Predicting regulatory mutations and their target genes by new computational integrative analysis: A study of follicular lymphoma.

Mutations in DNA regulatory regions are increasingly being recognized as important drivers of cancer and other complex diseases. These mutations can regulate gene expression by affecting DNA-protein binding and epigenetic profiles, such as DNA methylation in genome regulatory elements. However, identifying mutation hotspots associated with expression regulation and disease progression in non-coding DNA remains a challenge. Unlike most existing approaches that assign a mutation score to individual single nucleotide polymorphisms (SNP), a mutation block (MB)-based approach was introduced in this study to assess the collective impact of a cluster of SNPs on transcription factor-DNA binding affinity, differential gene expression (DEG), and nearby DNA methylation. Moreover, the long-distance target genes of functional MBs were identified using a new permutation-based algorithm that assessed the significance of correlations between DNA methylation at regulatory regions and target gene expression. Two new Python packages were developed. The Differential Methylation Region (DMR-analysis) analysis tool was used to detect DMR and map them to regulatory elements. The second tool, an integrated DMR, DEG, and SNP analysis tool (DDS-analysis), was used to combine the omics data to identify functional MBs and long-distance target genes. Both tools were validated in follicular lymphoma (FL) cohorts, where not only known functional MBs and their target genes (BCL2 and BCL6) were recovered, but also novel genes were found, including CDCA4 and JAG2, which may be associated with FL development. These genes are linked to target gene expression and are significantly correlated with the methylation of nearby DNA sequences in FL. The proposed computational integrative analysis of multiomics data holds promise for identifying regulatory mutations in cancer and other complex diseases.

Acute diverticulitis of the appendix.

Acute diverticulitis of the appendix (ADA), though uncommon, often presents similarly to acute appendicitis but carries a higher risk of complications such as perforation and malignancy. We report the case of a male patient in his 50s with acute right iliac fossa abdominal pain, diagnosed via CT scan with ADA. Urgent laparoscopic appendicectomy was performed, and the patient was discharged without further issues. This case highlights the importance of promptly identifying and managing such conditions to minimise complications and improve outcomes. Despite the overlap in symptoms between appendiceal diverticulitis and acute appendicitis, accurate diagnosis is crucial for appropriate treatment. Healthcare providers should maintain a high index of suspicion, particularly in older patients presenting with an acute appendicitis, like clinical picture to ensure timely intervention and optimal patient care.

Understanding GPs' referral decisions for younger patients with symptoms of cancer: a qualitative interview study.

BACKGROUND: Cancer incidence increases with age, so some clinical guidelines include patient age as one of the criteria used to decide whether a patient should be referred through the urgent suspected cancer (USC) pathway. Little is known about how strictly GPs adhere to these age criteria and what factors might influence their referral decisions for younger patients. AIM: To understand GPs' clinical decision making for younger patients with concerning symptoms who do not meet the age criteria for USC referral. DESIGN AND SETTING: Qualitative study using in-depth, semi-structured interviews with GPs working in surgeries across England. METHOD: Participants (n = 23) were asked to recall consultations with younger patients with cancer symptoms, describe factors influencing their clinical decisions, and discuss their overall attitude to age thresholds in cancer referral guidelines. A thematic analysis guided by the Framework approach was used to identify recurring themes. RESULTS: GPs' decision making regarding younger patients was influenced by several factors, including personal experiences, patients' views and behaviour, level of clinical concern, and ability to bypass system constraints. GPs weighted potential benefits and harms of a referral outside guidelines both on the patient and the health system. If clinical concern was high, GPs used their knowledge of local systems to ensure patients were investigated promptly even when not meeting the age criteria. CONCLUSION: While most GPs interpret age criteria flexibly and follow their own judgement and experience when making clinical decisions regarding younger patients, system constraints may be a barrier to timely investigation.

Performance of myotonometer in the assessment of skin involvement in systemic sclerosis.

