An ensemble approach to accurately detect somatic mutations using SomaticSeq

SomaticSeq is an accurate somatic mutation detection pipeline implementing a stochastic boosting algorithm to produce highly accurate somatic mutation calls for both single nucleotide variants and small insertions and deletions. The workflow currently incorporates five state-of-the-art somatic mutation callers, and extracts over 70 individual genomic and sequencing features for each candidate site. A training set is provided to an adaptively boosted decision tree learner to create a classifier for predicting mutation statuses. We validate our results with both synthetic and real data. We report that SomaticSeq is able to achieve better overall accuracy than any individual tool incorporated. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0758-2) contains supplementary material, which is available to authorized users

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

AS-SI’DĪ’S EXPOSITION ON AL-ADILLAH: ANCHORING ISLAMIC JURISPRUDENCE IN QUR’ĀNIC AND PROPHETIC FOUNDATIONS

This paper delves into the profound contributions of ‘Abdur Raḥmān Nāṣir As-Si’dī in elucidating the concept of Al-Adillah within the realm of Islamic jurisprudence. By exploring As-Si’dī’s systematic approach to the evidentiary sources of Fiqh, the study underscores the centrality of the Qur’ān and the Sunnah, alongside the complementary roles of Ijmā’ (consensus) and Al-Qiyās Aṣ-Ṣaḥīḥ (sound analogy), as foundational pillars for deriving legal rulings. As-Si’dī’s work reaffirms the integration and coherence of these sources within the Islamic legal framework, countering claims that Fiqh is devoid of scriptural basis. This investigation highlights As-Si’dī’s insistence on the rootedness of Islamic Aḥkām in these evidences, whether through direct textual references, scholarly consensus, or rational deduction. The paper emphasizes that true jurisprudential understanding and application hinge on tracing legal reasoning back to these established sources, a principle deeply embedded in traditional Islamic scholarship. Through As-Si’dī’s lens, the paper reveals the depth of Islamic legal theory’s fidelity to its foundational texts, offering insights into the enduring relevance and unity of Islamic jurisprudence

Clinical evaluation of Tukhm-e-Sambhalu (Vitex negundo Linn. seed) in Usr-e-Tams Ibtedayee (primary dysmenorrhoea)

563-567Primary dysmenorrhoea is painful menstrual cramps of uterine origin during menstruation without any identifiable pathological lesion. It is commonly seen in menstruating and lasting 12-24 h. Its prevalence is wide, as more than 70% of teenagers and 30-50% of menstruating women suffer from varying degree of discomfort. Tibbe-e-Unani claims to possess safe and effective therapeutic substances which are commonly prescribed in the management of primary dysmenorrhoea (Usr-e-Tams Ibtedayee), but despite being used in the treatment successfully, most of them have yet not been studied scientifically. Therefore, an attempt has been made in the present study to evaluate a single Unani drug Tukhm-e-Sambhalu (Vitex negundo) on 30 patients for its efficacy in primary dysmenorrhoea. The patients were administered test drug in powder form (5 g), by oral rout, twice a day for 7 days, starting 2 days before the onset of menstruation up to 5th day of menses, for three consecutive cycles. The important clinical features like pain in suprapubic region, pain in thigh, backache and headache were significantly reduced in patients treated with test drug. Thus, findings of this study suggested that Tukhm-e-Sambhalu is safe and effective in ameliorating the disease primary dysmenorrhoea

Clinical evaluation of Tukhm-e-Sambhalu (Vitex negundo Linn. seed) in Usr-e-Tams Ibtedayee (primary dysmenorrhoea)

Primary dysmenorrhoea is painful menstrual cramps of uterine origin during menstruation without any identifiable pathological lesion. It is commonly seen in menstruating and lasting 12-24 h. Its prevalence is wide, as more than 70% of teenagers and 30-50% of menstruating women suffer from varying degree of discomfort. Tibbe-e-Unani claims to possess safe and effective therapeutic substances which are commonly prescribed in the management of primary dysmenorrhoea (Usr-e-Tams Ibtedayee), but despite being used in the treatment successfully, most of them have yet not been studied scientifically. Therefore, an attempt has been made in the present study to evaluate a single Unani drug Tukhm-e-Sambhalu (Vitex negundo) on 30 patients for its efficacy in primary dysmenorrhoea. The patients were administered test drug in powder form (5 g), by oral rout, twice a day for 7 days, starting 2 days before the onset of menstruation up to 5th day of menses, for three consecutive cycles. The important clinical features like pain in suprapubic region, pain in thigh, backache and headache were significantly reduced in patients treated with test drug. Thus, findings of this study suggested that Tukhm-e-Sambhalu is safe and effective in ameliorating the disease primary dysmenorrhoea

Artificial intelligence based advancements in nanomedicine for brain disorder management: an updated narrative review

Nanomedicines are nanoscale, biocompatible materials that offer promising alternatives to conventional treatment options for brain disorders. The recent technological developments in artificial intelligence (AI), particularly machine learning (ML) and deep learning (DL), are transforming the nanomedicine field by improving disease diagnosis, biomarker identification, prognostic assessment and disease monitoring, targeted drug delivery, and therapeutic intervention as well as contributing to computational and methodological developments. These advancements can be achieved by analysis of large clinical datasets and facilitating the design and optimization of nanomaterials for in vivo testing. Such advancement offers exciting possibilities for the improvement in the management of brain disorders, including brain cancer, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, where early diagnosis, targeted delivery, and effective treatment strategies remain a great challenge. This review article provides an overview of recent advances in AI-based nanomedicine development to accelerate effective and quick diagnosis, biomarker identification, prognosis, drug delivery, methodological advancement and patient-specific therapies for managing brain disorders

