Phenotypic and genotypic evaluation of bleeding diagnostic dilemmas: Two case studies.

Inherited platelet disorders (IPDs) are a heterogeneous group of conditions that present significant challenges in diagnosis and management. Here, we report two cases of patients presenting with clinically significant bleeding but with unclear etiologies by conventional clinical laboratory testing. Further evaluation, utilizing a combination of high-dimensional multiplexed mass cytometry and genetic sequencing, revealed the underlying causes of bleeding in both cases, leading to definitive diagnoses. These cases underscore the potential utility of combined multimodal approaches in evaluating patients with bleeding disorders. Moreover, these high-parameter methods can offer substantial mechanistic insights and can enhance our understanding of the molecular pathogenesis of IPDs. Future studies involving larger patient cohorts are needed to further validate this strategy, directly comparing its diagnostic yield and accuracy with current clinical laboratory testing approaches, which can ultimately improve patient care.

Patient-reported outcomes in diabetes-related foot conditions: Is patient experience influenced by ethnicity? A mixed-methods systematic review.

AIMS: Research in diabetes-related foot conditions (DRFC) often focuses on ulcer-related care, whilst the patient experience and influence of sociodemographic factors are under-researched. This systematic review investigated patient-reported outcomes and experience in people with DRFC. METHODS: Multiple databases were searched from inception to 16 August 2023. All original articles that assessed any patient-reported outcome or experience in DRFC and reported participant ethnicity were included. Data were synthesized using a sequential contingent approach. Study quality was assessed using study design-specific tools. RESULTS: Twenty-three studies were included (11 qualitative, 11 quantitative and one mixed-methods). DRFC had a largely negative impact on various life dimensions, including social and daily life, work, emotional and psychological well-being, necessitating dependence on others in the form of emotional, social and/or religious support, which were experienced differently by different groups. Patient DRFC knowledge and self-care habits were typically suboptimal, and levels of hope and feeling of control over their condition varied between groups. Outcomes varied slightly between ethnicities across studies, with some ethnicity-specific themes identified such as beliefs about disease cause and footwear habits. Quantitative and qualitative findings were mostly congruent. CONCLUSIONS: DRFC profoundly and negatively impacts patient-reported outcomes and experience, with limited evidence suggesting an influence of ethnicity.

Factor VIII Levels and ISTH Disseminated Intravascular Coagulation Scores Do Not Distinguish Disseminated Intravascular Coagulation from the Coagulopathy of Liver Disease.

INTRODUCTION: Distinguishing disseminated intravascular coagulation (DIC) from the coagulopathy of liver disease represents a common clinical challenge. Here, we evaluated the utility of two diagnostic tools frequently used to differentiate between these conditions: factor VIII (FVIII) levels and the International Society on Thrombosis and Hemostasis (ISTH) DIC score. METHODS: To this end, we conducted a retrospective chart review of patients with DIC, liver disease, or both. Multiple logistic regression was performed, and receiver operating characteristic curves were generated to calculate the area under curve (AUC) for distinguishing DIC in the setting of liver disease. RESULTS: Among 123 patients with DIC, liver disease, or liver disease plus DIC, FVIII levels did not differ significantly. ISTH scores were lower in patients with DIC than in liver disease with or without DIC. Addition of several laboratory parameters to the ISTH score, including mean platelet volume, FV, FVIII, international normalized ratio, and activated partial thromboplastin time, improved AUC for distinguishing DIC in liver disease from liver disease alone (AUC = 0.76; p < 0.0001). CONCLUSION: We conclude that FVIII levels do not distinguish DIC from liver disease, and ISTH DIC scores are not predictive of DIC in patients with liver disease. Inclusion of additional lab variables within the ISTH DIC score may aid in identifying DIC in patients with liver disease.

Providing 0.1 Full-Time Equivalent (FTE) Support to Fellowship Core Faculty Improves Faculty Involvement in Fellowship Education and Recruitment.

