Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children’s Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. We report the study design and some elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy (NEHI), with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). This Registry is the largest longitudinal chILD cohort in the U.S. to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

AIMS The aim of this umbrella review was to identify tools and guidelines available to aid the deprescribing process of potentially inappropriate medications (PIM), evaluate their methods of development and validation, and describe at what level of evidence medications are included in the tools and guidelines. METHODS Searches were conducted on MEDLINE(Ovid), Embase.com, Cochrane CDSR, CINAHL (EBSCO), Web of Science Core Collection, and guideline databases from the date of inception to July 7, 2022. We described and compared the different characteristics and contents of tools and guidelines. RESULTS From 10,606 records screened, 23 systematic reviews and guidelines met the inclusion criteria. We then identified 90 tools (67 explicit, 12 mixed, 11 implicit), and 9 guidelines. The majority were developed for use in older adults (n = 74). Nineteen tools targeted older adults with limited life expectancy (LLE), and 7 targeted children <18 years. The majority (97%) of explicit/mixed tools were validated through Delphi techniques (n = 61). Two tools and eight guidelines provided information on the level of evidence for the included medications, of which less than a quarter were included based on high-quality evidence. CONCLUSION Existing tools are available for a diversity of populations. Discrepancies identified in categorizing medications as appropriate or not can be a result of low quality evidence. Particularly, tools for patients with LLE were developed based on very limited evidence, and research to generate this evidence is highly needed. Our medication lists, along with the level of evidence, could facilitate efforts to strengthen the evidence.

Dear Editor, I am writing to submit a letter titled “Usage of a Novel Inhaler Device for the Management of Asthma in Children with Special Needs” for your consideration. This letter highlights the importance of the inhaler device technique in children with asthma when they have comorbid conditions such as attention-deficit/hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD). These comorbidities often make it challenging for physicians to plan a treatment regimen, as it impacts the patient’s adherence to medication. We evaluated the effectiveness of a breath-actuated inhaler (BAI) in managing poorly controlled asthma in three pediatric patients with special needs. All patients showed significant improvement in their asthma symptoms, were well-controlled after one month of using the BAI and they found that device was easy to use. This letter contributes to the growing body of evidence supporting the effectiveness of BAI in the management of asthma, particularly in children with special needs. We hope this work to be submitted under the letter to editor section and it will be of interest to your readership and contribute to improving asthma management in children with comorbidities. Thank you for your consideration.

Population genomics applied to game species conservation can help delineate management units, ensure appropriate harvest levels, and identify populations needing genetic rescue to safeguard their adaptive potential. The ruffed grouse (Bonasa umbellus) is rapidly declining in much of the eastern USA due to a combination of forest maturation and habitat fragmentation. More recently, mortality from West Nile Virus may have affected connectivity of local populations; however, genetic approaches have never explicitly investigated this issue. In this study, we sequenced 54 individual low-coverage (~5X) grouse genomes to characterize population structure and assess migration rates across the landscape to identify potential barriers to gene flow. Surprisingly, we identified two genomic clusters with no clear geographic correlation, with large blocks of genomic differentiation associated with chromosomes 4 and 20, likely due to chromosomal inversions. After excluding these putative inversions from the data set, we found weak but non-significant signals of population subdivision. Estimated gene flow revealed reduced rates of migration in areas with extensive habitat fragmentation, while areas with more habitat continuity showed higher rates of genetic connectivity. Our findings provide a benchmark for wildlife managers to compare and scale the genetic diversity and structure of ruffed grouse populations in Pennsylvania and across the eastern USA, as well as reveal unexpected structural variation in the grouse genome that requires further study to understand its possible effects on individual fitness and population distribution.

Organic photovoltaics (OPV) has attracted tremendous attention as a promising alternative to silicon wafer-based technologies for building integration. While significant progress has been achieved on the power conversion efficiency of OPV technologies, their field stability is rarely studied. This work investigates the field performance and reliability of a large-area OPV module designed for BIPV application in the tropical region of Singapore for 4.5 years. The device suffered more than 14% degradation in power at the standard testing conditions from the initial performance, largely due to losses in fill factor (-12% relative). During the monitoring period, it exhibited comparable performance to more conventional silicon PV technologies, with an average specific energy yield of about 4 kWh/kWp/day and an average performance ratio of 0.96. Excellent performance at low light conditions was also observed. However, its field performance was heavily impacted by soiling, which typically led to a 5 to 10% loss in the current output after several months. Further, the device’s outdoor performance also showed a three-stage degradation process, including (1) an initial slow degradation in the first two years (about -1%/year), (2) a stable period with negligible performance loss from year 2 to year 3.5 and (3) a rapid degradation in the last year (about -5%/year).

