Sequential Screening Research Articles

Integration of Consensus‐Based Pharmacophore Mapping and Molecular Docking in Sequential Virtual Screening: Toward the Discovery of Novel PI3Kγ Inhibitors

AbstractNumerous research studies have demonstrated the significant correlation of phosphatidylinositol‐3 kinase gamma (PI3Kγ) with the onset and progression of various human diseases, highlighting PI3Kγ as a promising therapeutic target. However, PI3Kγ demonstrates considerable similarity with other isoforms in the PI3K family, presenting significant challenges in the creation of PI3Kγ inhibitors. This study presents an ensemble‐based virtual screening approach to discover novel inhibitors targeting PI3Kγ. Eganelisib (IPI‐549) is the sole selective PI3Kγ inhibitor that has progressed to clinical trials, making it a significant model for the advancement of novel PI3Kγ inhibitors. Initially, common feature pharmacophore and receptor–ligand pharmacophore models were independently developed using IPI‐549 and its potent derivatives, in conjunction with the crystal complex of PI3Kγ/IPI‐549. Both qualitative pharmacophore models proved highly effective at distinguishing between active and inactive compounds. Then, four widely utilized docking programs were chosen for assessment, where the Glide_SP mode demonstrated superior predictive accuracy in sampling ligand conformations during binding, effectively distinguishing between PI3Kγ inhibitors and noninhibitors. Finally, a virtual screening protocol was conducted to screen the ChEMBL database, utilizing similarity search, consensus‐based pharmacophore mapping, and sequential molecular docking. This process resulted in the identification of multiple molecules exhibiting notable promise as potent PI3Kγ inhibitors.

Effectiveness of Risk-Adapted Upper Gastrointestinal Cancer Screening in China: Prospective Cohort Study.

Previous studies have proved the effectiveness of endoscopic screening in rural areas; however, long-term, high-quality evidence regarding the effectiveness of risk-adapted upper gastrointestinal cancer (UGC) sequential screening strategies in resource-rich regions is currently lacking. The objectives were to validate the effectiveness of risk-adapted sequential screening strategies in UGC prevention and control and assess the potential of sequential screening to lower mortality rates. Based on the Cancer Screening Program in Urban China, a prospective, large-scale cohort study based on population was conducted to recruit individuals from 4 cities in China from 2013-2019. Those identified as having a high risk of UGC according to a validated risk-score model were advised to undergo endoscopy tests. Follow-up outcomes were tracked until June 2021. Incidence of UGC, UGC-related mortality, and all-cause mortality were evaluated between the screened and nonscreened cohorts. The study included 153,079 participants at baseline. In total, 113,916 (74.42%) of the participants were designated as low risk of UGC. The remaining 39,163 (25.68%) participants were deemed to be at high risk of UGC and were offered gastroscopy tests. Among the high-risk participants, 9627 (compliance rate 24.6%) adhered to the gastroscopy tests. Over a median follow-up of 6.05 (IQR 3.06-7.06) years, 622 UGC cases, 180 UGC deaths, and 1958 all-cause death cases were traced. The screened cohort exhibited the highest cumulative incidence of UGC (119.2 per 100,000 person-years), followed by the nonscreened and low-risk cohorts. Obvious reductions in both all-cause mortality and UGC mortality were observed between those who undertook screening (153.7 and 4.7 per 100,000 person-years, respectively) and the nonscreened group (245.3 and 27 per 100,000 person-years, respectively). The screening population showed a significant 36% and 82% reduction in both all-cause mortality (hazard ratio [HR] 0.64, 95% CI 0.49-0.83, P<.001) and UGC mortality (HR 0.18, 95% CI 0.04-0.74, P=.02), respectively, compared to the nonscreened group. Reductions of 35% in all-cause mortality (HR 0.65, 95% CI 0.49-0.86, P=.003) and 81% in UGC mortality (HR 0.19, 95% CI 0.05-0.80, P=.02) were observed in participants aged older than 55 years in the screened group compared to the nonscreened group. The reductions in all-cause mortality and UGC mortality were statistically significant in males (all-cause mortality: HR 0.64, 95% CI 0.47-0.88, P=.005; UGC mortality: HR 0.10, 95% CI 0.01-0.72, P=.02), but significant reductions were not observed in females (all P values were >.05). Our study suggests the significance of one-off risk-adapted UGC screening in reducing both all-cause mortality and UGC mortality, particularly among high-risk individuals, indicating its effectiveness in UGC prevention and management.

