bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating Caregiver Management of Asthma Exacerbations at Home
Authors: Yeung T , Amirav I
Published: September 2022

BACKGROUND: Effective management of asthma in the home setting requires asthma education from a health professional along with written plans for asthma exacerbations. These approaches can result in fewer acute asthma visits, fewer missed school days and better asthma control. Nevertheless, a large number of asthma exacerbations result in emergency department visits or hospital admission. Several studies suggest that care-givers may lack the knowledge, the skills, or the confidence to provide care for their child during an asthma exacerbation.

OBJECTIVES: The objective of this study was to determine the proportion of caregivers who appropriately manage their child’s acute asthma at home (as per the 2014 Global Initiative for Asthma guidelines) and to identify factors that may be associated with deviations from these guidelines.

DESIGN/METHODS: We studied caregivers of children who are known to suffer from asthma using a paper based questionnaire in a single-center outpatient asthma clinic. Caregivers of children aged 3 to 17 years with a physician made diagnosis of asthma greater than 6 months in duration were included. To avoid a diagnosis of bronchiolitis from our study group, new consultations for wheezing or cough without a prior diagnosis of asthma, and less than 3 years of age were excluded. For statistical analysis, we used Excel and STATA 11 for the z test of proportions and comparison of means with a one way ANOVA (a = 0.05).

RESULTS: Among the 45 caregivers surveyed, most had children with well controlled asthma based on low scores from a standard asthma control test and a limited number of emergency room visits (1.5±0.1 per year). Sixty-four percent of caregivers were able to correctly identify the initial treatment with 2 puffs of Ventolin; however, 54% did not choose repeating Ventolin treatment within 20 minutes for ongoing symptoms. Moreover, only 58% of caregivers had ever been given a written asthma action plan. Caregivers had a higher degree of confidence (reported on a scale of 1-10) in initiating management (8.9±1.5) compared with stopping treatment (7.3±2.5).

CONCLUSION: Despite a high degree of confidence in starting treatment for asthma attacks, half of the caregivers surveyed identified inappropriate steps to manage asthma exacerbations at home. Providing a written asthma action plan may improve caregiver confidence and knowledge in asthma exacerbation management. However, routine assessment and review by a healthcare professional is essential in reinforcing recommended behaviours for home asthma management.
Inner-City Fathers of Children Affected by Chronic Illness: A Systematic Scoping Review of Their Experiences
Authors: Kobylianskii A , Jegathesan T , Young E , Fung K , Huber J , Minhas R
Published: September 2022

BACKGROUND: Childhood chronic illness often impacts not just the child but the whole family, particularly the parents. Parents from inner-city backgrounds (defined as low income/socioeconomic status, unemployed, immigrant, refugee, or ethnic minority, and living in an urban area) face additional challenges. Research has traditionally centred on the mother’s role in caring for a child with a chronic illness, but with the increasing role of fathers caring for these children, research has shifted its focus on paternal experience. However, the experiences of inner-city fathers remain largely unknown.

OBJECTIVES: This systematic scoping review aims to explore the experiences of fathers of children with disabilities or chronic health conditions from inner city families, using the Double ABCX model as a conceptual framework.

DESIGN/METHODS: A systematic scoping review was conducted between November 2014 and January 2015 using the Arksey and O'Malley framework. Seven databases were searched (Medline, PsycInfo, Embase, Web of Science, CINAHL, Scopus, and Social Work Abstracts). Titles and abstracts meeting inclusion and exclusion criteria were included in the full text review for further assessment. Qualifying articles were critically appraised and relevant data were extracted. The Double ABCX model was used to qualitatively evaluate the articles in terms of stressors, resources, perception, coping, and adaptation.

RESULTS: 5114 articles were initially identified and 14 articles met the inclusion criteria. Most of the included studies were conducted in the USA. Most articles discussed fathers from low income/SES backgrounds, while others discussed ethnic minority, immigrant/refugee, and unemployed fathers. Fathers' stressors included financial strain and barriers to accessing healthcare. Fathers' resources, or sources of support, ranged from immediate to extended family members, depending on ethnicity. In terms of perceptions, fathers had different approaches to reconciling the care-giver role with cultural gender norms. Inner-city fathers had more desire for information about their children’s health, but some were uncomfortable with asking physicians. Inner-city fathers were more at risk for coping difficulties and used different coping strategies compared to higher income fathers. Inner-city fathers were at higher risk for maladaptation, including depression, PTSD and less acceptance of the child.

CONCLUSION: Fathers from inner-city backgrounds caring for their children affected by chronic illnesses and disabilities have unique experiences requiring a comprehensive approach to providing and communicating care to these children and caregivers. Findings from this review can be used to guide pediatricians in advocating for resources to reduce stressors, enhance coping, and promote positive adaptation for inner-city fathers.
Use of Mobile Technology in the Care of Adolescents With Diabetes
Authors: Ranawaya J , Saleh D , Gregroire K , Ruhland L
Published: September 2022

BACKGROUND: The advent of personalised cell phones and mobile technology has created an increasing desire to integrate these resources into the care of pediatric patients with diabetes. Adolescents in particular often have poor diabetes self-management practises and fail to meet glyce-mic targets. Mobile technology use is prevalent among adolescents and the idea of using this technology to assist with diabetes self-care is appealing. However, integrating this technology into clinical practice is challenging and many practitioners do notknow where to start.