The challenge of estimating tuberculosis mortality accurately in England and Wales

BACKGROUND: Accurate estimates of tuberculosis (TB) mortality are required to monitor progress towards the World Health Organization End TB goal of reducing TB deaths by 95% by 2035. We compared TB death data for England and Wales from the national surveillance system (Enhanced Tuberculosis Surveillance System [ETS]) and the vital registration system from the Office for National Statistics (ONS). METHODS: TB cases notified in ETS were matched to deaths in ONS (dONS) with International Classification of Diseases, Tenth Revision (ICD-10) codes indicating that TB caused/contributed to the death (A15–A19). Deaths captured in one but not both systems were assessed to identify if ONS captured all TB deaths and if there was under-notification of TB in ETS. We stratified deaths into active TB, TB sequelae, incidental deaths and not TB. RESULTS: Between 2005 and 2015, there were fewer deaths in ETS (dETS) than dONS with ICD-10 codes A15–A19 (n = 4207 vs. n = 6560); 57% of dETS were recorded as dONS and 53% of dONS were notified to ETS. A total of 9289 deaths were identified from dETS and dONS: 64% were due to active TB, 23% were TB sequelae, 6% were incidental and 7% were not TB. CONCLUSIONS: TB deaths in ETS and ONS differ substantially. Almost one third of TB deaths recorded by ONS are not due to active TB; this can be amended through coding changes

Circular DNA elements of chromosomal origin are common in healthy human somatic tissue

Somatic cells can accumulate structural variations such as deletions. Here, Møller et al. show that normal human cells generate large extrachromosomal circular DNAs (eccDNAs), most likely the products of excised DNA, that can be transcriptionally active and, thus, may have phenotypic consequences

Post-COVID-19 Invasive Fungal Sinusitis: A Case Series from Southern India

Acute Invasive Fungal Rhinosinusitis (AIFR) is a serious condition with aggressive course and high mortality rates. There is an upsurge in the incidence of invasive fungal rhinosinusitis in post COVID-19 patients. We have come across 20 AIFR cases in post COVID-19 patients. On retrospective exploration of the patient’s records, we found that 30% patients had received steroids and 90% had diabetes. All the patients were managed by administration of IV amphotericin B and local debridement of infected tissues. The mortality rate was as low as 15 %. We conclude that combined approach of Antifungal therapy with debridement of infected tissues improves the prognosis and survival of AIFR patients

Involvement of TSC genes and differential expression of other members of the mTOR signaling pathway in oral squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Despite extensive research, the five-year survival rate of oral squamous cell carcinoma (OSCC) patients has not improved. Effective treatment of OSCC requires the identification of molecular targets and signaling pathways to design appropriate therapeutic strategies. Several genes from the mTOR signaling pathway are known to be dysregulated in a wide spectrum of cancers. However, not much is known about the involvement of this pathway in tumorigenesis of OSCC. We therefore investigated the role of the tumor suppressor genes, <it>TSC1 </it>and <it>TSC2</it>, and other members of this pathway in tumorigenesis of OSCC.</p> <p>Methods</p> <p>Expression of genes at the RNA and protein levels was examined by semi-quantitative RT-PCR and western blot analyses, respectively. Loss of heterozygosity was studied using matched blood and tumor DNA samples and microsatellite markers from the <it>TSC1</it>, <it>TSC2 </it>and <it>PTEN </it>candidate regions. The effect of promoter methylation on TSC gene expression was studied by treating cells with methyltransferase inhibitor 5-azacytidine. Methylation status of the <it>TSC2 </it>promoter in tissue samples was examined by combined bisulfite restriction analysis (COBRA).</p> <p>Results</p> <p>The semi-quantitative RT-PCR analysis showed downregulation of <it>TSC1</it>, <it>TSC2</it>, <it>EIF4EBP1 </it>and <it>PTEN</it>, and upregulation of <it>PIK3C2A</it>, <it>AKT1</it>, <it>PDPK1</it>, <it>RHEB</it>, <it>FRAP1</it>, <it>RPS6KB1</it>, <it>EIF4E </it>and <it>RPS6 </it>in tumors. A similar observation was made for AKT1 and RPS6KB1 expression in tumors at the protein level. Investigation of the mechanism of downregulation of TSC genes identified LOH in 36.96% and 39.13% of the tumors at the TSC1 and TSC2 loci, respectively. No mutation was found in TSC genes. A low LOH rate of 13% was observed at the PTEN locus. Treatment of an OSCC cell line with the methyltransferase inhibitor 5-azacytidine showed a significant increase in the expression of TSC genes, suggesting methylation of their promoters. However, the 5-azacytidine treatment of non-OSCC HeLa cells showed a significant increase in the expression of the <it>TSC2 </it>gene only. In order to confirm the results in patient tumor samples, the methylation status of the <it>TSC2 </it>gene promoter was examined by COBRA. The results suggested promoter hypermethylation as an important mechanism for its downregulation. No correlation was found between the presence or absence of LOH at the TSC1 and TSC2 loci in 50 primary tumors to their clinicopathological variables such as age, sex, T classification, stage, grade, histology, tobacco habits and lymph node metastasis.</p> <p>Conclusion</p> <p>Our study suggests the involvement of TSC genes and other members of the mTOR signaling pathway in the pathogenesis of OSCC. LOH and promoter methylation are two important mechanisms for downregulation of TSC genes. We suggest that known inhibitors of this pathway could be evaluated for the treatment of OSCC.</p