In 2022, the American Council for Graduate Medical Education (ACGME) recommended that core faculty (CF) in medical subspecialty fellowships receive at least 0.1 full-time equivalent (FTE) salary support, with plans to enforce compliance in July 2023. After early feedback raised concerns about potential unintended consequences, ACGME deferred enforcement to July 2024. Hence, there is an urgent need to understand the ramifications of providing FTE support for CF. In 2020, the Yale hematology and medical oncology (HO) fellowship program began providing 0.1 FTE support to all CF. Perceptions regarding this were assessed via surveys distributed to all CF in 2021 and 2022 and to all HO fellows in 2021. The vast majority (83.3%) of CF survey respondents reported improved job satisfaction and an increased sense of involvement in the fellowship program as a result of the new 0.1 FTE-supported CF program. Most CF increased attendance at fellowship conferences, devoted more time to mentorship, and increased participation in recruitment. In free text comments, CF respondents described that providing 0.1 FTE support made them "feel rewarded," gave them "a sense of commitment" to the fellowship, and helped "offset clinical requirements." HO fellows reported "a positive impact" of the new program with faculty being "more present at lectures." The median number of times faculty were available to interview fellowship applicants rose markedly after introduction of the program. The FTE-supported CF program was viewed enthusiastically by fellows and faculty, resulting in increased CF involvement in fellowship education and recruitment.

Effects of interventions targeting the systemic inflammatory response to cardiac surgery on clinical outcomes in adults.

BACKGROUND: Organ injury is a common and severe complication of cardiac surgery that contributes to the majority of deaths. There are no effective treatment or prevention strategies. It has been suggested that innate immune system activation may have a causal role in organ injury. A wide range of organ protection interventions targeting the innate immune response have been evaluated in randomised controlled trials (RCTs) in adult cardiac surgery patients, with inconsistent results in terms of effectiveness. OBJECTIVES: The aim of the review was to summarise the results of RCTs of organ protection interventions targeting the innate immune response in adult cardiac surgery. The review considered whether the interventions had a treatment effect on inflammation, important clinical outcomes, or both. SEARCH METHODS: CENTRAL, MEDLINE, Embase, conference proceedings and two trial registers were searched on October 2022 together with reference checking to identify additional studies. SELECTION CRITERIA: RCTs comparing organ protection interventions targeting the innate immune response versus placebo or no treatment in adult patients undergoing cardiac surgery where the treatment effect on innate immune activation and on clinical outcomes of interest were reported. DATA COLLECTION AND ANALYSIS: Searches, study selection, quality assessment, and data extractions were performed independently by pairs of authors. The primary inflammation outcomes were peak IL-6 and IL-8 concentrations in blood post-surgery. The primary clinical outcome was in-hospital or 30-day mortality. Treatment effects were expressed as risk ratios (RR) and standardised mean difference (SMD) with 95% confidence intervals (CI). Meta-analyses were performed using random effects models, and heterogeneity was assessed using I2. MAIN RESULTS: A total of 40,255 participants from 328 RCTs were included in the synthesis. The effects of treatments on IL-6 (SMD -0.77, 95% CI -0.97 to -0.58, I2 = 92%) and IL-8 (SMD -0.92, 95% CI -1.20 to -0.65, I2 = 91%) were unclear due to heterogeneity. Heterogeneity for inflammation outcomes persisted across multiple sensitivity and moderator analyses. The pooled treatment effect for in-hospital or 30-day mortality was RR 0.78, 95% CI 0.68 to 0.91, I2 = 0%, suggesting a significant clinical benefit. There was little or no treatment effect on mortality when analyses were restricted to studies at low risk of bias. Post hoc analyses failed to demonstrate consistent treatment effects on inflammation and clinical outcomes. Levels of certainty for pooled treatment effects on the primary outcomes were very low. AUTHORS' CONCLUSIONS: A systematic review of RCTs of organ protection interventions targeting innate immune system activation did not resolve uncertainty as to the effectiveness of these treatments, or the role of innate immunity in organ injury following cardiac surgery.

Association of iron infusion reactions with ABO blood type.