OBJECTIVES: A clinically practical tool to assess skin biomechanical properties rapidly and accurately is still lacking. Our aim was to examine the intra- and inter-observer reproducibility of a myotonometer for objective skin property assessment in systemic sclerosis (SSc), comparing it with the modified Rodnan skin score (mRSS), and distinguishing patients from healthy controls. METHOD: Thirty-four patients (21 limited and 13 diffuse SSc), and 31 age and gender-matched healthy controls were enrolled. Skin tone and stiffness were measured at four different anatomical sites (the forearm, hand, leg, and foot) using a myotonometer. The correlation between the mRSS and skin properties was assessed. Also, hand functionality was evaluated for possible correlations between the variables. The differences in skin properties between dcSSc and lcSSc patients, and healthy controls were assessed using variance analysis. RESULTS: Intra- and inter-examiner reproducibility were excellent (ICC = 0.70 to 0.98) for tone and stiffness except for non-dominant hand tone, which showed good reliability (ICC = 0.64 to 0.74). Stiffness and tone values of the hands, forearms, and feet significantly correlated with mRSS total score (r = 0.40 to 0.71, p < 0.05). Additionally, tone and stiffness of the hands and forearms moderately correlated with hand function (p < 0.05). Tone and stiffness values increased in patients with dcSSc compared to healthy controls, or patients with lcSSc, at the hands, forearms, and legs (p < 0.05). CONCLUSIONS: Our findings emphasize the potential utility of the myotonometer for assessing skin properties and differentiating SSc patients from controls, demonstrating its promise as a valuable clinical evaluation tool in this context. Key Points •The myotonometer displayed excellent intra- and inter-examiner reproducibility for assessing skin properties. •Skin tone and stiffness parameters well correlated with the mRSS scores. •The myotonometer can distinguish patients with diffuse cutaneous SSc from healthy controls.

An evaluation of the Birchwood Junk Food Café, Skelmersdale.

Food waste is an issue of global concern requiring worldwide action. In the UK, £19 billion worth of food is wasted every year. A variety of initiatives have been developed to redistribute surplus food to those in need. The Birchwood Junk Food Café in Skelmersdale combines the reduction of food waste with community and societal benefits. The University of Manchester and the Birchwood Centre conducted an evaluation of the café including a customer satisfaction survey, a long-form health and wellbeing survey and qualitative interviews. Each day the café produces a three-course menu for the public on a 'pay-as-you-feel' basis. During an 18-month period, the café intercepted 32 729 kg of food that would otherwise have gone to waste, served over 1500 people, with 3500 covers, 60 different dishes and 1200 volunteer hours. Customer satisfaction was extremely high with 88% being repeated visitors and 86% rating the café as excellent. Volunteers include youth from the local Birchwood Centre, who gain valuable experiences. Customers benefit from social interactions and additional community cohesion. The café offers an unique opportunity to impact on the wider community and provides support and structure for the volunteers.

Assessment of drug-susceptible and multidrug-resistant tuberculosis (MDR-TB) in the Central Region of Somalia: A 3-year retrospective study.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) remains a public health emergency and a threat globally. Although increasing MDR-TB cases have been recently reported in Somalia, limited information is known. This study aims to determine the prevalence of drug-susceptible and MDR-TB in suspected patients referred to the TB Department in Mudug Hospital, Galkayo, Somalia, and identify potential factors associated with MDR-TB. METHODS: A 3-year hospital laboratory-based retrospective study was conducted by manually reviewing laboratory records of Mycobacterium tuberculosis specimens and GeneXpert MTB/RIF results from January 2019 to December 2021 at the reference mycobacteria laboratory department in Mudug Hospital. RESULTS: A total of 714 positive GeneXpert-MTB results were identified: 619 (86.7%) were drug susceptible (no Rifampin resistance [RR] detected) and 95 (13.3%) with RR detected or defined as MDR-TB. Most of the MDR-TB patients were males (71.6%, 68/95) and between the ages of 15 to 24 (31.6%, 30/95). Most isolates were collected in 2021 (43.2%, 41/95). Multivariate analyses show no significant difference between patients having MDR-TB and/or drug-susceptible TB for all variables. CONCLUSION: This study showed an alarming frequency of MDR-TB cases among M. tuberculosis-positive patients at a regional TB reference laboratory in central Somalia.

Recent advances in dynamic modeling and control studies of biomass gasification for production of hydrogen rich syngas.

