Using ex vivo bioengineered lungs to model pathologies and screening therapeutics: A proof-of-concept study.

Respiratory diseases, claim over eight million lives annually. However, the transition from preclinical to clinical phases in research studies is often hindered, partly due to inadequate representation of preclinical models in clinical trials. To address this, we conducted a proof-of-concept study using an ex vivo model to identify lung pathologies and to screen therapeutics in a humanized rodent model. We extracted and decellularized mouse heart-lung tissues using a detergent-based technique. The lungs were then seeded and cultured with human cell lines (BEAS-2B, A549, and Calu3) for 6-10 days, representing healthy lungs, cancerous states, and congenital pathologies, respectively. By manipulating cultural conditions and leveraging the unique characteristics of the cell lines, we successfully modeled various pathologies, including advanced-stage solid tumors and the primary phase of SARS-CoV-2 infection. Validation was conducted through histology, immunofluorescence staining, and pathology analysis. Additionally, our study involved pathological screening of the efficacy and impact of key anti-neoplastic therapeutics (Cisplatin and Wogonin) in cancer models. The results highlight the versatility and strength of the ex vivo model in representing crucial lung pathologies and screening therapeutics during the preclinical phase. This approach holds promise for bridging the gap between preclinical and clinical research, aiding in the development of effective treatments for respiratory diseases, including lung cancer.

Association of childhood and adolescence obesity with incidence and mortality of adulthood cancers. A systematic review and meta-analysis.

Background: Prevalence and subsequent conditions of childhood and adolescent obesity are increasing. It has been seen that obesity in youth is associated with adulthood cancer. This systematic review and meta-analysis aimed to determine the pooled association of childhood obesity with cancers in adulthood. Methods: In this systematic review, international electronic databases such as Scopus, PubMed, Web of Science, and EMBASE were searched using relevant keywords until February 2022. All Cohort studies assessing the association of childhood and adolescent obesity (under 18 years old) with the incidence and mortality of all types of cancers were included. Two independent reviewers screened and carried out the quality assessment of included studies. Between-studies heterogeneity was assessed using the I squared and Cochran's Q tests. Random/fixed-effect meta-analyses were used to pool the appropriate effect sizes (Hazard ratios (HR)). Results: Overall, 46 studies were found to be relevant and were included in this study. Based on the random-effects model meta-analysis, childhood obesity increased the hazard of cancer incidence and mortality in adulthood by 33% (HR: 1.33, 95%CI (1.25, 1.41)) and by 28% (HR: 1.28, 95%CI (1.13, 1.42)), respectively. In the subgroups meta-analysis, the HR of childhood obesity and adulthood cancer incidence mortality in women was higher than in men (HR=1.39, 95%CI (1.25, 1.53) vs HR= 1.20, 95%CI (1.07, 1.32)) and (HR= 1.40, 95%CI (1.10, 1.69) vs HR=1.20, 95%CI (1.04, 1.36)) respectively. Conclusion: This study found that obesity in childhood and adolescence is associated with a significant increase in the incidence and mortality of cancers in adulthood. Prevention of childhood obesity, in addition to its short-term beneficial effects, can reduce the burden of cancer in adulthood. The data sets of this study are present in the Tables of the current manuscript. Moreover this study was registered online in PROSPERO (registration code: CRD42022331958). Systemic review registration: https://www.crd.york.ac.uk/Prospero/, identifier CRD42022331958.

Long-term full-scale intelligent quotient outcomes following pediatric and childhood epilepsy surgery: A systematic review and meta-analysis.

