Screening Study Research Articles

MODL-13. ORGANOTYPIC BRAIN SLICE CULTURE PLATFORM AS A MODEL OF PEDIATRIC LOW GRADE GLIOMAS

Abstract BACKGROUND Pediatric low grade glioma (pLGG), the most common subgroup of central nervous system tumors in children, suffers from a paucity of models that support pLGG biological discovery, preclinical target identification, and drug screening studies. METHODS We propose the use of an organotypic brain slice culture (OBSC) platform as a novel model in which we are able to reliably support fresh, zero-passage pLGG patient tumor tissue for preclinical testing. We performed individualized drug screening with the frequently used up-front agents: carboplatin, vincristine, trametinib, and dabrafenib. RESULTS We have collected and established on OBSCs 100% (3/3) pLGGs since 2023. With these three patient samples, we have applied our quantitative drug screening algorithm, which combines tumor killing efficacy with healthy tissue toxicity, and yielded resultant drug sensitivity scores (DSS) to quantify patient-specific treatment efficacies. CONCLUSIONS Overall, these early results suggest that the OBSC platform may serve as a novel and reliable model for pLGG, filling a critical void in representative models for this common and often highly morbid pediatric tumor.

Discovery of novel natural-product-derived mutant isocitrate dehydrogenases 1 inhibitors: Structure-based virtual screening, biological evaluation and structure-activity relationship study

Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC50 values of 3.48 and 1.38 μM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight.

The Utility of Long-Read Sequencing in Diagnosing Genetic Autosomal Recessive Parkinson's Disease: a genetic screening study.

Mutations within the genes PRKN and PINK1 are the leading cause of early onset autosomal recessive Parkinson's disease (PD). However, the genetic cause of most early-onset PD (EOPD) cases still remains unresolved. Long-read sequencing has successfully identified many pathogenic structural variants that cause disease, but this technology has not been widely applied to PD. We recently identified the genetic cause of EOPD in a pair of monozygotic twins by uncovering a complex structural variant that spans over 7 Mb, utilizing Oxford Nanopore Technologies (ONT) long-read sequencing. In this study, we aimed to expand on this and assess whether a second variant could be detected with ONT long-read sequencing in other unresolved EOPD cases reported to carry one heterozygous variant in PRKN or PINK1. ONT long-read sequencing was performed on patients with one reported PRKN/PINK1 pathogenic variant. EOPD patients with an age at onset younger than 50 were included in this study. As a positive control, we also included EOPD patients who had already been identified to carry two known PRKN pathogenic variants. Initial genetic testing was performed using either short-read targeted panel sequencing for single nucleotide variants and multiplex ligation-dependent probe amplification (MLPA) for copy number variants. 48 patients were included in this study (PRKN "one-variant" n = 24, PINK1 "one-variant" n = 12, PRKN "two-variants" n = 12). Using ONT long-read sequencing, we detected a second pathogenic variant in six PRKN "one-variant" patients (26%, 6/23) but none in the PINK1 "one-variant" patients (0%, 0/12). Long-read sequencing identified one case with a complex inversion, two instances of structural variant overlap, and three cases of duplication. In addition, in the positive control PRKN "two-variants" group, we were able to identify both pathogenic variants in PRKN in all the patients (100%, 12/12). This data highlights that ONT long-read sequencing is a powerful tool to identify a pathogenic structural variant at the PRKN locus that is often missed by conventional methods. Therefore, for cases where conventional methods fail to detect a second variant for EOPD, long-read sequencing should be considered as an alternative and complementary approach.

High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS)

Disrupted proteome homeostasis (proteostasis) in amyotrophic lateral sclerosis (ALS) has been a major focus of research in the past two decades. However, the proteostasis processes that become disturbed in ALS are not fully understood. Obtaining more detailed knowledge of proteostasis disruption in association with different ALS-causing mutations will improve our understanding of ALS pathophysiology and may identify novel therapeutic targets and strategies for ALS patients. Here we describe the development and use of a novel high-content analysis (HCA) assay to investigate proteostasis disturbances caused by the expression of several ALS-causing gene variants. This assay involves the use of conformationally-destabilised mutants of firefly luciferase (Fluc) to examine protein folding/re-folding capacity in NSC-34 cells expressing ALS-associated mutations in the genes encoding superoxide dismutase-1 (SOD1A4V) and cyclin F (CCNFS621G). We demonstrate that these Fluc isoforms can be used in high-throughput format to report on reductions in the activity of the chaperone network that result from the expression of SOD1A4V, providing multiplexed information at single-cell resolution. In addition to SOD1A4V and CCNFS621G, NSC-34 models of ALS-associated TDP-43, FUS, UBQLN2, OPTN, VCP and VAPB mutants were generated that could be screened using this assay in future work. For ALS-associated mutant proteins that do cause reductions in protein quality control capacity, such as SOD1A4V, this assay has potential to be applied in drug screening studies to identify candidate compounds that can ameliorate this deficiency.