OBJECTIVES: We sought to determine risk factors for iv iron infusion-related reactions (IRR), and identify strategies for iron repletion after IRR. METHODS: We conducted a retrospective chart review of patients treated in the classical hematology clinic at Yale Cancer Center (n = 330 consecutive patients) from 2016 to 2021, who received iv ferumoxytol (60.3%), iron sucrose (14.8%), or iron dextran (10.9%). RESULTS: The iv iron IRR was noted in 58 (17.6%) patients, 62.1% of whom had previously tolerated iv iron. The severity of IRR was mild in 22, moderate in 23, and severe in 11 patients. Most (72.4%) patients who experienced IRR tolerated a subsequent iv iron infusion. On multivariable analysis, a history of non-medication allergies was associated with greater odds of IRR (odds ratio [OR] 2.12, 95% confidence interval (CI): 1.16-3.87, p = .01). No patients with type AB blood, and few with type A blood (n = 6), had IRR; compared to type A or AB together, patients with type B (OR 5.00, 95% CI: 1.56-16.06, p = .007) or type O (OR 3.71, 95% CI: 1.44-9.55, p = .007) blood had greater odds of IRR. CONCLUSIONS: This study highlights a possible association of blood type with iv iron IRR; prospective studies with larger patient numbers are warranted to explore this association.

The role of Augmentative and Alternative Communication in Speech and Language Therapy: A mini review.

Augmentative and Alternative Communication is an aided or unaided means of communication which supports existing communication abilities of an individual or replaces natural speech due to any speech and language disorder. The deficit could be developmental or acquired such as autism spectrum disorder, cerebral palsy, learning difficulties, dysarthria, dyspraxia or due to any acquired neurological condition such as aphasia and other degenerative disorders. Furthermore, it may be due to surgical procedures such as laryngectomy. Alternate means of communication have also been successfully used with COVID-19 patients. These tools may include pictures, symbols, signs or voice output devices. Parents of children with special needs and medical professionals have been reluctant in implementing the approach due to certain misconceptions. The aim of this review is to summarize the current evidence for the use of Augmentative and Alternative Communication with a range of disorders in relation to in relation to Pakistan.

Idiopathic pulmonary hemosiderosis - A rare cause of chronic anemia.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease marked by alveolar bleeding and accumulation of hemosiderin in the lungs. Here we present three cases of IPH. The first case is of a 26-year-old male with anemia, hemoptysis and dyspnea. Bronchoscopy confirmed diffuse alveolar hemorrhage (DAH). A diagnosis of IPH was made after ruling out other causes of DAH and observing good response to steroids. The patient's condition improved with prednisolone and azathioprine. The second case is of 26-year-old female with severe anemia. Imaging suggested IPH and lung biopsy confirmed it. She died shortly afterwards. The third case is of a 7-year-old male with chronic anemia. CT was suggestive of IPH and lung biopsy confirmed the diagnosis. Later, patient developed posterior reversible encephalopathy syndrome (PRES). This patient is stable on azathioprine and prednisolone. We aim to emphasize the importance of considering IPH as a differential in patients with DAH or chronic anemia.

Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges.

Signal transducers and activators of transcription 3 (STAT-3) is a transcription factor that regulates the gene expression of several target genes. These factors are activated by the binding of cytokines and growth factors with STAT-3 specific receptors on cell membrane. Few years ago, STAT-3 was considered an acute phase response element having several cellular functions such as inflammation, cell survival, invasion, metastasis and proliferation, genetic alteration, and angiogenesis. STAT-3 is activated by several types of inflammatory cytokines, carcinogens, viruses, growth factors, and oncogenes. Thus, the STAT3 pathway is a potential target for cancer therapeutics. Abnormal STAT-3 activity in tumor development and cellular transformation can be targeted by several genomic and pharmacological methodologies. An extensive review of the literature has been conducted to emphasize the role of STAT-3 as a unique cancer drug target. This review article discusses in detail the wide range of STAT-3 inhibitors that show antitumor effects both in vitro and in vivo. Thus, targeting constitutive STAT-3 signaling is a remarkable therapeutic methodology for tumor progression. Finally, current limitations, trials and future perspectives of STAT-3 inhibitors are also critically discussed.