The conversion of biomass through thermochemical processes has emerged as a promising approach to meet the demand for alternative renewable fuels. However, these processes are complex, labor-intensive, and time-consuming. To optimize the performance and productivity of these processes, modeling strategies have been developed, with steady-state modeling being the most commonly used approach. However, for precision in biomass gasification, dynamic modeling and control are necessary. Despite efforts to improve modeling accuracy, deviations between experimental and modeling results remain significant due to the steady-state condition assumption. This paper emphasizes the importance of using Aspen Plus® to conduct dynamics and control studies of biomass gasification processes using different feedstocks. As Aspen Plus® is comprising of its Aspen Dynamics environment which provides a valuable tool that can capture the complex interactions between factors that influence gasification performance. It has been widely used in various sectors to simulate chemical processes. This review examines the steady-state and dynamic modeling and control investigations of the gasification process using Aspen Plus®. The software enables the development of dynamic and steady-state models for the gasification process and facilitates the optimization of process parameters by simulating various scenarios. Furthermore, this paper highlights the importance of different control strategies employed in biomass gasification, utilizing various models and software, including the limited review available on model predictive controller, a multivariable MIMO controller.

Identifying functional regulatory mutation blocks by integrating genome sequencing and transcriptome data.

Millions of single nucleotide variants (SNVs) exist in the human genome; however, it remains challenging to identify functional SNVs associated with diseases. We propose a non-encoding SNVs analysis tool bpb3, BayesPI-BAR version 3, aiming to identify the functional mutation blocks (FMBs) by integrating genome sequencing and transcriptome data. The identified FMBs display high frequency SNVs, significant changes in transcription factors (TFs) binding affinity and are nearby the regulatory regions of differentially expressed genes. A two-level Bayesian approach with a biophysical model for protein-DNA interactions is implemented, to compute TF-DNA binding affinity changes based on clustered position weight matrices (PWMs) from over 1700 TF-motifs. The epigenetic data, such as the DNA methylome can also be integrated to scan FMBs. By testing the datasets from follicular lymphoma and melanoma, bpb3 automatically and robustly identifies FMBs, demonstrating that bpb3 can provide insight into patho-mechanisms, and therapeutic targets from transcriptomic and genomic data.

Comprehensive genetic analyses of childhood acute leukemia in Iraq using next-generation sequencing.

Background: Molecular analyses in hematological malignancies provide insights about genetic makeup. Probable etiological factors in leukemogenesis could also be disclosed. Since genetic analyses are still primitive in Iraq, a country of repeated wars, we conceived of performing next-generation sequencing (NGS), to disclose the genomic landscape of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) among a cohort of Iraqi children. Methods: Dried blood samples were collected from Iraqi children with ALL (n=55), or AML (n=11), and transferred to Japan where NGS was done. Whole-exome, whole-genome, and targeted gene sequencings were performed. Results: Somatic point mutations and the copy number variations among Iraqi children with acute leukemia were comparable with those in other countries, and cytosine-to-thymine nucleotide alterations were dominant. Strikingly, TCF3-PBX1 was the most recurrent fusion gene (22.4%) in B-cell precursor ALL (B-ALL), and acute promyelocytic leukemia (AML-M3) was subtyped in 5 AML cases. Additionally, a high frequency of RAS signaling pathway mutations was detected in children with B-ALL (38.8%), along with 3 AML cases that carried oncogenic RAS. Conclusions: Apart from disclosing the high frequency of TCF3-PBX1, NGS confirmed our previous finding of recurrent RAS mutations in Iraqi childhood acute leukemia. Our results suggest that the biology of Iraqi childhood acute leukemia is in part characteristic, where the war-aftermath environment or geography might play a role.

Patients' views on the decision to investigate cancer symptoms in older adults: a qualitative interview study in primary care.