OBJECTIVES: To describe the use, benefits, and limitations of mobile technology in diabetes care among adolescents and their parents, and to assess if mobile technology use is linked to lower HbA1c levels.

DESIGN/METHODS: This cross sectional study involved adolescents age 11-18 years and their parents who were recruited during their regular diabetes patient care visits at two separate pediatric diabetes centres. Patients and parents completed a questionnaire designed by study authors. Patients' two most recent HbA1c levels were recorded following survey completion.

RESULTS: 100 adolescents and 80 parents completed the questionnaire. Device ownership was high, with 89% of adolescents and 100% of parents owning at least 1 device. Only one third of the cohort reported using mobile technology for their diabetes care. The commonest reason for non-use was lack of awareness of apps for diabetes care (53% adolescents, 60% parents). Among mobile technology users, texting and calculation were the most frequently used apps. Apps for calorie and carb counting were also frequently used, among which CalorieKing™ was the highest reported (44% adolescents; 47% parents). Insulin pump specific programs including Diasend® and Medtronic CareLink® were reported by 14.8% adolescents and 14.3% parents. The average HbA1c for the entire cohort was 8.0%, with no statistically significant difference between adolescent mobile technology users and non-users (7.8% vs 8.3%; p=0.22). However, mean HbA1c was found to be lower among those adolescents whose parents used mobile technology for their management (7.6 % vs 8.2 %; p=0.04).

CONCLUSION: Only a minority of adolescents use mobile technology for their diabetes care, and lack of awareness was the major barrier to mobile technology use. Basic smartphone functions including texting and calculation were the most cited apps used. Parental technology use was associated with improved glycemic control. Considering the widespread use of mobile technology among young people, there remains untapped potential for greater use of this technology towards improved self-care in adolescents with diabetes.
Improving Diagnostic Efficiency in Children Aged 12-39 Months Referred for Autism Spectrum Disorder (ASD)
Authors: Lemay JF , Langenberger S , Amin P
Published: September 2022

BACKGROUND: Early diagnosis and intervention for ASD is important. The increasing prevalence of ASD in Canada is challenging teams performing ASD diagnostic evaluations to keep pace with demand. In October 2013, the ASD clinic at our Pediatric Tertiary Care Centre (PTCC) faced a waitlist of more than twelve months for children under 39 months of age; it became necessary to engage in a quality improvement with the aim of looking for efficiencies with a focus of reducing our waitlist.

OBJECTIVES: To present a) two years of experience (Jan. 2014-Dec. 2015) using our diagnostic assessment model for evaluation of children aged 12-39 months referred for ASD evaluation to PTCC, and b) psychometric performance of RITA-T (Rapid Interactive Test for Autism in Toddlers-developed by Choueiri/Wagner – Boston).

DESIGN/METHODS: This quality improvement project incorporated evidence-based practice with process improvement methodology. Our team utilized a Plan-Do-Study-Act (PDSA) approach in the development of a ‘new’ ASD standardized diagnostic process. Our new model included: a) an initial mandatory parent education session followed one week later by b) a child visit using the face-to-face ‘level 2 screening tool’ (RITA-T) + completion of M-CHAT (questionnaire) followed in 7-10 days by c) an ASD diagnostic evaluation appointment, and finally 5-7 days after evaluation d) an “After ASD Diagnosis” parent group session.

RESULTS: We assessed a total of 173 patients (81% male, mean age 30.74±5.53 mo., interval 15.4-39.0 mo.). The diagnostic process was completed within a max 30-day cycle (previously a period >4 months) and required less hours/child (12 vs. 20 hours – overall 40% net gain or 1384 hours). Waitlist was reduced to <1 month (compared to >12 mo. in Oct. 2013). A total of 143 children (82.7% of total cohort; 116 male/27 female) were diagnosed with ASD. The discriminative properties of RITA-T were calculated: Sensitivity: 0.99; Specificity 0.53; Positive Predictive Value 0.91; Negative Predictive Value: 0.94.

CONCLUSION: By following a combination of quality improvement methodology with evidence-based practice, we successfully reduced wait and cycle times at our PTCC for children aged 12-39 months referred for ASD diagnostic assessment. RITA-T showed very good discriminative properties and was instrumental in the overall process improvement. This sustainable diagnostic approach promoted practice innovation. Consequently, patients are now able to access critical community supports and resources in a timely manner.
Better Beginnings: At Risk Moms; What Are We Missing?
Authors: Lamond A , Drover A
Published: September 2022

BACKGROUND: Since 2005, the number of infants born to mothers using substances has increased 4-fold in an eastern Canadian province. These babies may be at risk of medical problems including a withdrawal syndrome called “neonatal abstinence syndrome”. Previous research has shown that mothers using substances may experience increased rates of domestic violence, mental illness and housing and food insecurity. Currently, these determinants of health are not routinely recorded on medical charts of pregnant women who are patients at the province’s largest maternity facility.

OBJECTIVES: The primary goal of this study is to determine the prevalence of smoking, alcohol use, substance use, domestic violence and food/ housing insecurity in mothers delivering in an eastern Canadian province maternity hospital.