Assessment of Potential Probiotic Yeasts Isolated from The Small Intestines of Cattle in Thailand

Y easts are widely studied and considered good candidates for probiotics due to their numerous benefits. This study aimed to investigate potential probiotic attributes of yeasts isolated from the small intestines of cattle in Thailand. Growth at body temperature, resistance to low pH, auto-aggregation capability, hydrophobicity, growth under gastrointestinal tract (GIT) conditions, safety profiles, antimicrobial activity, and extracellular enzyme production of yeast strains were evaluated in vitro. The results of sequential screening indicated that 829 out of 1,025 yeast strains could grow at both 37 and 39 °C, 682 strains could resist acidity at pH 2 for 24 h, 252 strains revealed greater than 83% auto-aggregation capability, and 97 strains showed higher than 90% hydrophobicity. Sixty strains grew well under simulated GIT conditions in the presence of pepsin, pancreatin, and bile salts. Thirteen strains of Diutina rugosa showed negative results for hemolytic, gelatinase, and phospholipase activities, while seven strains of Pichia kudriavzevii also showed negative results for the above activities, except for phospholipase. Neither D. rugosa nor P. kudriavzevii inhibited Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Additionally, 12 strains of D. rugosa and four strains of P. kudriavzevii produced phytase and cellulase, while only D. rugosa PCD3-6 exhibited protease and phytase activities. Therefore, D. rugosa (strains PCD3-6, PCD93-19, PYJ93-7, PYJ93-16, PCJ94-4, PCJ94-6, PCJ94-10, PYD100-8, CTD93-1, CTD93-2, CTJ93-5, CTJ93-6, and YTJ97-4) and P. kudriavzevii (strains PYI3-3, PCI3-4, PCJ90-7, and PYI91-15) were proposed as potential probiotic yeasts. They may be beneficially applied as feed additives to improve nutritional value and quality, thereby enhancing animal performance and health. Moreover, this work indicated useful preliminary results that could be a baseline for future research in human probiotic applications.

Design, pharmacokinetic, and pharmacodynamic evaluation of a lecithin-chitosan hybrid nanoparticle-loaded dual-responsive in situ gel of nebivolol for effective treatment of glaucoma

In this research work, optimized nebivolol-loaded lecithin-chitosan hybrid nanoparticles (NEB-LCNPs) were prepared using sequential screening and optimization designs. The design of experiments software (DoE) was used to obtain a robust formulation that can improve ocular delivery of the NEB in the treatment of glaucoma. The optimized NEB-LCNPs had a mean particle size of 170.5 ± 5.3 nm and drug loading of 10.5 ± 1.2%. These were further loaded in a dual-responsive in situ gel, designed and reported previously by our group. The NEB-LCNPs loaded in situ gel (NEB-LCNPs-ISG) was characterized for physicochemical properties, rheological behavior, stability, in vitro dissolution, and ocular in vivo studies. The ocular pharmacokinetics showed that NEB-LCNPs-ISG had two-fold higher aqueous humor exposure with AUC0–tlast of 375.4 ng × h/mL and sustained drug concentrations for longer durations (1.7-folds higher duration with a mean residence time of 10.6 h) in comparison to a conventional aqueous suspension of NEB (NEB-Susp). Similarly, the pharmacodynamic study showed that NEB-LCNPs-ISG resulted in a higher percentage reduction in intraocular pressure (% ΔIOP) of 28.1 ± 1.8% × h, which was 2.2-times higher reduction compared to NEB-Susp (74.2 ± 3.2% × h). In addition, the pharmacodynamic effect was more sustained with a mean response time of 11.3 ± 0.2 h, a 2.8-times higher response time compared to NEB-Susp (4.06 ± 0.3 h). These results suggest that NEB-LCNPs-ISG was more effective than the conventional aqueous suspension of NEB in the treatment of glaucoma.

Clinical strategy study on prenatal screening and diagnostic model for Down syndrome

Exploring efficient and easily implementable prenatal screening strategies aims at birth defect prevention and control. However, there have been limited economic evaluations of non-invasive prenatal screening (NIPS) strategies in China. Furthermore, these studies were predominantly confined to local or geographically proximate provinces and lacked universality and representativeness. This study assesses the health economics of current prenatal screening strategies and NIPS as first-line screening programs, analyzing their efficacy to determine an optimal strategy. From the perspective of health economics, cost-effectiveness, cost-benefit, and single-factor sensitivity were conducted for five different screening strategies using a decision tree model. Among pregnant women aged < 35 years who underwent only one screening for foetal Down syndrome (DS), the detection rate, false positive rate and positive predictive value of NIPS for foetuses with DS were superior to those of the other four serological screening methods. Although applying NIPS as first-line screening method yields the highest efficacy and benefits, it currently lacks cost-effectiveness when compared to serological screening and sequential NIPS screening strategies.

