. However, many respiratory diseases show distinctive seasonal trends. In this manuscript, we examined the contribution of these three factors to the progression of the COVID-19 pandemic. METHODS: Pearson correlation coefficients and time-lagged analysis were used to examine the relationship between NPIs, vaccinations and seasonality (using the average incidence of endemic human beta-coronaviruses in Sweden over a 10-year period as a proxy) and the progression of the COVID-19 pandemic as tracked by deaths; cases; hospitalisations; intensive care unit occupancy and testing positivity rates in six Northern European countries (population 99.12 million) using a population-based, observational, ecological study method. FINDINGS: The waves of the pandemic correlated well with the seasonality of human beta-coronaviruses (HCoV-OC43 and HCoV-HKU1). In contrast, we could not find clear or consistent evidence that the stringency of NPIs or vaccination reduced the progression of the pandemic. However, these results are correlations and not causations. IMPLICATIONS: We hypothesise that the apparent influence of NPIs and vaccines might instead be an effect of coronavirus seasonality. We suggest that policymakers consider these results when assessing policy options for future pandemics. LIMITATIONS: The study is limited to six temperate Northern European countries with spatial and temporal variations in metrics used to track the progression of the COVID-19 pandemic. Caution should be exercised when extrapolating these findings.

Pathfinder experiments with atom interferometry in the Cold Atom Lab onboard the International Space Station.

Deployment of ultracold atom interferometers (AI) into space will capitalize on quantum advantages and the extended freefall of persistent microgravity to provide high-precision measurement capabilities for gravitational, Earth, and planetary sciences, and to enable searches for subtle forces signifying physics beyond General Relativity and the Standard Model. NASA's Cold Atom Lab (CAL) operates onboard the International Space Station as a multi-user facility for fundamental studies of ultracold atoms and to mature space-based quantum technologies. We report on pathfinding experiments utilizing ultracold 87Rb atoms in the CAL AI. A three-pulse Mach-Zehnder interferometer was studied to understand the influence of ISS vibrations. Additionally, Ramsey shear-wave interferometry was used to manifest interference patterns in a single run that were observable for over 150 ms free-expansion time. Finally, the CAL AI was used to remotely measure the Bragg laser photon recoil as a demonstration of the first quantum sensor using matter-wave interferometry in space.

Multicenter Registry of Adenomas of the Pituitary and Related Disorders: Initial Description of Cushing Disease Cohort, Surgical Outcomes, and Surgeon Characteristics.

BACKGROUND AND OBJECTIVES: To address the lack of a multicenter pituitary surgery research consortium in the United States, we established the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). The goals of RAPID are to examine surgical outcomes, improve patient care, disseminate best practices, and facilitate multicenter surgery research at scale. Our initial focus is Cushing disease (CD). This study aims to describe the current RAPID patient cohort, explore surgical outcomes, and lay the foundation for future studies addressing the limitations of previous studies. METHODS: Prospectively and retrospectively obtained data from participating sites were aggregated using a cloud-based registry and analyzed retrospectively. Standard preoperative variables and outcome measures included length of stay, unplanned readmission, and remission. RESULTS: By July 2023, 528 patients with CD had been treated by 26 neurosurgeons with varying levels of experience at 9 academic pituitary centers. No surgeon treated more than 81 of 528 (15.3%) patients. The mean ± SD patient age was 43.8 ± 13.9 years, and most patients were female (82.2%, 433/527). The mean tumor diameter was 0.8 ± 2.7 cm. Most patients (76.6%, 354/462) had no prior treatment. The most common pathology was corticotroph tumor (76.8%, 381/496). The mean length of stay was 3.8 ± 2.5 days. The most common discharge destination was home (97.2%, 513/528). Two patients (0.4%, 2/528) died perioperatively. A total of 57 patients (11.0%, 57/519) required an unplanned hospital readmission within 90 days of surgery. The median actuarial disease-free survival after index surgery was 8.5 years. CONCLUSION: This study examined an evolving multicenter collaboration on patient outcomes after surgery for CD. Our results provide novel insights on surgical outcomes not possible in prior single-center studies or with national administrative data sets. This collaboration will power future studies to better advance the standard of care for patients with CD.