DESIGN/METHODS: This is a quantitative study involving all postpar-tum women delivering at the major delivery facility in province over a two month period (N=150). Participants were asked to complete an online, anonymous survey about their food/housing situation, domestic violence and substance use before and during pregnancy, as well as sociodemo-graphic questions.

RESULTS: Food and Housing Insecurity: The results of the study showed increased healthy eating behaviours during pregnancy; however the number of participants reliant on food banks remained at 4%. Our study found that while the majority of participants lived in a permanent residence, 2% of mothers used shelters or lived in a non-permanent residence. Mental health and Domestic Violence: While the majority of mother felt respected by their partner, family and friends, a significant amount reported feelings of isolation during pregnancy (12%). Women experiencing domestic violence stayed consistent before and during pregnancy at 2%. Smoking: Cigarette use in this population was slightly decreased from previous reports by the provincial perinatal program (12% vs. 14.9% reported) with rates of exposure to cigarette smoke much higher (24.7% vs. 6.4% reported). Alcohol use: Maternal reporting alcohol use during pregnancy was substantially increased from previous reports (13.3% vs. 0.9% reported). Those who reported consuming alcohol most frequently reported 1-2 drinks about 1-3 times per month. Substance Use: Currently, no reports within the province have captured the number of mothers using substances. This study shows approximately 5% of mothers using either marijuana, street/illicit drugs or methadone. Limitations: Mothers who did not speak English were excluded from the study.

CONCLUSION: The findings of this research indicate that important determinants of health are not being adequately recorded in Provincial databases thus programs are lacking.
Gender and Educational Inequalities in Extending Working Lives: Late-Life Employment Trajectories Across Three Decades in Seven Countries
Authors: Turek Konrad , Henkens Kene , Kalmijn Matthijs
Published: September 2022

Public policies encourage later retirement, but they often do not account for discrepancies in the capacity for extending working lives. This paper studies trends and inequalities in extending working lives between 1990 and 2019 from gender and education perspectives in seven countries (Australia, Germany, Russia, South Korea, Switzerland, United Kingdom, and United States). The three-decade-long data provide insights into the societal transition toward extended employment that began in the mid-1990s. Using latent class growth analysis, we identify five universal trajectories representing late-life employment in all countries: Early, Standard and Late Exit patterns, and stable Nonemployment and Late Employment patterns. Regression analyses show that Non-Employment dominated the 1990s, but it significantly declined, giving space to Late Employment as one of the major employment pathways. Gender and educational differences are considerable and stable and constitute important stratification markers of late careers. Progress toward later employment affects all analyzed countries but in different ways, suggesting the simple generalizations of one-country findings can be risky. We discuss the risks of universal progress toward extending employment that can bring unequal results and negative consequences for vulnerable groups. This study also contributes methodologically by exploring the trajectory-oriented perspective on late careers.
Reverse Flow Shunt Restricted Free Venous Flap for a Ring Avulsion Injury
Authors: Yassin Ahmed M. , Kokkinos Constantinos , Gorman Mark , Gnanalingham Sathyan , Nikkhah Dariush
Published: September 2022

Arterialized venous flaps can be an excellent option for reconstruction of digital defects. Previously, they remained unpopular owing to the high rate of venous congestion. Different techniques of restriction of the arteriovenous shunting have been described to mitigate this problem. In this article, the authors discuss a unique case whereby a reverse flow shunt restricted venous flap was used in an Urbaniak type III ring avulsion.
Using the Autospreaders as a Cutting Guide for Component Hump Reduction in Rhinoplasty
Authors: Al Jassim Abrar , Moubayed Sami P.
Published: September 2022

Dorsal preservation techniques as a means of addressing the dorsal hump have been popularized recently to avoid midvault disruption or dorsal resection. The pitfall of these techniques is the higher rate of dorsal hump recurrence of up to 15%. We present the use of the upper lateral cartilages (ULCs) as a turn-in flap and as a cutting guide during classic dorsal hump takedown. The cutting guide provides the perfect dorsal angulation and dictates the amount of resection needed. This translates to aesthetically pleasing dorsal lines, avoidance of dorsal irregularities, and decreased risk of hump recurrence.
Examining 5-Year Cervical Cytology Progression Among Minority Women Living With HIV and Baseline Negative Cytology
Authors: Sanchez-Covarrubias Alex P. , Crane Joshua , Montgomerie Emily K. , Potter JoNell E. , Duthely Lunthita M. , Bahadue Felicia , Jeudin Patricia P.
Published: September 2022

Objective

Women living with HIV (WLWH) have increased risk of human papillomavirus (HPV) infection, precancers, and invasive cervical cancers. This study aims to determine the rate of cervical cytologic progression and related factors in minority WLWH across 5 years.

Materials and Methods

We used our HIV clinic database, complemented with a retrospective chart review to identify WLWH with a baseline negative cervical cytology between 2009 and 2012 and 5-year follow-up. Data included race/ethnicity, age, years living with HIV, AIDS status, viral load, history of smoking, drug use, and HPV status. Multivariate logistic regression tested progression of negative cytology to low-grade/high-grade squamous intraepithelial lesions (LGSIL/HGSIL).