Anomalous origin of the left coronary artery from the pulmonary artery: A surgical certainty.

This study aims to assess the clinical presentation and the outcomes of a surgical correction of an anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). A retrospective review was carried out on the charts of six patients admitted for ALCAPA surgery at Aga Khan University Hospital, Karachi from March 2017 to May 2018.Dyspnoea, palpitation, poor feeding, fatiguability, pallor and a murmur of mitral regurgitation were the main presenting features. The pre-operative median left ventricular ejection fraction (LVEF) was 64%. Coronary reimplantation was performed in all the patients with a mitral valve repair being done in only one patient. The mea n LV EF was 66 .3%,p ost- ope rativel y. Mitra l regurgitation (MR) improved in patients post-operatively with trace in 2 patients and mild MR in one. Surgical correction by coronary re-implantation yields favourable outcomes in ALCAPA and significantly reduces the morbidity and mortality rates associated with the disease.

Perception of speech and language pathologists towards augmentative and alternative communication in Pakistan.

OBJECTIVE: To determine the level of understanding and use of augmentative and alternative communication devices in Pakistani speech pathologists.. METHODS: The cross-sectional survey was conducted from January to June 2015 in six major cities of Pakistan: Islamabad, Rawalpindi, Lahore, Karachi, Quetta and Peshawar. It comprised speech and language pathologists who were asked to fill a questionnaire that consisted of10 questions. Data was analysed using SPSS17. Result: Overall calculated mean and standard error of mean from the respondents who agreed and strongly agreed regarding understanding, opinion-assessment and treatment about augmentative and alternative communication was153±36.373 and 12.124 respectively. RESULTS: Of the 132 subjects, 68(51.5%) were in the education group and 64(48.5%) in the control group. Postintervention, 11(16.2%) women in the education group and 37(57.8%)in the control group developed severe preeclampsia. Subsequently, 44(64.7%) in the education group had no preeclampsia. The corresponding number in the control group was 15(23.4%). CONCLUSIONS: Speech pathologists had understanding of assessing and working with individuals using augmentative and alternative communication.

Anti-oxidative and anti-proliferative activities of extracted phytochemical compound thymoquinone.

OBJECTIVE: To evaluate the anti-oxidant and anti-proliferative potential of Thymoquinone extracted from the essential oil of indigenous herbs of Nigella sativa and Thymus vulgaris. METHODS: Extraction and quantification of Thymoquinone was carried out in July, 2017 in Department of Environmental Science, Lahore College for Women University (LCWU), Lahore. Thymoquinone was extracted from seeds of Nigella Sativa and aerial parts of Thymus vulgaris by employing soxhlet extraction with 1:4 ratios of nhexane and methanol. High Performance Liquid Chromatography was used to quantify Thymoquinone from the methanolic extracted oil of sample by applying calibration curve method. Extracted Thymoquinone was identified by sample peaks obtained at retention time were compared with peak of standard Thymoquinone at respective time. The Thymoquinone obtained from both samples was then subjected to Fourier-transform infrared spectroscopy for confirmation by identifying its functional groups. Anti-oxidant activities of both samples were measured using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric Reducing Antioxidant Power (FRAP) assay in Department of Environmental Science, LCWU. In-vitro anti-proliferative activities of extracted Thymoquinone were evaluated in HeLa cell cancer lines by cell proliferations Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay in Department of Microbiology, University of Veterinary and Animal Sciences (UVAS), Lahore. SPSS 18 and Graph pad prism 18 was used for data analysis. RESULTS: Soxhlet extraction with solvents ratios yielded 48.92% oil from Nigella sativa and 23.2 % from Thymus vulgaris. High Performance Liquid Chromatography peak of standard Thymoquinone was measured at retention time of 5.5 min which was then compared with the peak obtained from both samples at the similar retention time. The extracted Thymoquinone from both samples were quantified by calibration curve method showing 614.25 mg/L from Nigella sativa and 548.86 mg/L from Thymus vulgaris. The two anti-oxidant assays of both samples compared with standard Thymoquinone showed significant scavenging activities in dose amount manner. Cell proliferation of HeLa cancer significantly decreased with dose response manner (p<0.01), showing highest cell death in high concentration of Thymoquinone. Inhibitory concentration 50 (IC50) of cancer cell line treated with Nigella sativa oil was 0.5 µM and Thymus vulgaris was 18 µM compared to standard Thymoquinone, showing Inhibitory concentration50 (IC50) of 6 µM using Graph pad prism v.8.0. CONCLUSION: Both Nigella sativa and Thymus vulgaris were found to be the best source of Thymoquinone as chemotherapeutic drug expressed potent anti-oxidant and anti-proliferative activities.