Transabdominal-transvaginal ultrasound cervical length sequential screening to predict the risk of spontaneous preterm birth in singleton pregnancy women with low risk of preterm birth

Objective: To investigate the feasibility of predicting the risk of spontaneous preterm birth in singleton pregnancy women with low risk of preterm birth by transabdominal-transvaginal ultrasound cervical length sequential screening in the second trimester. Methods: This prospective longitudinal cohort study included singleton pregnant women at 11-13+6 gestational weeks who were admitted to Nanjing Drum Tower Hospital from January 2023 to September 2023. Transabdominal and transvaginal cervical lengths were measured during the mid-trimester fetal ultrasound scan at 18-24 weeks, and pregnancy outcomes were obtained after delivery. A short cervix was defined as a transvaginal cervical length of ≤25 mm, and the outcomes were defined as spontaneous preterm birth occurs between 20 and 36+6 weeks and extremely preterm birth before 32 weeks. The area under the receiver operating characteristic (ROC) curve was used to evaluate the effectiveness of predicting spontaneous preterm birth by transabdominal and transvaginal cervix length, as well as the effectiveness of predicting short cervix by transabdominal cervical length. The relationship between transabdominal and transvaginal cervical length was evaluated using a scatter plot. Results: A total of 562 cases were included in this study, comprising 33 cases of spontaneous preterm birth (7 cases occurring before 32 weeks) and 529 cases of term birth. (1) Compared to the term birth group, transabdominal cervical length (median: 37.6 vs 33.2 mm; Z=-3.838, P<0.001) and transvaginal cervical length (median: 34.0 vs 29.9 mm, Z=-3.030, P=0.002) in the spontaneous preterm birth group were significantly shorter. (2) The areas under the ROC curve for predicting spontaneous preterm birth by transabdominal and transvaginal cervical length were 0.699 (95%CI: 0.588-0.809) and 0.657 (95%CI: 0.540-0.774), respectively. The sensitivity, specificity and positive predictive value of transvaginal cervical length Conclusions: In singleton pregnancy women with low risk of preterm birth, transabdominal-transvaginal cervical length sequential screening can reduce unnecessary transvaginal ultrasounds by approximately 41% without missing the diagnosis of pregnant women with a short cervix. This method also enhances the effectiveness of transvaginal cervical length to spontaneous preterm birth.

Advocating Targeted Sequential Screening over Whole Exome Sequencing in 21-Hydroxylase Deficiency

Advocating Targeted Sequential Screening over Whole Exome Sequencing in 21-Hydroxylase Deficiency

1567P Physicians' adenoma detection rate and the risk of colorectal cancer in sequential screening programs: An observational cohort study

1567P Physicians' adenoma detection rate and the risk of colorectal cancer in sequential screening programs: An observational cohort study

High-throughput computational screening for optimal solvents in methyl 2-hydroxyisobutyrate-water separation

In the semiconductor industry, the efficacy of methyl 2-hydroxyisobutyrate (HBM) as a photoresist thinner is crucial but often compromised by water contamination. Additionally, the manufacturing process tends to form an azeotrope with water, rendering traditional distillation methods inefficient for purification. This study introduces a novel computational screening approach to identify optimal solvents for the liquid-liquid extraction of HBM, offering a sustainable alternative to conventional distillation. Our three-step sequential screening protocol utilizes molecular dynamics simulations to evaluate intermolecular interaction energy, partition coefficient, and environmental, health, and safety (EHS) parameters. Initially, a comprehensive database of 4919 solvents was screened using molecular dynamics simulations to assess interaction energies and partition coefficients. Solvents that met these energy criteria were further evaluated for their EHS profiles. This process identified seven solvents that optimize extraction efficiency while adhering to stringent environmental and safety standards. Our approach not only enhances the purity and performance of HBM in semiconductor manufacturing but also presents a green, cost-effective solution for other industrial chemical processes requiring refined solvent selection.