Results

Among 162 WLWH, 42% were African American, 30% non-Hispanic African Caribbean, and 26% Hispanic. At baseline, 21% had detectable viral load (>200 cp/mL), mean age was 44.8 (±11 years), and mean years living with HIV was 9.6 (±6.9). After 5 years, 19% of the cohort progressed to LGSIL/HGSIL. Human papillomavirus was detected consistently among women with cytologic changes (30% vs 7%, p < .01). Significant factors that predicted higher likelihood of progression to LGSIL/HGSIL were detection of HPV (adjusted odds ratios = 5.11 [1.31–19.93]; p = .02), and Centers for Disease Control and Prevention–defined AIDS status (adjusted odds ratios = 4.28 [1.04–17.63]; p = .04). Of the women who maintained negative cytology at 1 to 2 years (n = 102), 5 women (5%) progressed during the following 3 years before the recommended follow-up.

Conclusions

Human papillomavirus detection and AIDS status were significant factors predicting progression to LGSIL/HGSIL among minority WLWH. Providers screening WLWH for cervical intraepithelial neoplasia should carefully decide screening intervals for minority populations.
Tree nut allergy: a systematic review
Authors: Chu Derek K.
Published: September 2022

Purpose of review

Systematic scoping review, focusing on randomized clinical trials of recent research addressing tree nut allergy.

Recent findings

This review addresses published, unpublished, and re-analyzed studies on tree nut allergy definition, epidemiology, etiology, diagnosis, prognosis, and therapy.

The importance of tree nut allergy spans nations, economies, and cultures. While broad themes in epidemiology, etiology, diagnosis, prognosis, and therapy are emerging, the next major advance in tree nut allergy will require large, robust studies to deliver results important to patients and families.
Correlation of Anti-Tissue Transglutaminase Antibodies With the Mucosal Changes and IgA Status of Children With Celiac Disease
Authors: Donat Ester , Roca María , Castillejo Gemma , Sánchez-Valverde Félix , García-Burriel Jose Ignacio , Martínez-Ojinaga Eva , Eizaguirre Francisco Javier , Barrio Josefa , Cilleruelo Mª Luz , Pérez-Solís David , Ochoa-Sangrador Carlos , Vecino-López Raquel , Miranda-Cid Mª del Carmen , García-Calatayud Salvador , Torres-Peral Ricardo , Juste Mercedes , Armas Honorio , Barros-García Patricia , Leis Rosaura , Solaguren Rosa , Salazar José Carlos , García-Romero Ruth , Ortigosa Luis , Peña-Quintana Luis , Urruzuno Pedro , Codoñer-Franch Pilar , Garcia-Casales Zuriñe , Masiques Maria Llüisa , Galicia-Poblet Gonzalo , Crehuá-Gaudiza Elena , Balmaseda Elena , Rubio-Santiago Javier , Polanco-Allué Isabel , Román-Riechmann Enriqueta , Ribes-Koninckx Carmen ,   Coeliac Disease Working Group of the Spanish Gastroenterology, Hepatology, Paediatric Nutrition Society (SEGHNP)
Published: September 2022

Objectives:

The objective of this study was to assess the association between serological markers and changes of the intestinal mucosa in children with celiac disease (CD).

Methods:

Clinical data from CD patients under 15 years old were collected from the participating centers in an on-line multicenter nationwide observational Spanish registry called REPAC-2 (2011–2017). Correlation between anti-tissue transglutaminase antibodies (t-TGA) levels and other variables, including mucosal damage and clinical findings (symptoms, age, and gender), was assessed.

Results:

A total of 2955 of 4838 patients had t-TGA and a small bowel biopsy (SBB) performed for CD diagnosis. A total of 1931 (66.2%) patients with normal IgA values had a Marsh 3b-c lesion and 1892 (64.9%) had t-TGA Immunoglobulin A (IgA) ≥ 10 times upper limit of normal (ULN). There is a statistically significant association between t-TGA IgA levels and the degree of mucosal damage (P < 0.001), the higher the t-TGA IgA levels the more severe the mucosal damage. Those patients who reported symptoms had more severe mucosal damage (P = 0.001). On the contrary, there was a negative association between age and changes of the intestinal mucosa (P < 0.001). No association was found with gender. Regarding the IgA-deficient patients, 47.4% (18 cases) had t-TGA Immunoglobulin A (IgA) ≥ 10 times ULN and a Marsh 3b-c lesion was observed in 68.4% (26 patients). No statistical relation was found between t-TGA IgG levels and the changes of the intestinal mucosa, neither a relation with age, gender, or symptoms.

Conclusions:

There is a positive correlation between t-TGA IgA levels and the severity of changes of the intestinal mucosa. Such correlation was not found in IgA-deficient patients who had positive t-TGA IgG serology. The results in this group of patients support the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition recommendations about the need of performing a SBB in IgA-deficient individuals despite high t-TGA IgG levels.
The construction of neurogenesis-related ceRNA network of ischemic stroke treated by oxymatrine
Authors: Zhang Xiaoling , Yao Wentao , Zhao Wannian , Sun Yingru , Wu Zongkai , He Weiliang , Ji Yingxiao , Gao Yaran , Niu Xiaoli , Li Litao , Wang Hebo
Published: September 2022

Background

Known as a disease associated with high mortality, disability and a significant financial burden, ischemic stroke ranks as one of the three diseases threatening human health. Recent advances in omics technology created opportunities to uncover the mechanism in ischemic stroke occurrence and treatment. In this study, we aimed to construct the competitive endogenous RNA (ceRNA) networks of ischemic stroke treated by oxymatrine intervention.