OBJECTIVE: Cognitive measures are an important primary outcome of pediatric, adolescents, and childhood epilepsy surgery. The purpose of this systematic review and meta-analysis is to assess whether there are long-term alterations (≥ 5 years) in the Full-Scale Intelligence Quotient (FSIQ) of pediatric patients undergoing epilepsy surgery. METHODS: Electronic databases (EMBASE, MEDLINE, and Scopus) were searched for English articles from inception to October 2022 that examined intelligence outcomes in pediatric epilepsy surgery patients. Inclusion criteria were defined as the patient sample size of ≥ 5, average follow- up of ≥5 years, and surgeries performed on individuals ≤ 18 years old at the time of surgery. Exclusion criteria consisted of palliative surgery, animal studies, and studies not reporting surgical or FSIQ outcomes. Publication bias was assessed using a funnel plot and the Quality in Prognosis Studies (QUIPS) toolset was used for quality appraisal of the selected articles. A random-effects network meta-analysis was performed to compare FSIQ between surgical patients at baseline and follow-up and Mean Difference (MD) was used to calculate the effect size of each study. Point estimates for effects and 95% confidence intervals for moderation analysis were performed on variables putatively associated with the effect size. RESULTS: 21,408 studies were screened for abstract and title. Of these, 797 fit our inclusion and exclusion criteria and proceeded to full-text screening. Overall, seven studies met our requirements and were selected. Quantitative analysis was performed on these studies (N = 330). The mean long-term difference between pre- and post- operative FSIQ scores across all studies was noted at 3.36 [95% CI: (0.14, 6.57), p = 0.04, I2 = 0%] and heterogeneity was low. CONCLUSION: To our knowledge, this is the first meta-analysis to measure the long-term impacts of FSIQ in pediatric and adolescent epilepsy patients. Our overall results in this meta-analysis indicate that while most studies do not show long-term FSIQ deterioration in pediatric patients who underwent epilepsy surgery, there was an increase of 3.36 FSIQ points, however, the observed changes were not clinically significant. Moreover, at the individual patient level analysis, while most children did not show long-term FSIQ deterioration, few had significant decline. These findings indicate the importance of surgery as a viable option for pediatric patients with medically refractory epilepsy.

Bilateral Central Retinal Vein Occlusion and Stevens-Johnson Syndrome Associated with Coronavirus-19: A Case Report.

Purpose: To report a case of bilateral central retinal vein occlusion (CRVO) associated with coronavirus-19 (COVID-19) infection. Methods: A 43-year-old man presented to the emergency department with flu-like symptoms, severe erythema, a rash on his face, and respiratory distress. He was admitted to the intensive care unit, and the reverse transcriptase-polymerase chain reaction test was positive for the severe acute respiratory syndrome coronavirus-2 virus. The routine blood work was unremarkable. The dermatologist noted positive Nikolsky's sign, and the patient was diagnosed with Stevens-Johnson syndrome (SJS), which affected 18% of his body and was later confirmed by skin biopsy. Later, he reported worsening vision. Results: Ophthalmic examination and fundus fluorescein angiography showed bilateral CRVO. Despite best medical efforts, including treatment with systemic dexamethasone and remdesivir, the patient died on the 6 days of his hospitalization. Conclusion: This was a rare bilateral CRVO and SJS case in a young patient, probably caused by the COVID-19 infection.

The Utility of Research Domain Criteria in Diagnosis and Management of Dual Disorders: A Mini-Review.

The Research Domain Criteria (RDoC) initiative has been considered a comprehensive alternative classification framework for understanding neuropsychiatric ailments, as opposed to the longstanding, traditional DSM framework. Where the DSM categorizes neuropsychiatric disorders as each being distinct and diagnostically defined by the presence of specified symptoms, RDoC provides a multidimensional conceptualization of psychiatric disorders with neurobiological roots. By taking a multidimensional approach, RDoC overcomes two major constraints of the DSM framework: that is, that the DSM is categorical in its approach to psychiatric disorders to the point of understating the intersectionality between concomitant disorders, and that the DSM focuses mainly on clinical features. RDoC seems to better account for the intersection between dual disorders and considers a range of factors, from the more microscopic (e.g., genetics or molecular functions) to the more macroscopic (e.g., environmental influences). The multidimensional approach of RDoC is particularly appealing in the context of dual disorders. Dual disorders refers to a concurrent psychiatric disorder with an addiction disorder. RDoC accounts for the fact that there is often overlap in symptoms across and bidirectional influence between various disorders. However, to date, there is limited research into the clinical utility of RDoC, and less so in the context of the clinical management of dual disorders. In this Mini-Review, we discuss how RDoC differs from the DSM, what outcomes have been reported in utilizing RDoC clinically, the utility of RDoC for the diagnosis, management, and monitoring of psychopathology, and the limitations of RDoC as well as avenues for future research.

Strategies to overcome the side effects of chimeric antigen receptor T cell therapy.

Chimeric antigen receptor (CAR) therapy is a method directing T lymphocytes against antigens on the surface of tumors, increasing target cell elimination. Genetic engineering enhances the capability of immune cells to detect new antigens expressed on cell surfaces. CAR T cell therapy is a significant breakthrough for treating human malignancies; however, different side effects (e.g., cytokine release syndrome) restrict its application. Improving design and using various combined receptors enhance the performance of these cells. This review discusses limitations and risk factors associated with CAR T cell therapy. We also review some alternative approaches for developing the next generation of CAR T cells.