1379-P: Detection of Type 2 Diabetes—Evidence from a Pilot Screening Study in Denmark

1379-P: Detection of Type 2 Diabetes—Evidence from a Pilot Screening Study in Denmark

Enantioselective Synthesis of Allylic Sulfones via Rhodium-Catalyzed Direct Hydrosulfonylation of Allenes and Alkynes.

A highly regio- and enantioselective hydrosulfonylation using commercially available sodium sulfinates is reported, providing the first direct asymmetric rhodium-catalyzed hydrosulfonylation of allenes/alkynes to synthesize chiral allylic sulfones. Ligand screening studies demonstrated the indispensable role of the C1-symmetric P,N-ligand (Rax,S,S)-StackPhim for achieving both high regioselecitivity (>20:1) and enantioselectivity (up to 97% ee). Notably, the operationally simple method and mild conditions allow for the rapid preparation of chiral allylic sulfones with a wide scope of functional groups. Moreover, the use of sodium tert-butyldimethylsilyloxymethanesulfinate enables the collective synthesis of various chiral sulfone derivatives after simple transformations of the protected hydroxymethyl product.

Bias due to coarsening of time intervals in the inference for the effectiveness of colorectal cancer screening.

Observational studies are frequently used to estimate the comparative effectiveness of different colorectal cancer (CRC) screening methods due to the practical limitations and time needed to conduct large clinical trials. However, time-varying confounders, e.g. polyp detection in the last screening, can bias statistical results. Recently, generalized methods, or G-methods, have been used for the analysis of observational studies of CRC screening, given their ability to account for such time-varying confounders. Discretization, or the process of converting continuous functions into discrete counterparts, is required for G-methods when the treatment and outcomes are assessed at a continuous scale. This paper evaluates the interplay between time-varying confounding and discretization, which can induce bias in assessing screening effectiveness. We investigate this bias in evaluating the effect of different CRC screening methods that differ from each other in typical screening frequency. First, using theory, we establish the direction of the bias. Then, we use simulations of hypothetical settings to study the bias magnitude for varying levels of discretization, frequency of screening and length of the study period. We develop a method to assess possible bias due to coarsening in simulated situations. The proposed method can inform future studies of screening effectiveness, especially for CRC, by determining the choice of interval lengths where data are discretized to minimize bias due to coarsening while balancing computational costs.

Early Postoperative Small Bowel Obstruction after Colorectal Surgery: Incidence and Exploratory Analysis of Potential Risk Factors.

Early postoperative small bowel obstruction (EPSBO) is a common complication following colorectal surgery, which can significantly impact patient outcomes. This study aimed to investigate the incidence of EPSBO and identify potential risk factors among patients who underwent colorectal surgery. A descriptive study was conducted on a cohort of 100 patients who underwent colorectal surgery at a tertiary center at SKIMS, Srinagar, Jammu & Kashmir, India. Descriptive, bivariate, and predictive screening analyses were performed to examine patient characteristics, assess association between different relevant variables and EPSBO, and identify significant predictors, respectively. Our study included a total of 100 patients, with a mean age of 50.39 years. Postsurgery, 11% of the individuals in the cohort developed EPSBO. Early postoperative small bowel obstruction developed around 4.30 days after surgery, and radiographic data revealed dilated gut loops in 72.70% of EPSBO cases. Bivariate analysis revealed significant association between EPSBO and variables such as previously operated, medical comorbidities, smoking status, anemia, neoadjuvant chemoradiotherapy (NACRT), bowel preparation, operative procedure, surgery duration, and type of anastomosis (p < 0.05). History of previous bowel habits, previously operated, perioperative bowel preparation, and blood transfusion were identified as the most influential predictors of EPSBO in the predictive screening study. This study provides insights into the incidence of EPSBO and its potential risk factors for postcolorectal surgery among patients. The findings emphasize the need to take the patient's history of past bowel habits and other factors into account when determining the risk of EPSBO. Future studies should go deeper into these correlations and consider treatments to reduce the occurrence of EPSBO in this patient population. Ahmad B, Ul Hag MF, Shah MA, et al. Early Postoperative Small Bowel Obstruction after Colorectal Surgery: Incidence and Exploratory Analysis of Potential Risk Factors. Euroasian J Hepato-Gastroenterol 2024;14(1):70-74.