Method

The middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke was constructed, and oxymatrine was administered. Then RNA-Sequencing was performed and integrated analysis of mRNAs, lncRNAs and circRNAs was conducted to reveal the pharmacology of oxymatrine. Functional enrichment analysis was performed to explore the underlying mechanism of differentially expressed (DE) mRNAs. The protein-protein interaction (PPI) network of neurogenesis-related genes and long noncoding RNAs (lncRNAs)/circular RNAs (circRNAs) based ceRNA networks were constructed.

Results

First, this study revealed the DE-mRNAs, DE-lncRNAs and DE-circRNAs between Oxymatrine treated group and the MCAO group. Then, the common 1231 DE-mRNAs, 32 DE-lncRNAs and 31 DE-circRNAs with opposite trends were identified. The Kyoto Encyclopedia of Genes and Genomes to identify the functional enrichment of 1231 DE-mRNAs were enriched in neurogenesis-related biological processes. Based on neurogenesis-related DE-mRNAs, the PPI network was constructed, and hub genes were identified based on centrality. Finally, both the lncRNA-based and circRNAs-based ceRNA networks were constructed.

Conclusion

In summary, this study identified novel coding and noncoding ischemic stroke targets of oxymatrine-treated MCAO. Most importantly, we identified lncRNAs and circRNAs candidates as potential oxymatrine targets and constructed the neurogenesis-related ceRNA networks.
A neural basis of rational inattention models: consistency of cognitive cost with the mutual information criterion
Authors: Wu Qi , Nakazato Shinji , Yang Bojian , Shimokawa Tetsuya
Published: September 2022

The rational inattention model has recently attracted much attention as a promising candidate to model bounded rationality in the research field of decision-making and game theory. However, in contrast to this energetic promotion of the theoretical works, empirical verification of the validity of the RI model has not progressed much. Furthermore, to our knowledge, the central assumption of the RI model, that the amount of mutual information obtained from signals adequately represents the cognitive cost of information, has not been tested from a neuroscientific perspective. The purpose of the present study was to test whether the amount of mutual information adequately represents the cognitive cost of information from a neuroscientific perspective. We proposed a sequential investment task, in which the two main models of RI can be treated simultaneously in a more realistic experimental environment. We used a model-fitting approach to analyze the subjective information cost, and compared the model parameters representing the information cost with the concentration of oxidized hemoglobin in the brain blood. Our results showed that the cost parameter λ of the stochastic choice type model, which fits the behavioral data of the present experiment better than the Kalman filter type model, was significantly positively correlated with the activation status of the rostral prefrontal cortex and dorsolateral prefrontal cortex. The cognitive cost represented by the amount of mutual information employed in the RI model is consistent with the activation of brain regions associated with cognitive cost, and, thus, indirectly supports the assumption of the RI model.
The Genomic Landscape of Rare Disorders in the Middle East
Authors: Naofal Maha El , Ramaswamy Sathishkumar , Alsarhan Ali , Nugud Ahmed , Taylor Alan , Jain Ruchi , Halabi Nour , Yaslam Sawsan , Alfalasi Roudha , Shenbagam Shruti , Bitzan Martin , Yavuz Lemis , Wafadari Deena , Abulhoul Hamda , Shankar Shiva , Maazmi Munira Al , Rizk Ruba , Alloub Zeinab , Elbashir Haitham , Babiker Mohamed O. E. , Chencheri Nidheesh , AlBanna Ammar , Sultan Meshal , Bitar Mohamed El , Kherani Safeena , Thalange Nandu , Alshryda Sattar , Donato Roberto Di , Tzivinikos Christos , Majid Ibrar , Freeman Alexandra F. , Gonzalez Corina , Khan Arif O. , Hamdan Hisham , Abuhammour Walid , Awadhi Mohamed Al , Khayat Abdulla Al , Alsheikh-Ali Alawi , Tayoun Ahmad N. Abou
Published: September 2022

BACKGROUND

Rare diseases collectively impose significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans.

METHODS

We established a clinical genomics and genetic counselling facility, within a multidisciplinary tertiary paediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population.

RESULTS

We present data on 529 patients with rare diseases (47% females; Average age, 4 years) representing 41 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 35.7% (95% CI, 31.8% - 39.9%) and was higher for genomic sequencing-based testing than chromosomal microarrays (41.2% versus 16.9%, P=0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 124 Mendelian disorders identified in this cohort, the majority (N = 110) were encountered only once, and those with recessive inheritance accounted for ~60% of sequencing diagnoses. Of patients with positive genetic findings (N = 189), 71.9% were less than 5 years of age, and 65.6% were offered modified management and/or intervention plans. Interestingly, 18.5% of patients with positive genetic findings received delayed diagnoses (age range 7 – 37 years), most likely due to lack of access to genomic investigations in this region. One such genetic finding ended over a 10-year long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders.