Exploring Fusarium head blight resistance in a winter triticale germplasm collection

AbstractFusarium head blight (FHB; caused by Fusarium graminearum) is a destructive disease of wheat (Triticum spp.), barley (Hordeum vulgare), rye (Secale cereale L.), and triticale (×Triticosecale Wittmack) not only reducing their yield but also contaminating the grain with mycotoxins such as deoxynivalenol (DON). Developing varieties with genetic resistance is integral to successfully manage FHB. Triticale acreage worldwide is steadily increasing. However, the genetic diversity of triticale for FHB resistance is not well characterized. In the present study, a sequential screening of a set of winter triticale accessions from a global collection was done for their type‐2 FHB resistance and DON accumulation. In the first‐year screening, 298 triticale accessions were tested for FHB in an artificially inoculated, misted‐field nursery with high inoculum density. Most of the triticale accessions were susceptible to FHB, and only 8% of the accessions showed resistance in the field nursery screening. Next, the 24 resistant accessions identified in the nursery screening were tested for 2 years in greenhouse and 17 accessions showed significantly lower FHB severity in Year 2 and/or Year 3. These 17 resistant accessions were further tested for their FHB severity and DON accumulation in Year 4 in greenhouse and for DON accumulation in Year 5 in the field FHB nursery. Eight accessions showed significantly lower FHB severity and nine accessions showed DON accumulation of less than 1 mg/kg in Year 4 greenhouse testing. Eleven accessions had significantly lower DON concentration than the susceptible check in the Year 5 field screening. The resistant accessions common across all years identified in the study can be used for enhancing FHB resistance and reducing DON accumulation in triticale breeding programs.

A health economic pilot study comparing two diabetic retinopathy screening strategies

To compare two screening strategies for diabetic retinopathy (DR), and to determine the health-economic impact of including optical coherence tomography (OCT) in a regular DR screening. This cross-sectional study included a cohort of patients (≥ 18 years) with type 1 or 2 diabetes mellitus (T1D or T2D) from a pilot DR screening program at Oslo University Hospital, Norway. A combined screening strategy where OCT was performed in addition to fundus photography for all patients, was conducted on this cohort and compared to our existing sequential screening strategy. In the sequential screening strategy, OCT was performed on a separate day only if fundus photography indicated diabetic macular edema (DME). The presence of diabetic maculopathy on fundus photography and DME on OCT was determined by two medical retina specialists. Based on the prevalence rate of diabetic maculopathy and DME from the pilot, we determined the health-economic impact of the two screening strategies. The study included 180 eyes of 90 patients. Twenty-seven eyes of 18 patients had diabetic maculopathy, and of these, 7 eyes of 6 patients revealed DME on OCT. When diabetic maculopathy was absent on fundus photographs, OCT could not reveal DME. Accordingly, 18 patients (20%) with diabetic maculopathy would have needed an additional examination with OCT in the sequential screening strategy, 6 (33%) of whom would have had DME on OCT. In an extended healthcare perspective analysis, the cost of the sequential screening strategy was higher than the cost of the combined screening strategy. There was a weak association between diabetic maculopathy on fundus photography and DME on OCT. The health economic analysis suggests that including OCT as a standard test in DR screening could potentially be cost-saving.

The Uptake of Partner Participation in Sequential Preconception Carrier Screening