BACKGROUND: Cancer is predominantly a disease of older adults. To date there has been little research on the experiences of older adults or their views on the diagnostic pathway. AIM: To gain an improved understanding of the views and experiences of older adults on all aspects of cancer investigation. DESIGN AND SETTING: This was a qualitative study using semi-structured interviews with patients aged ≥70 years. Patients were recruited from primary care in West Yorkshire, UK. METHOD: Data were analysed using a thematic framework analysis. RESULTS: The themes identified in participants' accounts included the patients' process of decision making, the value of having a diagnosis, the patients' experience of cancer investigations, and the impact of the COVID-19 pandemic on the diagnostic pathway. Older adults in this study indicated a clear preference for having clarity on the cause of symptoms and the diagnosis, even in the face of unpleasant investigations. Patients suggested they wanted to be involved in the decision process. CONCLUSION: Older adults who present to primary care with symptoms suggestive of cancer may accept diagnostic testing solely for the benefit of knowing the diagnosis. There was a clear patient preference that referrals and investigations for cancer symptoms should not be deferred or delayed based on age or subjective assessments of frailty. Shared decision making and being involved in the decision-making process are important to patients, regardless of age.

A Systematic Review and Meta-Analysis of Bag Extraction Versus Direct Extraction for Retrieval of Gallbladder After Laparoscopic Cholecystectomy.

This analysis aims to evaluate the comparative outcomes of gallbladder extraction with a bag versus direct extraction in laparoscopic cholecystectomy (LC). A systematic online search was conducted using the following databases: PubMed, Scopus, Cochrane database, The Virtual Health Library, Clinical trials.gov, and Science Direct. Comparative studies comparing bag versus direct extraction of the gallbladder in LC were included. Outcomes were surgical site infection (SSI), the extension of fascial defect to extract the gallbladder, intra-abdominal collection, bile spillage, and port-site hernia. Revman 5.4 (Cochrane, London, United Kingdom) was used for the data analysis. The results show eight studies were eligible to be included in this review with a total number of 1805 patients divided between endo-bag (n=835) and direct extraction (n=970). Four of the included studies were randomized controlled trials (RCTs) while the rest were observational studies. The rate of SSI and bile spillage were significantly higher in the direct extraction group: odds ratio (OR)=2.50, p=0.006 and OR=2.83, p=0.01, respectively. Comparable results were observed regarding intra-abdominal collection between the two groups(OR=0.01, p=0.51). However, the extension of a fascial defect was higher in the endo-bag group (OR=0.22, p=0.00001), and no difference was observed regarding the port-site hernia rate (OR-0.70, p=0.55). In conclusion, extraction of the gallbladder with an endo-bag provides a lower rate of SSI and bile spillage with similar results regarding post-operative intra-abdominal collection. Although with the endo-bag, the fascial defect will more likely need to be increased to extract the gallbladder. However, the port-site hernia rate remains similar between the two groups.

Paediatric haemophagocytic lymphohistiocytosis: clinical presentation and outcome of 20 patients at a single institution.

Paediatric haemophagocytic lymphohistiocytosis (pHLH) is a potentially life-threatening condition with significant diagnostic and therapeutic difficulties. The purpose of this study was to describe the clinical presentation, the diagnostic challenges, and the outcomes of haemophagocytic lymphohistiocytosis (HLH) in children assessed at Mukalla Hospital, Yemen. Data from 20 medical records of HLH patients admitted between January 2010 and May 2022 were retrospectively analysed. The median age at presentation was 3.5 ± 5.1 years. Male: female ratio was 1:1. The median time for referral to the hospital was 30 ± 64 days. The most common clinical manifestations were fever and pallor in 95% of cases, and splenomegaly (85%). Hepatomegaly, chest, renal and neurological manifestations were detected in 80%, 45%, 15% and 20% of cases, respectively. Bone marrow haemophagocytosis was detected in 60% of cases. Sixteen patients fulfilled the HLH diagnostic criteria, and 11 patients (55%) received the HLH 2004 protocol. Out of the 20 patients, three (15%) patients are alive. Fourteen patients died, with overall mortality of 82.35%. All mortalities were due to HLH disease with multi-organ failure. Relapse was noticed in five patients either during treatment or after full recovery. pHLH is a challenging emergency with a high mortality rate. High clinical suspicion is essential for early detection and intervention to improve the prognosis.

Primary central nervous system lymphoma: a real-world comparison of therapy access and outcomes by hospital setting.