CONCLUSIONS

Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this historically underrepresented population.
Lung remodeling regions in long-term Covid-19 feature basal epithelial cell reprogramming
Authors: Wu Kangyun , Zhang Yong , Austin Stephen R. , Declue Huqing Yin , Byers Derek E. , Crouch Erika C. , Holtzman Michael J.
Published: September 2022

Respiratory viruses, including SARS-CoV-2, can trigger chronic lung disease that persists and even progresses after expected clearance of infectious virus. To gain an understanding of this process, we examined a series of consecutive fatal cases of Covid-19 that came to autopsy at 27-51 d after hospital admission. In each patient, we identify a stereotyped bronchiolar-alveolar pattern of lung remodeling with basal epithelial cell hyperplasia and mucinous differentiation. Remodeling regions also feature macrophage infiltration and apoptosis and a marked depletion of alveolar type 1 and 2 epithelial cells. This entire pattern closely resembles findings from an experimental model of post-viral lung disease that requires basal-epithelial stem cell growth, immune activation, and differentiation. The present results thereby provide evidence of possible basal epithelial cell reprogramming in long-term Covid-19 as well and thereby a pathway for explaining and correcting lung dysfunction in this type of disease.
Children’s syntax is supported by the maturation of BA44 at 4 years, but of the posterior STS at 3 years of age
Authors: Klein Cheslie C. , Berger Philipp , Goucha Tomás , Friederici Angela D. , Wiesmann Charlotte Grosse
Published: September 2022

Within the first years of life, children learn major aspects of their native language. However, the ability to process complex sentence structures, a core faculty in human language called syntax, has been found to emerge only slowly. A milestone in the acquisition of syntax is reached around the age of 4, when children learn a variety of syntactic concepts, including, for example, subordinate clauses. Here, we ask which maturational changes in the child’s brain underlie the emergence of syntactic abilities around this critical age. We relate markers of cortical brain maturation to 3- and 4-year-olds’ syntactic in contrast to other language abilities. Our results show that distinct cortical brain areas support syntax in the two age groups: While 3-year-old children’s syntactic abilities were associated with increased surface area in the most posterior part of the left superior temporal sulcus, 4-year-old children showed an association with cortical thickness in the left posterior part of Broca’s area, i.e. BA44. The present findings suggest that syntactic abilities rely on the maturation of distinct cortical regions in 3- compared to 4-year-olds. The observed shift to more mature regions involved in syntax may underlie the behavioral milestones in syntax acquisition around 4 years of age.
Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19
Authors: Schultheiß Christoph , Willscher Edith , Paschold Lisa , Gottschick Cornelia , Klee Bianca , Bosurgi Lidia , Dutzmann Jochen , Sedding Daniel , Frese Thomas , Girndt Matthias , Höll Jessica I. , Gekle Michael , Mikolajczyk Rafael , Binder Mascha
Published: September 2022

Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair quality of life. Underlying mechanisms ranging from persistent virus to innate and adaptive immune dysregulation have been discussed. Here, we profiled plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero) including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as potential biomarker for persistent viral reservoirs. At a median time of eight months after infection, we found pronounced dysregulation in almost all tested soluble factors including both pro-inflammatory and pro-fibrotic cytokines. These perturbations were remarkably independent of ongoing symptoms, but further correlation and regression analyses suggested PASC specific patterns involving CCL2/MCP-1 and IL-8 as well as long-term persistence of high IL-5 and IL-17F levels. None of the analyzed factors correlated with the detectability or levels of circulating S1 indicating that this represents an independent subset of patients with PASC. This data confirms prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrates its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes.
Efficacy of a Growth Hormone-Releasing Hormone Agonist in a Murine Model of Cardiometabolic Heart Failure with Preserved Ejection Fraction
Authors: Kanashiro-Takeuchi Rosemeire M. , Takeuchi Lauro M. , Dulce Raul A. , Kazmierczak Katarzyna , Balkan Wayne , Cai Renzhi , Sha Wei , Schally Andrew V. , Hare Joshua M.
Published: September 2022

Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need owing to its diverse pathophysiology and lack of effective therapies. Potent synthetic, agonists (MR-356 and MR409) of growth hormone-releasing hormone (GHRH) improve the phenotype of models of HF with reduced ejection fraction (HFrEF) and in cardiorenal models of HFpEF. Endogenous GHRH exhibits a broad range of regulatory influences in the cardiovascular (CV) system, aging and plays a role in several cardiometabolic conditions including obesity and diabetes. Whether agonists of GHRH can improve the phenotype of cardiometabolic HFpEF remains untested and unknown. Here we tested the hypothesis that MR-356 can mitigate/reverse the cardiometabolic HFpEF phenotype. C57BL6N mice received a high fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of HFD+L-NAME regimen, animals were randomized to receive daily injections of MR-356 or placebo during a 4-week period. Control animals received no HFD+L-NAME or agonist treatment. Our results showed the unique potential of MR-356 to treat several HFpEF-like features including cardiac hypertrophy, fibrosis, capillary rarefaction, and pulmonary congestion. MR-356 improved cardiac performance by improving diastolic function, global longitudinal strain (GLS), and exercise capacity. Importantly, the increased expression of cardiac pro-brain natriuretic peptide (pro-BNP), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) was restored to normal levels suggesting that MR-356 reduced myocardial stress associated with metabolic inflammation in HFpEF. Thus, agonists of GHRH may be an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype.
Genome-wide association study of a semicontinuous trait: Illustration of the impact of the modeling strategy through the study of Neutrophil Extracellular Traps levels
Authors: Munsch Gaëlle , Proust Carole , Labrouche-Colomer Sylvie , Aïssi Dylan , Boland Anne , Morange Pierre-Emmanuel , Roche Anne , de Chaisemartin Luc , Harroche Annie , Olaso Robert , Deleuze Jean-François , James Chloé , Emmerich Joseph , Smadja David M , Jacqmin-Gadda Hélène , Trégouët David-Alexandre
Published: September 2022

