Cardiac Filaminopathy: Prevalence, Clinical Features, and Genetic Insights in Saudi Arabia

Cardiac filaminopathy, resulting from mutations in the FLNC gene that encodes filamin C, is increasingly recognized as a significant cause of inherited cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. This review synthesizes current knowledge about the genetic basis, clinical manifestations, and prevalence of cardiac filaminopathy, with a specific focus on Saudi Arabia. The unique genetic landscape of the Saudi population, characterized by a high prevalence of consanguinity, suggests a potentially elevated burden of cardiac filaminopathy condition, although data remain limited. We highlight the need for more comprehensive genetic screening and research to understand better and manage cardiac filaminopathy in Saudi Arabia

Drugs targeting the NO-sGC-cGMP pathway in the treatment of patients with COPD-associated pulmonary hypertension: a systematic review

BackgroundPulmonary hypertension (PH) due to chronic obstructive pulmonary disease (COPD) is categorized as group 3 PH and is associated with increased mortality and morbidity. Currently, there are no approved therapies for those who have PH secondary to COPD due to conflicting evidence. Therefore, this systematic review aims to summarize the current evidence on the effectiveness of drugs targeting the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway on clinical outcomes among patients with COPD-associated PH.MethodsWe conducted a comprehensive search of electronic databases, including Embase, Medline, Cochrane, and Scopus, from inception to 1 February 2024. Studies investigating the efficacy of drugs targeting the NO-sGC-cGMP pathway on clinical outcomes in patients with COPD-associated PH were included. Exclusion criteria encompassed case reports, systematic reviews, review articles, conference abstracts with no full text, non-full-text articles, non-English manuscripts, opinion articles, and book chapters. Two distinct Cochrane risk-of-bias tools designed for randomized and non-randomized clinical trials were used to evaluate the risk of bias within the selected studies for inclusion.ResultsFourteen studies, comprising a total of 567 adult patients diagnosed with PH secondary to COPD, met the inclusion criteria and were included in this systematic review. Among these, nine studies reported significant improvements in clinical parameters related to pulmonary hemodynamics. Improvement in exercise capacity was observed in four out of seven studies. Three studies evaluated dyspnea severity and quality of life following treatment with agents targeting the NO-sGC-cGMP pathway. Of these, three demonstrated improvement in dyspnea severity while two reported enhancements in health-related quality of life. Substantial heterogeneity was evident regarding the potential of pharmacological agents targeting the NO-sGC-cGMP pathway to enhance gas exchange, lung function, and arterial oxygenation in COPD patients with concurrent PH.ConclusionThe short-term use of oral drugs targeting the NO-sGC-cGMP pathway, particularly sildenafil, demonstrates promising potential for enhancing pulmonary hemodynamics, exercise capacity, dyspnea severity, and health-related quality of life but not lung function and oxygenation status in adult patients with COPD-associated PH. Further double-blind, randomized, placebo-controlled trials are needed to assess the therapeutic benefits of agents targeting the NO-sGC-cGMP pathway, particularly inhaled therapies for managing PH due to COPD.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/#recordDetails, CRD42023453503

AI-Guided Repurposing of FDA-Approved Anti-Leukemic Molecularly Targeted Therapies for Fatal Blast Crisis Chronic Myeloid Leukemia: Integrative Genomics for Precision Medicine of Relapsed/Refractory Cancers in the Post-Pandemic Era

Background: The COVID-19 pandemic accelerated the paradigm of drug repurposing, leading to the rapid identification of new uses for existing therapeutics under urgent clinical need. This success story has ignited a broader movement towards leveraging repurposing strategies for relapsed, refractory, and traditionally difficult-to-treat diseases, specifically cancers. Chronic myeloid leukemia (CML), although treatable in the chronic phase (CP), is usually fatal in the blast crisis phase (BC-CML), exemplifying a pressing challenge to oncology, where standard tyrosine kinase inhibitor (TKI) therapies often fail, resulting in poor survival outcomes. Methods and Results: In a multi-institutional cohort of 141 CML patients, we performed WES across disease phases (123 CP-CML, 6 AP-CML, 12 BC-CML). Mutational landscapes were interrogated using the AI-driven PanDrugs2 platform to identify druggable targets and repurposable FDA-approved anti-leukemic therapies. A 54% surge in mutational burden was observed transitioning from AP-CML to BC-CM, revealing 67 recurrent pan-leukemic gene mutations. Notably, actionable alterations were found in NPM1, DNMT3A, PML, AKT1, CBL, JAK2, TET2, IDH1, and BCL2, with therapeutic opportunities using existing agents such as venetoclax, ivosidenib, decitabine, and azacitidine. Emerging vulnerabilities, including RPTOR and BCR mutations, suggest further avenues for mTOR and BTK inhibitor applications beyond traditional TKI paradigms. Conclusions: Our integrated genomic and AI-guided approach demonstrates the transformative potential of drug repurposing for BC-CML, highlighting immediate actionable options where conventional therapies fail. This strategy not only offers hope for patients with BC-CML but also paves a visionary path toward precision medicine frameworks for relapsed, refractory, and otherwise intractable cancers in the post-pandemic clinical era. Prospective multi-omics studies and tailored clinical trials are urgently warranted to expand these opportunities across the oncology landscape