Whole-Exome Sequencing in Idiopathic Short Stature: Rare Mutations Affecting Growth.

Idiopathic short stature (ISS) is a common diagnosis of exclusion in patients with short stature (SS). In this article, we aimed to identify the genetic causes of SS in patients with ISS and investigate treatment options. Fourteen children with diagnosis of ISS were identified, and whole-exome sequencing (WES) was subsequently conducted on blood-derived DNA. Five patients were correctly diagnosed with ISS and four had rare mutations that have not been previously reported. Four patients had mutations known to cause SS and one had a mutation that was known not to affect height. WES can help identify rare mutations implicated in ISS.

Long-term Trends in Hypertension Prevalence, Awareness, Treatment, and Control Rate in the Middle East and North Africa: a Systematic Review and Meta-analysis of 178 Population-Based Studies.

PURPOSE OF REVIEW: This study investigated and pooled the long-term trends in prevalence, awareness, treatment, and control of hypertension (HTN) in the Middle East and North Africa (MENA) region. In this systematic review and meta-analysis, we searched MEDLINE/PubMed, Web of Science, Google Scholar, EMBASE, and Scopus between database inception and November 2020. All cross-sectional studies that investigated the prevalence of pre-HTN, HTN, awareness, treatment, and control in the MENA counties were included. The selection study, data extraction, and quality assessment were conducted by two investigators independently. Heterogeneity between studies was assessed using Cochran's Q test and I-squared, and due to sever heterogeneity between studies, the random effect model was used to pool the estimates. Sensitivity analysis was performed to estimate the long-term trends in prevalence, awareness, treatment, and control rates of HTN according to definition of HTN as systolic blood pressure of 140 mm Hg or more, or diastolic blood pressure of 90 mm Hg or more, or being on pharmacological treatment for HTN. RECENT FINDINGS: Overall, 178 studies met the inclusion criteria. Studies comprised 2,262,797 participants with a mean age of 45.72 ± 8.84 years. According to random effect model, the pooled prevalence of pre-HTN and HTN was 33% (95% CI 28, 39) and 26% (25, 27), respectively. Over the past three decades, prevalence of hypertension increased significantly in the region. The pooled awareness, treatment, and control rates were 50% (48, 53), 41% (38, 44), and 19% (17, 21), receptively. The pooled awareness, treatment, and control rates of HTN were lower significantly in men than women. According to definition of HTN as blood pressures above 140/90 mm Hg, over the past three decades, although the awareness and treatment rates did not change significantly, the control rates improved significantly in the region. The findings showed that HTN is a significant public health problem in the MENA region. Although there are low levels of pooled awareness, treatment, and control rates, the control rates improved over the past three decades in the region.

Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report.

BACKGROUND: Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature. CASE PRESENTATION: We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient's phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient's father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature. CONCLUSION: We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

Late infantile form of multiple sulfatase deficiency.

SUMMARY: Multiple sulfatase deficiency (MSD) is a lysosomal storage disorder (LSD) that results in the accumulation of sulfate esters which go on to cause neurological deterioration and mental delay, skin changes, and dysmorphism. The disease can be categorized into three subtypes based on the age of onset: neonatal, late infantile, or juvenile. Our patient is a 2.5-year-old girl, the only child of a healthy couple. Prior to the presentation of the disease, she had not been noted to have any previous health complications. The condition began at the age of 6 months with developmental regression and global hypotonia. Following thorough evaluation and testing, the patient was diagnosed with severe late infantile MSD, although some features, such as minimal mental deterioration, minimal dysmorphic facial features, and minimal organ enlargement, did not fully correlate with the diagnosis, since in cases of severe forms of the condition these features are almost always quite marked. The unexpected minimalism of some of the patient's MSD signs in spite of the severity of her MSD condition made her case worth further studying. LEARNING POINTS: Treating dermatologic signs and symptoms greatly eased our patient's discomfort. We would suggest the use of appropriate supportive treatment for symptom management regardless of the life expectancy of the patient. As regards the diagnosis of MLD, given that in some cases the patient may present with irregular features of the condition, a genetic evaluation may be useful for accurate diagnosis. If motor function impairment is followed by dermatologic involvement, as seen in our patient and in many cases in the literature, MSD must be considered, and additional tests should be done to rule it out.