Abstract

Semicontinuous data, characterized by an excess of zeros followed by a non-negative and right-skewed distribution, are frequently observed in biomedical research. Different statistical models have been proposed to investigate the association of covariates with such outcome. Motivated by the search of genetic factors associated with Neutrophil Extracellular Traps (NETs), a semicontinuous biomarker involved in thrombosis, we here investigated the impact of the selected model for semicontinuous traits in the context of a Genome Wide Association Study (GWAS). We compared three models that jointly model zero and positive values while allowing the estimation of a single association parameter of covariates with the global mean: Tobit, Negative Binomial and Compound Poisson-Gamma. We assessed the fit of these models to a sample of 657 participants of the FARIVE study measured for NETs plasma levels. For each of these three models, we performed a GWAS on NETs in FARIVE participants and results were compared. A simulation study was also conducted to evaluate the control of the type I error. Compound Poisson-Gamma and Negative Binomial models fitted NETs data observed in FARIVE better than the Tobit model. However, the Negative Binomial model suffered from an inflation of its type I error, attributable to extreme positive values of the NETs and low frequency variants. Conversely, the Compound Poisson-Gamma model was robust to both phenomena. Using the latter model, a GWAS identified a genome wide significant locus on chr21q21.3. The lead variant was rs57502213, a deletion of two nucleotides located ∼40kb upstream the non-coding RNA (miR155HG) hosting the miR-155 that was recently highlighted to have a role in NETs formation. This work indicates that the modeling strategy for a semicontinuous outcome in the framework of GWAS studies is crucial. The choice of the model should take into account the nature of the process generating zero values and the presence of extreme values. Our work also suggests that the Compound Poisson-Gamma model, while still marginally employed, can be a robust modeling strategy for GWAS analysis on a semicontinuous trait.
Is the Sars-CoV-2 virus a possible trigger agent for the development of achalasia?
Authors: Furuzawa-Carballeda Janette , Icaza-Chávez María Eugenia , Aguilar-León Diana , Uribe-Uribe Norma , del Carmen Nuñez-Pompa María , Trigos-Díaz Alonso , Areán-Sanz Rodrigo , Fernández-Camargo Dheni A. , Enrique Coss-Adame E , Valdovinos Miguel A. , Briceño-Souza Eduardo , Chi-Cervera Luis A. , Olivares-Flores Miriam , Torres-Villalobos Gonzalo
Published: September 2022

BACKGROUND

Previous studies have suggested that achalasia is an autoimmune disease whose probable causal agent is a neurotropic virus that chronically infects the myenteric plexus of the esophagus and, in a genetically susceptible host, induces the disease. The association between achalasia and coronaviruses has not been reported in the literature.

AIMS

To evaluate the presence of the SARS-CoV-2 virus, the ACE2 expression, the tissue architecture, and immune response in the lower esophageal sphincter muscle (LESm) of achalasia patients who had SARS-CoV-2 (achalasia-COVID-19) infection before laparoscopic Heller myotomy (LHM) and compare the findings with type II achalasia patients and transplant donors (controls) without COVID-19.

METHODS

The LESm of 7 achalasia-COVID-19 patients (diagnosed by PCR), ten achalasia patients, and ten controls without COVID-19 were included. The presence of the virus was evaluated byin situ PCRand immunohistochemistry. ACE2 receptor expression and effector CD4 T cell and regulatory subsets were determined by immunohistochemistry.

RESULTS

Coronavirus was detected in 6/7 patients-COVID-19. The SARS-CoV-2 was undetectable in the LESm of the achalasia patients and controls. The ACE2 receptor was expressed in all the patients and controls. One patient developed achalasia type II post-COVID-19. The percentage of Th22/Th17/Th1/pDCreg was higher in achalasia and achalasia-COVID-19 pre-HLM vs. controls. The Th2/Treg/Breg cell percentages were higher only in achalasia vs. controls.

CONCLUSION

The presence of the SARS-CoV2 and its receptor in the LESm of type II achalasia-COVID-19 patients but not in the controls suggests that it could affect the myenteric plexus. Unlike achalasia, patients-COVID-19 have an imbalance between effector CD4 T cells and the regulatory mechanisms.
Efficacy of electroacupuncture versus transcutaneous electrical acupoints stimulation on subclinical premature ovarian insufficiency: study protocol for a randomized controlled trial
Authors: Wang Jialing , Dai Linglin , Xu Yani , Zhang Xufen , Zhang Yutong , Tang Ding , Zhan Mingjie , Wang Chao , Wang Zhanglian , Chen Lifang
Published: September 2022

Introduction

“Subclinical stage” of premature ovarian insufficiency (POI) refers to menstrual disorders with FSH levels in the range of 15-25 U/L in women under 40 years old caused by diminished ovarian function. Early intervention of subclinical POI may be able to protect ovarian function more effectively and prevent further development to POI. Currently, no standard-of-care exists for subclinical POI. Previous studies have shown effectiveness of electroacupuncture (EA) on POI and transcutaneous electrical acupoint stimulation (TEAS) on diminished ovarian reserve, but no published studies focus on the treatment of subclinical POI. This study aims to assess whether EA or TEAS will be effective in improving ovarian function at the subclinical stage of POI and preventing the progression.