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Whole-lung lavage in a patient with pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare syndrome in which phospholipoproteinaceous matter accumulates in the alveoli leading to compromised gas exchange. Whole-lung lavage is considered the gold standard for severe autoimmune PAP and offers favorable long-term outcomes. In this case report, we describe the perioperative management and procedural specifics of a patient undergoing WLL for PAP in which an anesthesiologist serves as the proceduralist and a separate anesthesiologist provides anesthesia care for the patient.

VEGFA SNPs (rs34357231 & rs35569394), Transcriptional Factor Binding Sites and Human Disease.

Purpose: The human vascular endothelial growth factor (VEGF)-A gene transcribes a signaling protein involved in the regulation of angiogenesis, vasculogenesis and endothelial cell growth. Two insertion/deletion (I/D) simple nucleotide polymorphisms (SNPs, rs34357231 & rs35569394) in the promoter region of the gene have been significantly associated with several human diseases. These SNPs were computationally examined with respect to changes in punitive transcriptional factor binding sites (TFBS) and these changes were discussed in relation to the diseases. Methods: The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all the TFBS in the VEGFA gene from 2.7 kb upstream of the transcriptional start site to 1.6 kb past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results: Regulatory SNPs (rSNPs) in the promoter region of the VEGFA gene alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS. The VEGFA-deletion (D) allele of these SNPs has been found to be a risk factor for diabetic retinopathy, diabetic microvascular complications in patients with type 1 diabetes mellitus, breast cancer in north Indian patients, and bladder cancer. The changes in TFs associated with the TFBS are examined with respect to these human diseases. Conclusion: The VEGFA-insertion (I) allele provides punitive TFBS for the AR, EGR1 & 2, KLF5 and SP1 TFs whose BS do not occur with the VEGFA-D allele. These TFs have been linked to prostate cancer, cancer suppression and oncogenic processes and if not regulating the VEGFA gene may pose a risk for disease.

Computational DIO2 rSNP Analysis, Transcriptional Factor Binding Sites and Disease.

Purpose: The DIO2 gene transcribes the deiodinase type 2 enzyme that changes the thyroid prohormone, thyroxine (T4), to the biologically active triiodothyronine (T3) hormone. T3 plays a vital part in the regulation of energy balance and glucose metabolism. DIO2 single-nucleotide polymorphisms (SNPs) were computationally examined with respect to changes in punitive transcriptional factor binding sites (TFBS) and these changes were discussed in relation to human disease. Methods: The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all the TFBS in the DIO2 gene from 2.4 kb upstream of the transcriptional start site to 508 bp past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results: Regulatory SNPs (rSNPs) in the promoter region novel SNP (-2035bp), 5’UTR (rs12885300), intron one (rs225010, 225011 and rs225012), exon two [rs225014 (Thr92Ala)] and 3’ UTR (rs6574549, rs225015 and rs225017) of the DIO2 gene are in linkage disequilibrium. These rSNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS. Conclusion: The alleles of each rSNP were found to generate unique TFBS resulting in potential changes in TF DIO2 regulation. These regulatory changes were discussed with respect to changes in human health resulting in disease or sickness.

¿Cuándo realizar biopsia renal en pacientes con diabetes mellitus tipo2? Modelo predictivo de enfermedad renal no diabética / When to perform renal biopsy in patients with type 2 diabetes mellitus? Predictive model of non-diabetic renal disease