USPSTF Recommendations and Overdiagnosis.

Overdiagnosis is the concept that some cancers detected at screening would never have become clinically apparent during a woman's lifetime in the absence of screening. This could occur if a woman dies of a cause other than breast cancer in the interval between mammographic detection and clinical detection (obligate overdiagnosis) or if a mammographically detected breast cancer fails to progress to clinical presentation. Overdiagnosis cannot be measured directly. Indirect methods of estimating overdiagnosis include use of data from randomized controlled trials (RCTs) designed to evaluate breast cancer mortality, population-based screening studies, or modeling. In each case, estimates of overdiagnosis must consider lead time, breast cancer incidence trends in the absence of screening, and accurate and predictable rates of tumor progression. Failure to do so has led to widely varying estimates of overdiagnosis. The U.S. Preventive Services Task Force (USPSTF) considers overdiagnosis a major harm of mammography screening. Their 2024 report estimated overdiagnosis using summary evaluations of 3 RCTs that did not provide screening to their control groups at the end of the screening period, along with Cancer Intervention and Surveillance Network modeling. However, there are major flaws in their evidence sources and modeling estimates, limiting the USPSTF assessment. The most plausible estimates remain those based on observational studies that suggest overdiagnosis in breast cancer screening is 10% or less and can be attributed primarily to obligate overdiagnosis and nonprogressive ductal carcinoma in situ.

Breast Cancer High-Penetrance Genes BRCA1 and BRCA2 Mutations Using Next-Generation Sequencing Among Iraqi Kurdish Women.

Background BRCA1andBRCA2genesare the main high-penetrance genes that are responsible for most cases of inherited breast cancer. The present study aimed to detect the frequencies of inherited breast cancer caused by BRCA1 and BRCA2 genes among Kurdish breast cancer patients, including all the exome of these two genes, using next-generation sequencing (NGS). Methodology Seventy women who were diagnosed with breast cancer and registered at Nanakali Hospital in Erbil, Iraq, were included. Blood samples were collected for molecular testing (polymerase chain reaction (PCR)) targeting all exomes of BRCA1 and BRCA2 genes. All exome regions are sequenced by NGS using the Miseq system (Illumina Inc., San Diego, CA). Obtained data were visualized using Integrative Genomics Viewer (IGV 2.3 Software, Broad Institute, Cambridge, MA). Data were interpreted based on the National Center for Biotechnology Information (NCBI), Clinically Relevant Variation (ClinVar) archives, and other databases. Results Among 70 samples, more than forty-two variants have been detected, 20 on BRCA1 and 22 on BRCA2. Regarding clinical significance, six (14.28%) variants were pathogenic, four of them on theBRCA1 gene, which were: c.3607C>T, c.3544C>T, c.68_69del, and c.224_227delAAAG, and two pathogenic variants were on BRCA2 gene: c.100G>T, and c.1813delA. Also, two (4.76%) variants were conflict interpretations of pathogenicity, one (2.38%) was a variant of uncertain significant VUS, and the rest 29 (69%) variants were benign.In addition, four new variants (three in BRCA1 and one in BRCA2 gene), never previously reported, were identified. Conclusions In conclusion, analyzing the BRCA1/2 genes provide a better prediction for the risk of developing breast cancer in the future. Variant types and frequencies differ among different populations and ethnicities, the common mutations worldwide may not be prevalent in the Kurdish population. The current research findings will be useful for future screening studies of these two genes in the Kurdish population.

Simultaneous alleviation of verification and reference standard biases in a community-based tuberculosis screening study using Bayesian latent class analysis.