Introduction: Carrier screening that is performed in the preconception period allows for couples at risk for having children affected with certain single gene (Mendelian) conditions to be identified. This is the most optimal timeframe to perform such screening. Most obstetric providers utilize a sequential process in which the patient first undergoes screening and their partner is only offered testing if the initial results reveal that the first is a carrier for one or more autosomal recessive (AR) deleterious variants. If the partner fails to undergo screening, the couple cannot obtain meaningful and actionable risk information for future or current pregnancies. In this study, we sought to assess the frequency of completed carrier screening risk assessment among individuals and couples who were undergoing preconception screening at two prenatal screening programs staffed by genetic counselors and geneticists. Materials and Methods: We reviewed the screening outcomes for individuals and couples who presented for preconception carrier screening from January 1, 2020 through December 30, 2021 at Insight Medical Genetics and the clinical genetics program at Northwestern Medicine. All individuals received pretest genetic counseling prior to screening and posttest counseling after results were available. We evaluated individuals who were found to be a carrier of at least one deleterious variant and whether the partner of that person underwent carrier screening, and, if so, which type of screening. Results: 548 patients who identified as women underwent preconception carrier screening during the study period, along with 3 men presenting for initial screening. These screens consisted of a panel containing primarily autosomal recessive conditions with a few X-linked conditions. 247 individuals (45.1%) were positive for at least one pathogenic variant; of these, 244 (98.8%) were variants in genes associated with autosomal recessive conditions. A total of 219 partners (88.7%) underwent carrier screening, including the 3 female partners of the men who initiated carrier screening. Of note, 4 of the patients who underwent carrier screening reported not having a partner at the time of screening; accordingly, the partners who underwent screening represent 89.8% of individuals eligible for partner screening following an initial positive result. Of the 219 partners who underwent carrier screening, 201 (91.8%) chose a carrier screening panel of 150+ conditions, while 18 chose a more limited panel that included the gene(s) of relevance based on their partner’s results, with or without additional genes relevant to their learned/self-identified ethnicity or race. Conclusions: Approximately 10% of couples presenting for preconception genetic counseling and carrier screening found to be at potential risk for a child with an autosomal recessive condition did not obtain the requisite information to fully assess their risk of having an affected child. It is possible that the frequency of couples who do not obtain complete and actionable screening information is even higher when carrier screening is provided without the assistance of certified genetic counselors or geneticists. Recently, cell free DNA-based maternal screening has been introduced that assesses the risk for a limited number of genetic conditions in the fetus that may not require assessment of the partner. Nonetheless, providers must communicate to their patients that meaningful risk information can only be obtained when the partner undergoes screening in cases where the initial member of the couple is found to be a carrier of at least one autosomal recessive condition. Laboratories and professional societies need to develop effective educational outreach to patients and providers alike to improve the screening process for couples who want to determine if they are at risk to have a child with an inherited condition.

Head-to-head comparison of diagnostic accuracy of TB screening tests: Chest-X-ray, Xpert TB host response, and C-reactive protein.

Accessible, accurate screening tests are necessary to advance tuberculosis (TB) case finding and early detection in high-burden countries. We compared the diagnostic accuracy of available TB triage tests. We prospectively screened consecutive adults with ≥2 weeks of cough presenting to primary health centers in the Philippines, Vietnam, South Africa, Uganda, and India. All participants received the index tests: chest-X-ray (CXR), venous or capillary Cepheid Xpert TB Host Response (HR) testing, and point-of-care C-reactive protein (CRP) testing (Boditech iChroma II). CXR images were processed using computer-aided detection (CAD) algorithms. We assessed diagnostic accuracy against a microbiologic reference standard (sputum Xpert Ultra, culture). Optimal cut-points were chosen to achieve sensitivity ≥90% and maximize specificity. Two-test screening algorithms were considered, using two approaches: 1) sequential negative serial screening in which the second screening test is conducted only if the first is negative and positive is defined as positive on either test and 2) sequential positive serial screening, in which the second screening test is conducted only if the first is positive and positive is defined as positive on both tests. Between July 2021 and August 2022, 1,392 participants with presumptive TB had valid results on index tests and the reference standard, and 303 (22%) had confirmed TB. In head-to-head comparisons, CAD4TB v7 showed the highest specificity when using a cut-point that achieves 90% sensitivity (70.3% vs. 65.1% for Xpert HR, difference 95% CI 1.6 to 8.9; 49.7% for CRP, difference 95% CI 17.0 to 24.3). Among the possible two-test screening algorithms, three met WHO target product profile (TPP) minimum accuracy thresholds and had higher accuracy than any test alone. At 90% sensitivity, the specificity was 79.6% for Xpert HR-CAD4TB [sequential negative], 75.9% for CRP-CAD4TB [sequential negative], and 73.7% for Xpert HR-CAD4TB [sequential positive]. CAD4TB achieves TPP targets and outperforms Xpert HR and CRP. Combining screening tests further increased accuracy. Cost and feasibility of two-test screening algorithms should be explored. NCT04923958.