INTRODUCCIÓN: La nefropatía diabética (ND) es una complicación frecuente de la diabetes mellitus (DM), y su diagnóstico suele ser clínico. Sin embargo, en numerosas ocasiones la enfermedad renal que presentan los pacientes diabéticos es debida a otras causas cuyo diagnóstico es histológico. El objetivo del estudio fue determinar los datos clínicos y analíticos predictores de ND y enfermedad renal no diabética (ERND), y elaborar un modelo predictivo (score) para confirmar o descartar ND. MATERIAL Y MÉTODOS: Estudio observacional, transversal y retrospectivo de biopsias renales realizadas en pacientes diabéticos tipo 2 entre 2000 y 2018. RESULTADOS: Se incluyeron 207 pacientes diabéticos con una edad media de 64,5 ± 10,6 años; el 74% eran varones. La biopsia mostró ND en 126 (61%) y en 81 ERND (39%). La retinopatía diabética estaba presente en el 58% de los pacientes con ND y en el 6% del grupo con ERND (p < 0,001). Histología encontrada en la ERND: glomerulopatías primarias (52%), nefroangioesclerosis (16%), nefritis intersticial inmunoalérgica (15%) y vasculitis (8,5%). En el análisis multivariable, la retinopatía (OR 26,7; IC 95%: 6,8-104,5), la isquemia crónica de miembros inferiores (OR 4,37; IC 95%: 1,33-14,3), la insulinoterapia (OR 3,05; IC 95%: 1,13-8,25), una evolución de la DM ≥ 10 años (OR 2,71; IC 95%: 1,1-6,62) y la proteinuria nefrótica (OR 2,91; IC 95%: 1,2-7,1) fueron predictores independientes de ND. La microhematuria, definida como ≥ 10 hematíes/campo (OR 0,032; IC 95%: 0,01-0,11) y el sobrepeso (OR 0,21; IC 95%: 0,08-0,55) lo fueron de ERND. Según el modelo predictivo resultante del estudio multivariable para ND, el rango de puntuación varió de -6 a 8 puntos. Todos los pacientes con un score > 3 era tenían ND, y el 94% de los casos con score ≤ 1 punto fueron ERND. CONCLUSIONES: La ERND es frecuente en pacientes con DM (39%). La etiología más frecuente son las glomerulonefritis primarias. La ausencia de retinopatía y la presencia de microhematuria son altamente sugestivas de ERND. La utilización de un sistema de puntuación facilita la indicación de biopsia renal en pacientes diabéticos

INTRODUCTION: Diabetic nephropathy (DN) is one of the most frequent complications in patients with diabetes mellitus (DM) and its diagnosis is usually established on clinical grounds. However, kidney involvement in some diabetic patients can be due to other causes, and renal biopsy might be needed to exclude them. The aim of our study was to establish the clinical and analytical data that predict DN and no-diabetic renal disease (NDRD), and to develop a predictive model (score) to confirm or dismiss DN. MATERIAL AND METHODS: We conducted a transversal, observational and retrospective study, including renal biopsies performed in type 2 DM patients, between 2000 and 2018. RESULTS: Two hundred seven DM patients were included in our study. The mean age was 64.5 ± 10.6 years and 74% were male. DN was found in 126 (61%) of the biopsies and NDRD in 81 (39%). Diabetic retinopathy was presented in 58% of DN patients, but only in 6% of NDRD patients (P < .001). Patients with NDRD were diagnosed of primary glomerulopathies (52%), nephroangiosclerosis (16%), inmunoallergic interstitial nephritis (15%) and vasculitis (8.5%). In the multivariate analysis, retinopathy (OR 26.7; 95% CI: 6.8-104.5), chronic ischaemia of lower limbs (OR 4,37; 95% CI: 1.33-14.3), insulin therapy (OR 3.05; 95% CI: 1.13-8.25), time course of DM ≥ 10 years (OR 2.71; 95% CI: 1.1-6.62) and nephrotic range proteinuria (OR 2.91; 95% CI: 1.2-7.1) were independent predictors for DN. Microhaematuria defined as ≥ 10 red blood cells per high-power field (OR 0.032; 95% CI: 0.01-0.11) and overweight (OR 0.21; 95% CI: 0.08-0.5) were independent predictors of NDRD. According to the predictive model based on the multivariate analysis, all patients with a score > 3 had DN and 94% of cases with a score ≤ 1 had NDRD (score ranked from -6 to 8 points). CONCLUSIONS: NDRD is common in DM patients (39%), being primary glomerulonephritis the most frequent ethology. The absence of retinopathy and the presence of microhematuria are highly suggestive of NDRD. The use of our predictive model could facilitate the indication of performing a renal biopsy in DM patients