A review: Therapeutics potentials of phytochemical drugs and their loading in pH specific degradable Nano-drug carrier targeting colorectal cancer.

Increasing incidents of colorectal cancer have shifted researchers' attention to the production and improvement of anti-cancer drugs by the scientific investigation of vast pool of synthetic, biological and natural products. Thymoquinone and thymohydroquinone are considered the ideal compounds for the cancer therapy as they are economically and environmental friendly and have less toxicity level to the survival and diseased model up to increased dosage level. For colorectal cancer, researches are shifting towards the oral drug delivery instead of injection, as administering drugs through oral route shows maximum absorption of drugs, improves patient life quality and is cost-effective. Naturally occurring polysaccharides as oral drug carriers, such as pectin, have the ability to break down completely in colon, making it suitable for targeted drug delivery against cancer cells. Pectin with polymeric base is an efficient nano drug carrier. The current study reviews the delivery of thymoquinone/thymohydroquinone through pectin nano carriers to treat colorectal cancer.

Legacy and emerging flame retardants (FRs) in the freshwater ecosystem: A review.

In this review article, we have compiled and reviewed the previously published available literature on environmental distribution, behaviour, fate and regional trends of legacy and emerging flame retardants (FRs) including brominated (BFRs), organo-phosphate (OPFRs), novel brominated flame retardants (NBFRs) and dechlorane plus (DP) in the freshwater ecosystem. Transport and fate is discussed briefly with the evidences of de-bromination, sedimentation and accumulation in biota. De-bromination of BDE-209 is considered of concern because the lower brominated congeners are more toxic and mobile thus posing increased risk to the freshwater ecosystem. The available data on temporal and spatial trends as yet, is too few to show any consistent trends, enabling only general conclusions to be drawn. There is a lack of temporal studies in Asia, while, overall the trends are mixed, with both increasing and decreasing concentrations of BFRs and OPFRs. OPFRs and NBFRs have replaced classical BFRs (polybrominated diphenyl ethers (PBDEs)) in some countries but the amount of PBDEs in the environment is still considerable. Knowledge gaps and recommendations for future research are discussed emphasizing on further monitoring, advanced analytical methodologies, and risk assessment studies to completely understand the science of flame retardants in the freshwater ecosystem.

Cost-effectiveness of rapid vs in-house vs send-out ADAMTS13 testing for immune thrombotic thrombocytopenic purpura.

ABSTRACT: While awaiting confirmatory results, empiric therapy for patients suspected to have immune thrombotic thrombocytopenic purpura (iTTP) provides benefits and also accrues risks and costs. Rapid assays for ADAMTS13 may be able to avoid the cost and risk exposure associated with empiric treatment. We conducted, to our knowledge, the first cost-effectiveness evaluation of testing strategies with rapid vs traditional ADAMTS13 assays in patients with intermediate- to high-risk PLASMIC scores, with and without caplacizumab use. We built a Markov cohort simulation with 4 clinical base-case analyses: (1) intermediate-risk PLASMIC score with caplacizumab; (2) intermediate-risk PLASMIC score without caplacizumab; (3) high-risk PLASMIC score with caplacizumab; and (4) high-risk PLASMIC score without caplacizumab. Each of these evaluated 3 testing strategies: (1) rapid assay (<1-hour turnaround); (2) in-house fluorescence resonance energy transfer (FRET)-based assay (24-hour turnaround); and (3) send-out FRET-based assay (72-hour turnaround). The primary outcome was the incremental net monetary benefit reported over a 3-day time horizon and across accepted willingness-to-pay thresholds in US dollars per quality-adjusted life-year (QALY). While accruing the same amount of QALYs, the rapid assay strategy saved up to $46 820 (95% CI, $41 961-$52 486) per patient tested. No parameter variation changed the outcome. In probabilistic sensitivity analyses, the rapid assay strategy was favored in 100% (3 base cases and scenario analyses) and 99% (1 base-case and scenario analysis) across 100 000 Monte Carlo iterations within each. Rapid ADAMTS13 testing for patients with intermediate- or high-risk PLASMIC scores yields significant per patient cost savings, achieved by reducing the costs associated with unnecessary therapeutic plasma exchange and caplacizumab therapy in patients without iTTP.