Atrial Fibrillation in a WPW Patient after the Consumption of Energy Drinks: A Case Report

This is a case of a young male who developed fast atrial fibrillation after he consumed three cans of Energy drinks (EDs). Treatment required electrical cardioversion and surprisingly, when he reverted to sinus rhythm, the ECG showed a type A Wolff Parkinson White syndrome (WPW) (left-sided accessory pathway), with no previous history.</jats:p

Role of dysregulated prostanoids, nitric oxide and endothelin in cigarette smoke-and hypoxia-induced pulmonary vascular remodelling in COPDassociated pulmonary hypertension

Pulmonary hypertension (PH) due to chronic obstructive pulmonary disease (COPD) is classified as Group 3 PH, with no current proven targeted therapies. Studies suggest that cigarette smoke, the most risk factor for COPD can cause vascular remodelling and eventually PH as a result of dysfunction and proliferation of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs). In addition, hypoxia is a known driver of pulmonary vascular remodelling in COPD, and it is also thought that the presence of hypoxia in patients with COPD may further exaggerate cigarette smoke-induced vascular remodelling; however, the underlying cause is not fully understood. Three main pathways (prostanoids, nitric oxide and endothelin) are currently used as a therapeutic target for the treatment of patients with different groups of PH. However, drugs targeting these three pathways are not approved for patients with COPD-associated PH due to lack of evidence. Thus, this review aims to shed light on the role of impaired prostanoids, nitric oxide and endothelin pathways in cigarette smoke- and hypoxia-induced pulmonary vascular remodelling and also discusses the potential of using these pathways as therapeutic target for patients with PH secondary to COPD

Drugs targeting the NO-sGC-cGMP pathway in the treatment of patients with COPD-associated pulmonary hypertension: a systematic review

Background: Pulmonary hypertension (PH) due to chronic obstructive pulmonary disease (COPD) is categorized as group 3 PH and is associated with increased mortality and morbidity. Currently, there are no approved therapies for those who have PH secondary to COPD due to conflicting evidence. Therefore, this systematic review aims to summarize the current evidence on the effectiveness of drugs targeting the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway on clinical outcomes among patients with COPD-associated PH. Methods: We conducted a comprehensive search of electronic databases, including Embase, Medline, Cochrane, and Scopus, from inception to 1 February 2024. Studies investigating the efficacy of drugs targeting the NO-sGC-cGMP pathway on clinical outcomes in patients with COPD-associated PH were included. Exclusion criteria encompassed case reports, systematic reviews, review articles, conference abstracts with no full text, non-full-text articles, non-English manuscripts, opinion articles, and book chapters. Two distinct Cochrane risk-of-bias tools designed for randomized and non-randomized clinical trials were used to evaluate the risk of bias within the selected studies for inclusion. Results: Fourteen studies, comprising a total of 567 adult patients diagnosed with PH secondary to COPD, met the inclusion criteria and were included in this systematic review. Among these, nine studies reported significant improvements in clinical parameters related to pulmonary hemodynamics. Improvement in exercise capacity was observed in four out of seven studies. Three studies evaluated dyspnea severity and quality of life following treatment with agents targeting the NO-sGC-cGMP pathway. Of these, three demonstrated improvement in dyspnea severity while two reported enhancements in health-related quality of life. Substantial heterogeneity was evident regarding the potential of pharmacological agents targeting the NO-sGC-cGMP pathway to enhance gas exchange, lung function, and arterial oxygenation in COPD patients with concurrent PH. Conclusion: The short-term use of oral drugs targeting the NO-sGC-cGMP pathway, particularly sildenafil, demonstrates promising potential for enhancing pulmonary hemodynamics, exercise capacity, dyspnea severity, and health-related quality of life but not lung function and oxygenation status in adult patients with COPD-associated PH. Further double-blind, randomized, placebo-controlled trials are needed to assess the therapeutic benefits of agents targeting the NO-sGC-cGMP pathway, particularly inhaled therapies for managing PH due to COPD. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/#recordDetails, CRD42023453503