The susceptibility of wild caught sand flies to infection by a subspecies of Leishmania mexicana isolated from proechimys iheringi denigratus (Rodentia, echimyidae)

Várias espécies de flebotomíneos silvestres foram coletados no mesmo local onde o roedor Proechimys iheringi denigratus foi encontrado infectado com uma subespécie de Leishmania mexicana. A ausência de infecçäo natural desses flebotomíneos nos permitiu testar, com relativa segurança, a susceptibilidade de algumas dessas espécies à infecçäo por esse parasito. O sucesso obtido nas infecçöes experimentais sugere que uma ou mais das espécies de flebotomíneos encontradas em alta densidade nesse local podem ser um vetor, em potencial, dessa subespécie de L. mexicana

Leishmania mexicana in proechimys ihering denigratus moojen (Rodentia, echimyidae) in a region endenic for American cutaneous Leishmaniasis

Três isolados de Leishmania foram obtidos de cinco entre 27 exemplares do roedor Proechimys iheringi denigratus capturados na regiäo de Três Braços, na mata atlântica do Estado da Bahia, Brasil. O isolamento desse parasito foi feito através de inoculaçäo de triturado de pele, braço e fígado em patas de hamsters. Em pelo menos um dos casos, (MTB-574), o parasito foi isolado da pele. Metástase foi observada nos hamsters inoculaçäos, os parasitos cresceram abundantemente em meios artificiais de cultura e um padräo suprapapilário típico foi obtido em Lutzomyia longipalpis, indicando que o parasito pertence ao complexo L. mexicana. Todos os isolados reagiram positivamente com anticorpos monoclonais de L. m. mexicana e L. m. amazonensis. A análise isoenzimática diferenciou o parasito de isolados padröes de L. m. mexicana, L. m. amazonensis, L. m. aristedesi, L. m. pifanoi, L. m. garnhami e L. m. ssp(Goias-W. Barbosa). O parasito parece ser uma subespécie de L. mexicana muito próxima a L. m. amazonensis, da qual difere pela menor mobilidade eletroforética de GPI, PEP e ALAT. Este é o primeiro registro do isolamento de um parasito do gênero Leishmania em um roedor capturado no Estado da Bahia

universal contact lens design for the Post-refractive surgery cornea

As the number of laser refractive procedures increase there is an increasing demand for post-surgical contact lens correction of residual ametropia. The surgically induced central corneal flattening together with irregular astigmatism dictates special lens design considerations. A retrospective study of the performance of a selected reverse geometry [RGL] gas permeable contact lens is presented together with a brief history of RGL contact lenses. A retrospective records review of five patients: two radial keratotomy [RK], two laser-assisted in situ keratomileusis [LASIK], and one combination RK/LASIK is discussed in this study. Post-operative time for our retrospective cohort ranged from 7 months to 15 years. All five were fitted successfully using Paragon HDS [58 Dk] material in a reverse geometry [RGL] aspheric contact lens design. Patient demographics, best-corrected visual acuities [BCVA], corneal topography, subjective quality of vision and fitting data were compiled. Mean lens diameter was 10.3 mm [10.0 to 10.4 mm] with a mean base curve of 8.32 mm [7.9 to 8.5]. The lenses provided good centration, movement and comfort with an improvement of 1 to 3 lines in visual acuity. In addition, monocular diplopia was eliminated and all patients reported a subjective improvement in their quality of vision. The RGL aspheric lens design used in this study provided exceptional cornea-lens relationships for a range of surgically-altered corneas resulting in excellent comfort, improved visual acuity, and subjectively enhanced quality of vision