Cost-effectiveness of bevacizumab therapy in the care of patients with hereditary hemorrhagic telangiectasia.

ABSTRACT: No US Food and Drug Administration- or European Medicines Agency-approved therapies exist for bleeding due to hereditary hemorrhagic telangiectasia (HHT), the second-most common inherited bleeding disorder worldwide. The current standard of care (SOC) includes iron and red cell supplementation, alongside the necessary hemostatic procedures, none of which target underlying disease pathogenesis. Recent evidence has demonstrated that bleeding pathophysiology is amenable to systemic antiangiogenic therapy with the anti-vascular endothelial growth factor bevacizumab. Despite its high cost, the addition of longitudinal bevacizumab to the current SOC may reduce overall health care resource use and improve patient quality of life. We conducted, to our knowledge, the first cost-effectiveness analysis of IV bevacizumab in patients with HHT with the moderate-to-severe phenotype, comparing bevacizumab added to SOC vs SOC alone. The primary outcome was the incremental net monetary benefit (iNMB) reported over a lifetime time horizon and across accepted willingness-to-pay thresholds, in US dollar per quality-adjusted life year (QALY). Bevacizumab therapy accrued 9.3 QALYs while generating $428 000 in costs, compared with 8.3 QALYs and $699 000 in costs accrued in the SOC strategy. The iNMB of bevacizumab therapy vs the SOC was $433 000. No parameter variation and no scenario analysis, including choice of iron supplementation product, changed the outcome of bevacizumab being a cost-saving strategy. Bevacizumab therapy also saved patients an average of 133 hours spent receiving HHT-specific care per year of life. In probabilistic sensitivity analysis, bevacizumab was favored in 100% of all 10 000 Monte Carlo iterations across base-case and all scenario analyses. Bevacizumab should be considered for more favorable formulary placement in the care of patients with moderate-to-severe HHT.

From Antibodies to Artificial Intelligence: A Comprehensive Review of Diagnostic Challenges in Hashimoto's Thyroiditis.

Hashimoto's thyroiditis (HT) poses diagnostic challenges due to its diverse clinical presentation and the intricacies of autoimmune thyroid diseases. This comprehensive narrative review explores the evolving landscape of diagnostic challenges in HT, aiming to provide a thorough understanding of the complexities involved in its diagnosis. The diagnostic criteria for HT involve a multifaceted approach, including clinical features, laboratory findings, and imaging studies. Serum antibodies against thyroid antigens, primarily thyroperoxidase (TPO) and thyroglobulin, play a crucial role in confirming the autoimmune nature of the disease. However, seronegative HT adds complexity by presenting without detectable antibodies. The significance of addressing diagnostic challenges lies in potential delays and misdiagnoses, emphasizing the need for accurate and timely intervention. The review explores future directions, emphasizing molecular and cellular aspects, genetic factors, and the emerging field of thyroid regeneration. Standardized diagnostic criteria are essential, considering the subjective nature of the current process. The heterogeneity of disease manifestations complicates targeted treatments, necessitating a deeper understanding of clinical presentations and underlying pathophysiology. Future research directions and challenges outlined in this review contribute to advancing our understanding and improving diagnostic precision in HT.