Control of plant virus diseases largely depends on the induced plant defense achieved by the external application of synthetic chemical inducers with the ability to modify defense-signaling pathways. However, most of the molecular mechanisms underlying these chemical inducers remain unknown. Here, we developed a lentinan-loaded hydrogel with a core-shell structure and discovered how it protects plants from different virus infections. The hydrogel was synthesized by adding a chitosan shell on the surface of the polyanion sodium alginate-Ca 2+-lentinan (LNT) hydrogel (SL-gel) to form a CSL-gel. CSL-gels exhibit the capacity to prolong the stable release of lentinan and promote Ca 2+ release. Application of CSL-gels on the root of plants induces broad-spectrum resistance against TMV, TRV, PVX and TuMV). RNA-seq analysis identified that the calmodulin-like protein 19 gene ( NbCML19) is upregulated by the sustained release of Ca 2+ from the CSL-gel, and silencing and overexpression of NbCML19 alter the susceptibility and resistance of tobacco to TMV. Our findings provide evidence that this novel and synthetic CSL-gel strongly inhibits the infection of plant viruses by the sustainable release of LNT and Ca 2+. This study uncovers a novel mode of action by which CSL-gels trigger NbCML19 expression through the stable and sustained release of Ca 2+.

Objective: Globally, early and optimal feeding practices and strategies for small and vulnerable infants are limited. We aim to share the challenges faced and implementation lessons learned from a complex, mixed methods research study on infant feeding. Design: A formative, multisite, observational cohort study using convergent parallel, mixed-methods design. Setting: 12 tertiary/secondary, public/private hospitals in India, Malawi, and Tanzania Population or Sample: Moderately low birthweight infants (MLBW; 1.50-2.49kg) Methods: We assessed infant feeding and care practices through: 1) assessment of in-facility documentation of 603 MLBW patient charts; 2) intensive observation of 148 MLBW infants during facility admission; and 3) prospective one-year follow-up of 1114 MLBW infants. Focus group discussions and in-depth interviews gathered perspectives on infant feeding among clinicians, families, and key stakeholders. Results: Hospital-level guidelines and provision of care for MLBW infants varied across and within countries. 89% of charts had missing data on time to first feed; 56% lacked discharge weights. Among 148 infants observed in-facility, 18.5% were discharged prior to meeting stated weight goals. Despite challenges during COVID, 90% of the prospective cohort was followed until 12 months of age. Conclusions: Enrolment and follow-up of this vulnerable population required additional effort from researchers and the community. Using a mixed-methods exploratory study allowed for a comprehensive understanding of MLBW health and evidence-based planning of targeted large-scale interventions. Multi-site partnerships in global health research, which require active and equal engagement, are instrumental in avoiding duplication and building a stronger, generalizable evidence base.

Background: The findings of individual epidemiological studies that suggest an association between some Persistent Organic Pollutants (POPs) and Gestational Diabetes Mellitus (GDM) are inconclusive. Objectives: To estimate the strength of the association between POPs exposure and GDM in a systematic review with meta-analysis. Search strategy: MEDLINE, Scopus, and Web of Science were searched until 2022. Selection criteria: Cohort and case-control studies analyzing the association between POPs and GDM in healthy pregnant women. Data collection and analysis: Quality was assessed using QUIPS scale and standardized mean differences (SMD) and 95% confidence intervals (CI) was pooled using random-effect model. Main results: Fourteen articles including 11,422 participants were selected. The risk of bias of included studies was high in 4 (28.6%), moderate in 9 (64.3%) and low in 1 (7.14%). Only six POPs showed a significative SMD between GDM cases and controls: Perfluorobutanesulfonic acid (PFBS) 0.33 (95% CI 0.23, 0.43; I2=0%); Perfluorodecanoic acid (PFDA) -0.11 (95% CI -0.20, -0.01, I2 = 0.0%); 2,2’,3,4,4’,5,5’-Heptachlorobiphenyl (PCB 180) 0.37 (95% CI 0.19, 0.56; I2=25.3%); 2,2’,4,4’,5-Decabromodiphenyl ether (BDE 99) 0.36 (95% CI 0.14, 0.59; I2=0%); 2,2’,4,4’,6-Decabromodiphenyl ether (BDE 100) 0.42 (95% CI 0.19, 0.38; I2=0%); and, Hexachlorobenzene (HCB) 0.22 (95% CI 0.01, 0.42, I2=39.6%). For other POPs, no statistically significant association was observed. Conclusion: The available evidence is variable on quality and results were heterogeneous making impossible to establish a clear association between POPs exposure and risk of GDM. Improve the methodology of epidemiological studies assessing the association of POPs and risk of adverse clinical outcomes are needed.