Methods

114 subclinical POI patients between 25 and 40 years will be randomly assigned to three groups (an EA group, a TEAS group and a waiting for treatment group) in this randomized, controlled, assessor-blinded trial. The treatment will last for three months and the follow-up will last for twelve months. The primary outcomes will be anti-Mullerian hormone (AMH) and follicle-stimulating hormone (FSH). Secondary outcomes will include serum estradiol (E2), luteinizing hormone (LH), FSH/LH ratio, the menstrual status assessment, and modified Kupperman Menopausal Index. We will also investigate the incidence of adverse events.

Trial registration

Trial was registered in the Chinese Clinical Trail Registry (ChiCTR-2100045598); Pre-results.
Dynamic ctDNA mutational complexity in melanoma patients receiving immunotherapy
Authors: Fitzgerald Sandra , Blenkiron Cherie , Stephens Rosalie , Mathy Jon , Somers-Edgar Tiffany , Rolfe Gill , Martin Richard , Jackson Christopher , Eccles Michael , Robb Tamsin , Rodger Euan , Lawrence Ben , Guilford Parry , Lasham Annette , Print Cristin
Published: September 2022

Circulating tumour DNA (ctDNA) analysis promises to improve the care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 New Zealand (NZ) unresectable advanced-stage cutaneous melanoma patients through multiple cycles of immunotherapy, to identify the breadth and complexity of tumour genomic information that ctDNA analysis can reliably report. During the course of treatment, a high level of dynamic mutational complexity was identified in blood plasma of these patients, including: multiple BRAF mutations in the same patient, clinically-relevant BRAF mutations emerging through therapy, and co-occurring sub-clonal BRAF and NRAS mutations. The technical validity of this ctDNA analysis was supported by high sample analysis-reanalysis concordance as well as by concordance between three ctDNA measurement technologies: droplet digital polymerase chain reaction (ddPCR), a custom melanoma-specific amplicon next-generation sequencing (NGS) panel and mass spectrometry. In addition, we observed >90% concordance in the detection of ctDNA when using cell-stabilising collection tubes followed by 7-day delayed processing, compared to standard EDTA blood collection protocols with rapid processing. We also found that undetectability of ctDNA at a proportion of treatment cycles was associated with both clinical benefit (best RECIST response) and prognosis (disease-specific survival). In summary, we found that multiple ctDNA processing and analysis methods consistently identified complex longitudinal patterns of clinically-relevant mutations, adding support for expanded implementation of this technology to guide in-treatment tailored cancer therapy.
Therapeutic and Interventional Bronchoscopy Performed in Critically ill COVID-19 patients: A Systematic Review
Authors: Samadder Saikat
Published: September 2022

Background

Coronavirus disease 2019 (COVID-19) is a highly infectious disease responsible for huge number of deaths in global population. Bronchoscopy was contraindicated for acute respiratory failure in critical patients due to possible transmission of virus to healthcare provider due to aerosol generating procedure (AGP). The safety, efficacy, complication rate, deaths, and transmission rate of virus to healthcare workers due to therapeutic and interventional bronchoscopy performed on COVID-19 patients are accessed.

Methods

A systematic review of literature was performed as per PRISMA 2020 guidelines. To obtain literatures available in PubMed, MEDLINE, and Google Scholars with timeline from 1st Jan 2020 – 10th Dec 2021. Databases were searched with MeSH terms bronchoscopy and COVID-19 it fetched 7350 articles. Applying primary inclusion criteria of bronchoscopy in COVID-19 patients. Secondary inclusion criteria therapeutic and interventional bronchoscopy excluding the articles on diagnostic bronchoscopy.

Result

Total 72 clinically relevant literatures were identified and included for further review. 1887/2558 patients underwent bronchoscopy for treatment of severe or critical COVID-19 pneumonia. therapeutic bronchoscopy was performed in 1241/1887 (65.8%) patients and interventional bronchoscopy was performed in 831/1887 (44.03%) patients. Overall, complications observed in 200/1887 (10.5%) patients. Total, 579/1887 (30%) patients died as per the literatures. Total 15 HCW (8%) were found infected during the studies. It led to successful completion of procedures in 924/940 (98.3%) patients. All three types of bronchoscopes were found to be safe for the patients. The safety, efficacy, complication rate to be 97.5%, and 98.3%, and 2.5% respectively in severely SARS-CoV-2 infected patients undergoing bronchoscopy.

Conclusion

This study suggests that bronchoscopy is a safe and effective procedure to be performed in patients suffering from COVID-19 pneumonia. Proper use of personal protective equipments (PPE) during bronchoscopic procedure reduced the risk of transmission of the virus from the patients to the healthcare provider.