Background: This study analyzes sociodemographic barriers for primary CNS lymphoma (PCNSL) treatment and outcomes at a public safety-net hospital versus a private tertiary academic institution. We hypothesized that these barriers would lead to access disparities and poorer outcomes in the safety-net population. Methods: We reviewed records of PCNSL patients from 2007-2020 (n = 95) at a public safety-net hospital (n = 33) and a private academic center (n = 62) staffed by the same university. Demographics, treatment patterns, and outcomes were analyzed. Results: Patients at the safety-net hospital were significantly younger, more commonly Black or Hispanic, and had a higher prevalence of HIV/AIDS. They were significantly less likely to receive induction chemotherapy (67% vs 86%, P = .003) or consolidation autologous stem cell transplantation (0% vs. 47%, P = .001), but received more whole-brain radiation therapy (35% vs 16%, P = .001). Younger age and receiving any consolidation therapy were associated with improved progression-free (PFS, P = .001) and overall survival (OS, P = .001). Hospital location had no statistical impact on PFS (P = .725) or OS (P = .226) on an age-adjusted analysis. Conclusions: Our study shows significant differences in treatment patterns for PCNSL between a public safety-net hospital and an academic cancer center. A significant survival difference was not demonstrated, which is likely multifactorial, but likely was positively impacted by the shared multidisciplinary care delivery between the institutions. As personalized therapies for PCNSL are being developed, equitable access including clinical trials should be advocated for resource-limited settings.

Clinical implementation of HyperArc.

The aim of this study was to present our experience on clinical implementation of HyperArc including dosimetric comparison between VMAT and HyperArc plans and dosimetric verification of HyperArc. In this study, eleven previously treated cases of brain metastasis were selected from our brain stereotactic radiotherapy program. The cases were retrospectively planned using HyperArc technique and the plan quality was evaluated. In addition, dosimetric effects of HyperArc plan with different energies and using jaw tracking technique were evaluated. Furthermore, dosimetric verification of HyperArc plans was performed using ion chamber and radiochromic film. Our results of dosimetric comparison shows that HyperArc technique improved both conformity index and gradient index compared to VMAT plans. We also found that using 6MV flattening filter free (6MV-FFF) beam improves gradient index in HyperArc plans compared to using 6MV flattening filter beam. Furthermore, our results show that jaw tracking technique reduces the size of low dose volume while maintaining similar target coverage, conformity index, and gradient index. In our dosimetric verification study, results of ion chamber and film measurement indicate no significant difference between VMAT and HyperArc plans. In conclusion, HyperArc simplifies planning of stereotactic treatment for brain and improves the dosimetry in treatment plans. Additionally, HyperArc provides for a safe and efficient treatment delivery system for stereotactic treatments to brain.

abc4pwm: affinity based clustering for position weight matrices in applications of DNA sequence analysis.

BACKGROUND: Transcription factor (TF) binding motifs are identified by high throughput sequencing technologies as means to capture Protein-DNA interactions. These motifs are often represented by consensus sequences in form of position weight matrices (PWMs). With ever-increasing pool of TF binding motifs from multiple sources, redundancy issues are difficult to avoid, especially when every source maintains its own database for collection. One solution can be to cluster biologically relevant or similar PWMs, whether coming from experimental detection or in silico predictions. However, there is a lack of efficient tools to cluster PWMs. Assessing quality of PWM clusters is yet another challenge. Therefore, new methods and tools are required to efficiently cluster PWMs and assess quality of clusters. RESULTS: A new Python package Affinity Based Clustering for Position Weight Matrices (abc4pwm) was developed. It efficiently clustered PWMs from multiple sources with or without using DNA-Binding Domain (DBD) information, generated a representative motif for each cluster, evaluated the clustering quality automatically, and filtered out incorrectly clustered PWMs. Additionally, it was able to update human DBD family database automatically, classified known human TF PWMs to the respective DBD family, and performed TF motif searching and motif discovery by a new ensemble learning approach. CONCLUSION: This work demonstrates applications of abc4pwm in the DNA sequence analysis for various high throughput sequencing data using ~ 1770 human TF PWMs. It recovered known TF motifs at gene promoters based on gene expression profiles (RNA-seq) and identified true TF binding targets for motifs predicted from ChIP-seq experiments. Abc4pwm is a useful tool for TF motif searching, clustering, quality assessment and integration in multiple types of sequence data analysis including RNA-seq, ChIP-seq and ATAC-seq.