Acute Necrotizing Encephalopathy of Childhood from Eastern AfricaHilary Chipongo1, Shaffin Rajan1, Abizer Sarkar 2 Ronald Mclarty 3, Esmail Sangey1

Title of Case-A rare case of left sided obturator hernia diagnosed by Computed TomographyAuthors- Manisha Aryal, Suraj Keshari, Archana Pandey, Abhishek Pandey, Ishwor PaudelKeywords- Obturator hernia, Case report, Richter’s hernia, Obstructed hernia, Computed Tomography

Aim: This study evaluated the effects of SHR0302 on the pharmacokinetics of cytochrome P450 (CYP) probe substrates. Methods: We performed a single-center, open-label, three-period drug-drug interaction (DDI) study in 24 healthy subjects (NCT05392127). Subjects received a single oral dose of 5 mg warfarin (CYP2C9), 20 mg omeprazole (CYP2C19), and 15 mg midazolam (CYP3A4) on day 1, 8, and 22, and received 0.5 mg repaglinide (CYP2C8) on day 7, 14, and 28. Multiple oral doses of 8 mg SHR0302 were administered once daily from day 8 to day 28. Results: The exposure of S-warfarin and repaglinide were comparable before and after SHR0302 administration. AUC of midazolam was not affected by SHR0302, whereas the administration of SHR0302 slightly decreased the Cmax of midazolam by 7.6% (single dose) and 15.7% (once daily for 14 days). The AUC0-t, AUC0-inf, and Cmax of omeprazole were slightly decreased after a single dose of SHR0302 by 19.2%, 21.8%, and 23.5%, respectively. In the presence of SHR0302 for 14 days, the AUC0-t, AUC0-inf, and Cmax of omeprazole were marginally reduced by 3.0%, 16.4%, and 8.3%, respectively. According to the induction mechanism of the CYP enzyme, for the investigation of the induction effect, the results of multiple administration of the perpetrator were more reliable than those of the single dose. Conclusion: The results demonstrated that co-administration of SHR0302 is unlikely to have a clinically meaningful effect on the exposure of drugs metabolized by CYP3A4, CYP2C8, CYP2C9, and CYP2C19 in healthy subjects.

IntroductionTumoral calcinosis (TC) is a rare clinicopathological entity characterized by the presence of calcified deposits in periarticular soft tissue. The calcified deposits predominantly comprise of calcium hydroxy apatite crystals and amorphous calcium phosphate1. Clinically, they appear as a painless slowly growing mass in the vicinity of large joints such as hips, shoulder, and elbow 2, 3. However, it has also been reported in other areas such as the neck, arms, hands, spine, legs, and feet 3. The progressive growth of the mass may result in pain, nerve compression, and functional impairment4. The overlying skin is usually intact; however, long-standing lesions may lead to skin ulceration and sinus tract formation with chalk white drainage 2.The diagnosis of TC is based on clinical and imaging findings. It has a characteristic radiographic appearance of multilobulated calcification in periarticular soft tissues, commonly on the extensor side of the articulation. Radiolucent lines separate the lobules (fibrous septa)5, 6. Ultrasound can be used to examine lesions, especially with minimal calcification, appearing as heterogeneous multiloculated mass with multiple cavities separated by hyperechoic thin septa. Color doppler may detect blood flow in some of these septa. MRI is superior to CT scan in detecting the extent of the lesions and their relationship with surrounding structures 6. However, histopathological examination is required for definitive diagnosis. Treatment options include both medical and surgical intervention5, 7.We present a case of tumoral calcinosis with peculiar presentation. A case of 4-year-old female with tumoral calcinosis of the extensor indicis proprius tendon on the right wrist.

Title : Cutaneous presentation of Candida krusei fungemia refractory to amphotericin BAuthors : Michelle Toker, BS1, Carson Kirkpatrick, MD1, Pooja Srivastava, MD1,2, Bijal Amin, MD1,2, Benedict Wu, DO, PhD1Affiliations :1- Division of Dermatology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA2- Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USACorresponding author :Michelle Toker, BSAlbert Einstein College of Medicine, Montefiore Medical Center1300 Morris Park Avenue, Bronx, New York, 10461Email: [email protected]: 516-946-4726Funding and support : NoneConflicts of Interest : NoneManuscript word count : 599Reference count : 5Figure count : 2Table count : 0Key words : disseminated fungemia, candida, oncology, leukemia, cutaneous fungal infection, rash, pathology, infectious disease