Effectiveness of a stepwise approach for screening of atrial fibrillation after stroke: insights from the SAFAS study

Abstract Background Detection of atrial fibrillation (AF) is critical after ischemic stroke, providing information regarding the mechanism of the event and leading to modification in the antithrombotic strategy. While most guidelines recommend screening patients for AF with 12-lead ECG, telemetry, long-duration Holter monitoring and implantable cardiac monitor (ICM), the optimal timing and combination of such screening tools remain unclear. Objective This study aimed at investigating the suitability of a sequential combination of screening techniques (12-lead ECG, telemetry, in hospital long-lasting Holter monitoring, and ICM in the detection of AF after stroke. Methods Patients without previously known AF admitted to the Dijon University Hospital stroke unit for acute ischemic stroke were prospectively enrolled. After a stepwise screening approach for AF based on admission ECG, telemetry monitoring during the stroke unit stay and long-duration Holter monitoring during hospital stay, cryptogenic stroke patients were implanted of an ICM. Primary endpoint was the presence of AF detected during the 3-year period after stroke based on this sequential screening approach. Results A total of 240 patients were included. Among them, 104 (43.3%) patients had a documented cause of stroke non-related to AF. Among the remaining 136 patients (53.7% male, 70.8±13.7 yo), AF was detected in 82 (60%) patients over the acute screening phase or the 3-year follow-up with ICM. AF was diagnosed using 12-lead ECG, in-hospital telemetry, and in hospital long-lasting Holter monitoring in 17 (13%), 25 (18%), and 18 (13%) patients, respectively. AF was detected after the first 24 hours on the long-lasting Holter monitoring in 66% of patients. Among the 76 (56%) patients classified as cryptogenic after the complete stroke work-up and implanted from an ICM, AF was detected in 22 (29%) patients. AF occurred during the first, second, and third years of implantable monitoring in 14 (18.4%), 5 (6.6%), and 3 (3.9%) patients, respectively (Figure 1). Mean time from ICM implantation to AF diagnosis was 308+/-279 days. Finally, among all AF detected, 72% (60/83) were found during the initial intensive in-hospital screening. Conclusion A stepwise approach for AF screening after ischemic stroke allows the early detection of AF in a substantial number of patients during hospital stay. Even with such proactive initial monitoring strategy, invasive monitoring remains complementary to non-invasive screening tools not to overlook more distant AF episodes. Studies focusing on the relative risk of ischemic stroke recurrence according to AF timing and burden are needed.Figure 1

Facilitators, Barriers, and Opportunities to Implementing Sexual History Screening and Human Immunodeficiency Virus Pre-Exposure Prophylaxis at a Federally Qualified Health Center.

Sexual history screening (SHS) is recommended to determine risk for acquisition of human immunodeficiency virus (HIV) and eligibility for pre-exposure prophylaxis (PrEP). SHS and PrEP are underutilized, sequential screening, and prevention practices. This study aimed to understand factors impacting the implementation of SHS and PrEP at a multi-site federally qualified health center (FQHC) in Connecticut. Guided by the Consolidated Framework for Implementation Research, semistructured interviews were conducted on Zoom with primary care providers (PCPs), medical assistants, clinical leadership, and PrEP navigators. Convenience and purposive sampling took place via email until thematic saturation was achieved. Thematic analysis was conducted. Twenty-two participants were interviewed for this study. PCPs lacked knowledge and reported limited or no use of SHS to determine patients' level of HIV risk, which may explain why most PCPs relied on patients to request PrEP. While PCPs perceived organizational support to prescribe PrEP, clinical staff were unaware of structural resources. Lastly, participants described a vertical trajectory of influence from external sources (policies and insurance) to time allocated to appointments that limits their ability to implement SHS and PrEP, further complicated by the electronic health record and disparities in structural resources across clinical sites. This study provides foundational evidence for future research on implementation strategies to improve HIV prevention through universal, comprehensive SHS to identify patients for PrEP. Overcoming barriers to SHS and PrEP, particularly in clinical settings such as FQHCs that care for vulnerable populations, may improve identification, prevention, and treatment of HIV and aid in ending the HIV epidemic.

Analysing Health Professionals&amp;apos; Adherence to National Guidelines and Comparing Diabetes Care in Specialized Care Centres and Hospitals