Asthma medication adherence, control, and psychological symptoms: a cross-sectional study

Abstract Background Nonadherence to therapies and psychological disorders are associated with poor asthma control. This study aims to assess the prevalence of anxiety and depressive symptoms, asthma control, and adherence to inhalers and to investigate whether there is an association of anxiety and depressive symptoms with adherence to inhalers and asthma control. Methods We measured anxiety and depressive symptoms using the Hospital Anxiety and Depression Scale in patients with asthma. Asthma Control Test and the 10-Item Test of Adherence to Inhalers Scale were used to assess levels of asthma control adherence to inhalers, respectively. Univariate and multivariate regression models assessed the associations of anxiety and depressive symptoms with adherence to inhalers and asthma control. Results A total of 287 patients completed the study, of whom 72% were female. The mean ± SD age and body mass index of our study population were 44 ± 13 years and 29 ± 7.2 kg/m2, respectively. Poor adherence to inhaler use was highly prevalent (49.8%; 95% CI: 43.8 to 55.7). The prevalence of anxiety, depression and poor asthma control was 27.2% (95% CI: 22.1 to 32.7), 20.9% (95% CI: 16.3 to 26.1), and 22.7% (95% CI: 17.9 to 27.9), respectively. We found a negative relationship between asthma control and anxiety, and depressive symptoms (adjusted β: -0.25; 95% CI: -0.36 to -0.14; p < 0.001 and adjusted β: -0.29; 95% CI: -0.40 to -0.18; p < 0.001, respectively). A negative relationship was also observed between adherence to inhalers and anxiety and depressive symptoms (adjusted β: -0.34; 95% CI: -0.46 to -0.22; p < 0.001 and adjusted β: -0.36; 95% CI: − 0.48 to − 0.24; p < 0.001, respectively). Conclusions The high prevalence of uncontrolled asthma symptoms and poor adherence to inhalers and their impact on anxiety and depression levels among patients with asthma point to the need for early screening for psychological symptoms and recognition of nonadherence as part of asthma assessment and management plan in primary care in Saudi Arabia to avoid further worsening of asthma symptoms. Further studies are needed to explore the effectiveness of specific psychoeducational interventions and investigate the long-term impact of early psychological symptom detection on asthma outcomes

Evaluation of thiamine as adjunctive therapy in COVID-19 critically ill patients: a two-center propensity score matched study

Abstract Background Thiamine is a precursor of the essential coenzyme thiamine pyrophosphate required for glucose metabolism; it improves the immune system function and has shown to reduce the risk of several diseases. The role of thiamine in critically ill septic patient has been addressed in multiple studies; however, it’s role in COVID-19 patients is still unclear. The aim of this study was to evaluate the use of thiamine as an adjunctive therapy on mortality in COVID-19 critically ill patients. Methods This is a two-center, non-interventional, retrospective cohort study for critically ill patients admitted to intensive care units (ICUs) with a confirmed diagnosis of COVID19. All patients aged 18 years or older admitted to ICUs between March 1, 2020, and December 31, 2020, with positive PCR COVID-19 were eligible for inclusion. We investigated thiamine use as an adjunctive therapy on the clinical outcomes in critically ill COVID-19 patients after propensity score matching. Results A total of 738 critically ill patients with COVID-19 who had been admitted to ICUs were included in the study. Among 166 patients matched using the propensity score method, 83 had received thiamine as adjunctive therapy. There was significant association between thiamine use with in-hospital mortality (OR = 0.39; 95% CI 0.19–0.78; P value = 0.008) as well as the 30-day mortality (OR = 0.37; 95% CI 0.18–0.78; P value = 0.009). Moreover, patients who received thiamine as an adjunctive therapy were less likely to have thrombosis during ICU stay [OR (95% CI) 0.19 (0.04–0.88), P value = 0.03]. Conclusion Thiamine use as adjunctive therapy may have potential survival benefits in critically ill patients with COVID-19. Additionally, it was associated with a lower incidence of thrombosis. Further interventional studies are required to confirm these findings. </jats:sec