The parasite Plasmodium falciparum causes the most severe form of malaria and to invade and replicate in red blood cells (RBCs), it exports hundreds of proteins across the encasing parasitophorous vacuole membrane (PVM) into this host cell. The exported proteins help modify the RBC to support rapid parasite growth and avoidance of the human immune system. Most exported proteins possess a conserved Plasmodium Export Element (PEXEL) motif with the consensus RxLxE/D/Q amino acid sequence, which acts as a proteolytic cleavage recognition site within the parasite’s endoplasmic reticulum (ER). Cleavage occurs after the P 1 L residue and is thought to help release the protein from the ER so it can be putatively escorted by the HSP101 chaperone to the parasitophorous vacuole space surrounding the intraerythrocytic parasite. HSP101 and its cargo are then thought to assemble with the rest of a Plasmodium Translocon for Exported proteins (PTEX) complex, that then recognises the xE/D/Q capped N terminus of the exported protein and translocates it across the vacuole membrane into the RBC compartment. Here, we present evidence that supports a dual role for the PEXEL’s conserved P 2’ position E/Q/D residue, firstly, for plasmepsin V cleavage in the ER, and secondly, for efficient PTEX mediated export across the PVM into the RBC. We also present evidence that the downstream ‘spacer’ region separating the PEXEL motif from the folded functional region of the exported protein controls cargo interaction with PTEX as well. The spacer must be of a sufficient length and permissive amino acid composition to engage the HSP101 unfoldase component of PTEX to be efficiently translocated into the RBC compartment.

While the estimate of hospital costs concerns the past, its planning focus on the future. However, many public hospitals in low and middle-income countries don’t have robust accounting health systems to evaluate and project their expenses. In Brazil, public hospitals are funded based on government estimates of available hospital infrastructure, historical expenditures and population needs. However, these pieces of information are not always readily available for all hospitals. To solve this challenge, we propose a flexible simulation-based optimisation algorithm that integrates this dual task: estimating and planning hospital costs. The method was applied to a network of 17 public hospitals in Brazil to produce the estimates. Setting the model parameters for population needs and future hospital infrastructure can be used as a cost-projection tool for divestment, maintenance, or investment. Results show that the method can aid health managers in hospitals’ global budgeting and policymakers in improving fairness in hospitals’ financing.

ChatGPT: First Glance from a Perspective of Clinical PharmacologyAuthors: Julie Rudbech Krumborg1,2, Nicolaj Mikkelsen1,2, Per Damkier1,2, Zandra Nymand Ennis1,2, Daniel Pilsgaard Henriksen1,2, Mads Lillevang-Johansen1,2, Sidsel Arnspang Pedersen1,2, Troels K Bergmann1,31. Department of Clinical Pharmacology, Odense University Hospital, Denmark2. Department of Clinical Research, Faculty of Health Science, University of Southern Denmark, Denmark3. Department of Regional Health Research, University of Southern Denmark, Esbjerg, DenmarkCorresponding author: Julie Rudbech Krumborg: [email protected] : Artificial intelligence, Clinical Pharmacology, Drug Information Services, evidence-based medicine, Medical WritingConflict of interest statement: The authors state no conflicts of interest

Objectives: Circulating nucleocapsid (NCP) antigen of SARS-CoV-2 is increased in severely ill COVID-19 patients. However, clinical deterioration of COVID-19 often happens about one week after benign initial presentation. The role of NCP antigenemia as a biomarker in those cases remains unclear. We investigated NCP clearance kinetics in hospitalized patients as a risk assessment tool for predicting necessity of intensive care treatment of COVID-19 patients. Methods: Serum NCP was quantified using a commercial NCP-specific ELISA in hospitalized COVID-19 patients (n=63) during their hospital stay. Results were correlated to COVID-19 disease severity, inflammation parameters, antibody response and results of SARS-CoV-2 PCR from nasopharyngeal swabs.   Results: We demonstrate that NCP antigen levels in serum remained elevated in 45.6% of patients requiring treatment on intensive care units (ICU) after >8 days post positive SARS-CoV-2 PCR, compared to complete clearance in all non-ICU patients. This was in contrast to mucosal clearance of virus as measured by PCR. Antigen clearance was associated with higher IgG against S1 but not NCP.   Conclusions: Detection of NCP antigenemia after 8 days post COVID-19 diagnosis identifies patients who will require intensive care. Lack of NCP clearance after one week can thus help to assess the risk to develop severe COVID-19.

Benign penile nodules in infants can cause distress to mothers and diagnostic challenges for physicians. Smegma pearls, characterized by desquamated epithelial cells, are a common type of benign nodule that can be managed with reassurance. We present similar case which presented to the rural primary care centre in Nepal.