The socioeconomic impact of diabetes treatment includes significant costs for diagnosis, treatments, hospitalizations, and associated social challenges. According to the International diabetic federation (IDF) guidelines, effective management entails a holistic strategy including nutritious diet, avoiding carbonated beverages, quitting smoking, and routine exercising. Targeted weight loss is critical, comprising antidiabetic medications, a specific food plan, and lifestyle changes to attain a 7-8% glycated hemoglobin level. Proper medicine and footwear use reduces ulcer risks and further complications. The IDF emphasizes detailed treatment plans and sequential screenings. Diabetes management is obligatory, focusing glycaemic control, lifestyle changes, and risk assessment. A study examines treatment programs, medical behaviour, and factors impacting diabetic care reception. This study examined diabetes mellitus treatment in medical facilities by conducting health information reviews in outpatient clinics with a sample size of 400 records. Java applets detected problems, indicating 95% confidence in therapy. Cross-sectional studies in Peshawar hospitals included 250 patients, whereas specialized diabetic treatment centers evaluated 150 patients. Documented care differed; public hospitals had lower foot inspection rates (16.4%) than specialized care (14%). Statistical analysis, such as the Chung test and binary logistic regression, was used to assess variable relationships. Smoking was common (86%), and 59.8% relied on oral anti-diabetic medications. Less than 30% follow up examinations were recorded in public hospitals which showed discrepancies in documentation. Diabetes management can be improved, particularly through better screening procedures. Discrepancies between provided and documented care underscore the need for higher documentation standards. Private clinics demonstrated comparatively better care, possibly influenced by consultation fees, facility availability, and a comfortable environment—attributes lacking in public hospitals in Pakistan.

Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons.

Alpha-synuclein (αSyn) protein levels correlate with the risk and severity of Parkinson's disease and related neurodegenerative diseases. Lowering αSyn is being actively investigated as a therapeutic modality. Here, we systematically map the regulatory network that controls endogenous αSyn using sequential CRISPR-knockout and -interference screens in an αSyn gene (SNCA)-tagged cell line and induced pluripotent stem cell-derived neurons (iNeurons). We uncover αSyn modifiers at multiple regulatory layers, with amino-terminal acetyltransferase B (NatB) enzymes being the most potent endogenous αSyn modifiers in both cell lines. Amino-terminal acetylation protects the cytosolic αSyn from rapid degradation by the proteasome in a Ube2w-dependent manner. Moreover, we show that pharmacological inhibition of methionyl-aminopeptidase 2, a regulator of NatB complex formation, attenuates endogenous αSyn in iNeurons carrying SNCA triplication. Together, our study reveals several gene networks that control endogenous αSyn, identifies mechanisms mediating the degradation of nonacetylated αSyn, and illustrates potential therapeutic pathways for decreasing αSyn levels in synucleinopathies.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Identification of Potent siRNA Delivery Peptides Using Computer Modeling.

Peptides with suitable aggregation behavior and electrical properties are potential siRNA delivery vectors. However, identifying suitable peptides with ideal delivery and safety features is difficult owing to the variations in amino acid sequences. Here, a holistic program based on computer modeling and single-cell RNA sequencing (scRNA-seq)is used to identify ideal siRNA delivery peptides. Stage one of this program consists of a sequential screening process for candidates with ideal assembly and delivery ability; stage two is a cell subtype-level analysis program that screens for high in vivo tissue safety. The leading candidate peptide selected from a library containing 12 amino acids showed strong lung-targeted siRNA delivery capacity after hydrophobic modification. Systemic administration of these compounds caused the least damage to liver and lung tissues and has little impact on macrophage and neutrophil numbers. By loading STAT3 siRNA, strong anticancer effects are achieved in multiple models, including patient-derived xenografts (PDX). This screening procedure may facilitate the development of peptide-based RNA interference (RNAi) therapeutics.

A Clinical Prediction Model to Assess Risk for Pancreatic Cancer Among Patients With Acute Pancreatitis.

We aimed to develop and validate a prediction model as the first step in a sequential screening strategy to identify acute pancreatitis (AP) individuals at risk for pancreatic cancer (PC). We performed a population-based retrospective cohort study among individuals 40 years or older with a hospitalization for AP in the US Veterans Health Administration. For variable selection, we used least absolute shrinkage and selection operator regression with 10-fold cross-validation to identify a parsimonious logistic regression model for predicting the outcome, PC diagnosed within 2 years after AP. We evaluated model discrimination and calibration. Among 51,613 eligible study patients with AP, 801 individuals were diagnosed with PC within 2 years. The final model (area under the receiver operating curve, 0.70; 95% confidence interval, 0.67-0.73) included histories of gallstones, pancreatic cyst, alcohol use, smoking, and levels of bilirubin, triglycerides, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin. If the predicted risk threshold was set at 2% over 2 years, 20.3% of the AP population would undergo definitive screening, identifying nearly 50% of PC associated with AP. We developed a prediction model using widely available clinical factors to identify high-risk patients with PC-associated AP, the first step in a sequential screening strategy.