Data_Sheet_1_Inhaled therapies targeting prostacyclin pathway in pulmonary hypertension due to COPD: systematic review.docx

BackgroundPulmonary hypertension due to chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is classified as group 3 pulmonary hypertension. Inhaled treprostinil, a prostaglandin I2 analogue also known as prostacyclin, has recently been approved as a first drug for patients with pulmonary hypertension secondary to ILD. However, due to a lack of evidence, no therapies are currently approved for those with COPD-associated pulmonary hypertension. Thus, this systematic review aims to summarise the current evidence to assess the impact of inhaled prostaglandin I2 analogue use on the pulmonary hemodynamics, exercise function, lung function, and gas exchange in patients with pulmonary hypertension due to COPD.MethodsWe systematically searched the electronic databases of Medline, Embase, Scopus and Cochrane from inception to 1 February 2023. Studies of adult patients with a confirmed diagnosis of COPD-associated pulmonary hypertension who received inhaled drugs targeting the prostacyclin pathway were included in the systematic review. Case reports, systematic reviews, conference abstracts with no full text, non-full-text articles, non-English manuscripts and book chapters were excluded from this systematic review. A risk-of-bias assessment was carried out for the studies included in this review, using two different Cochrane risk-of-bias tools for randomised and non-randomised clinical trials.ResultsA total of four studies met our inclusion criteria and were included in this systematic review. The results of one prospective clinical trial showed an improvement in the pulmonary hemodynamics (e.g., cardiac index, cardiac output and mean pulmonary artery pressure) in response to inhaled prostacyclin use in patients with pulmonary hypertension secondary to COPD. However, the severity of dyspnoea, lung function, exercise capacity and gas exchange were not affected when inhaled prostacyclin was used for patients with COPD-related pulmonary hypertension.ConclusionThis systematic review demonstrated that although inhaled prostacyclin does not seem to improve COPD-related outcomes (e.g., lung function and exercise capacity), short-term use of inhaled prostacyclin has the potential to reduce mean pulmonary artery pressure and pulmonary vascular resistance without impairing ventilation-perfusion mismatch. Further studies with larger sample sizes are warranted.Systematic review registrationCRD42022372803, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=372803.</p

Data_Sheet_2_Inhaled therapies targeting prostacyclin pathway in pulmonary hypertension due to COPD: systematic review.docx

BackgroundPulmonary hypertension due to chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is classified as group 3 pulmonary hypertension. Inhaled treprostinil, a prostaglandin I2 analogue also known as prostacyclin, has recently been approved as a first drug for patients with pulmonary hypertension secondary to ILD. However, due to a lack of evidence, no therapies are currently approved for those with COPD-associated pulmonary hypertension. Thus, this systematic review aims to summarise the current evidence to assess the impact of inhaled prostaglandin I2 analogue use on the pulmonary hemodynamics, exercise function, lung function, and gas exchange in patients with pulmonary hypertension due to COPD.MethodsWe systematically searched the electronic databases of Medline, Embase, Scopus and Cochrane from inception to 1 February 2023. Studies of adult patients with a confirmed diagnosis of COPD-associated pulmonary hypertension who received inhaled drugs targeting the prostacyclin pathway were included in the systematic review. Case reports, systematic reviews, conference abstracts with no full text, non-full-text articles, non-English manuscripts and book chapters were excluded from this systematic review. A risk-of-bias assessment was carried out for the studies included in this review, using two different Cochrane risk-of-bias tools for randomised and non-randomised clinical trials.ResultsA total of four studies met our inclusion criteria and were included in this systematic review. The results of one prospective clinical trial showed an improvement in the pulmonary hemodynamics (e.g., cardiac index, cardiac output and mean pulmonary artery pressure) in response to inhaled prostacyclin use in patients with pulmonary hypertension secondary to COPD. However, the severity of dyspnoea, lung function, exercise capacity and gas exchange were not affected when inhaled prostacyclin was used for patients with COPD-related pulmonary hypertension.ConclusionThis systematic review demonstrated that although inhaled prostacyclin does not seem to improve COPD-related outcomes (e.g., lung function and exercise capacity), short-term use of inhaled prostacyclin has the potential to reduce mean pulmonary artery pressure and pulmonary vascular resistance without impairing ventilation-perfusion mismatch. Further studies with larger sample sizes are warranted.Systematic review registrationCRD42022372803, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=372803.</p