Estimation of prevalence and diagnostic test accuracy in tuberculosis (TB) prevalence surveys suffer from reference standard and verification biases. The former is attributed to the imperfect reference test used to bacteriologically confirm TB disease. The latter occurs when only the participants screening positive for any TB-compatible symptom or chest X-ray abnormality are selected for bacteriological testing (verification). Bayesian latent class analysis (LCA) alleviates the reference standard bias but suffers verification bias in TB prevalence surveys. This work aims to identify best-practice approaches to simultaneously alleviate the reference standard and verification biases in the estimates of pulmonary TB prevalence and diagnostic test performance in TB prevalence surveys. We performed a secondary analysis of 9869 participants aged ≥15 years from a community-based multimorbidity screening study in a rural district of KwaZulu-Natal, South Africa (Vukuzazi study). Participants were eligible for bacteriological testing using Xpert Ultra and culture if they reported any cardinal TB symptom or had an abnormal chest X-ray finding. We conducted Bayesian LCA in five ways to handle the unverified individuals: (i) complete-case analysis, (ii) analysis assuming the unverified individuals would be negative if bacteriologically tested, (iii) analysis of multiply-imputed datasets with imputation of the missing bacteriological test results for the unverified individuals using multivariate imputation via chained equations (MICE), and simultaneous imputation of the missing bacteriological test results in the analysis model assuming the missing bacteriological test results were (iv) missing at random (MAR), and (v) missing not at random (MNAR). We compared the results of (i)-(iii) to the analysis based on a composite reference standard (CRS) of Xpert Ultra and culture. Through simulation with an overall true prevalence of 2.0%, we evaluated the ability of the models to alleviate both biases simultaneously. Based on simulation, Bayesian LCA with simultaneous imputation of the missing bacteriological test results under the assumption that the missing data are MAR and MNAR alleviate the reference standard and verification biases. CRS-based analysis and Bayesian LCA assuming the unverified are negative for TB alleviate the biases only when the true overall prevalence is <3.0%. Complete-case analysis produced biased estimates. In the Vukuzazi study, Bayesian LCA with simultaneous imputation of the missing bacteriological test results under the MAR and MNAR assumptions produced overall PTB prevalence of 0.9% (95% Credible Interval (CrI): 0.6-1.9) and 0.7% (95% CrI: 0.5-1.1) respectively alongside realistic estimates of overall diagnostic test sensitivity and specificity with substantially overlapping 95% CrI. The CRS-based analysis and Bayesian LCA assuming the unverified were negative for TB produced 0.7% (95% CrI: 0.5-0.9) and 0.7% (95% CrI: 0.5-1.2) overall PTB prevalence respectively with realistic estimates of overall diagnostic test sensitivity and specificity. Unlike CRS-based analysis, Bayesian LCA of multiply-imputed data using MICE mitigates both biases. The findings demonstrate the efficacy of these advanced techniques in alleviating the reference standard and verification biases, enhancing the robustness of community-based screening programs. Imputing missing values as negative for bacteriological tests is plausible under realistic assumptions.

Segmentation and Multi-Timepoint Tracking of 3D Cancer Organoids from Optical Coherence Tomography Images Using Deep Neural Networks.

Recent years have ushered in a transformative era in in vitro modeling with the advent of organoids, three-dimensional structures derived from stem cells or patient tumor cells. Still, fully harnessing the potential of organoids requires advanced imaging technologies and analytical tools to quantitatively monitor organoid growth. Optical coherence tomography (OCT) is a promising imaging modality for organoid analysis due to its high-resolution, label-free, non-destructive, and real-time 3D imaging capabilities, but accurately identifying and quantifying organoids in OCT images remain challenging due to various factors. Here, we propose an automatic deep learning-based pipeline with convolutional neural networks that synergistically includes optimized preprocessing steps, the implementation of a state-of-the-art deep learning model, and ad-hoc postprocessing methods, showcasing good generalizability and tracking capabilities over an extended period of 13 days. The proposed tracking algorithm thoroughly documents organoid evolution, utilizing reference volumes, a dual branch analysis, key attribute evaluation, and probability scoring for match identification. The proposed comprehensive approach enables the accurate tracking of organoid growth and morphological changes over time, advancing organoid analysis and serving as a solid foundation for future studies for drug screening and tumor drug sensitivity detection based on organoids.

Cranial Ultrasound Findings in Infants With Congenital Cytomegalovirus Infection in a Universal Newborn Screening Study in Minnesota.

Congenital cytomegalovirus (cCMV) is the most common infectious cause of neurodevelopmental deficits in US children. To inform patient management, it is important to define whether central nervous system (CNS) manifestations are present at birth. This study characterized neuroimaging findings in infants with cCMV identified by a universal screening study in Minnesota during February 2016-December 2022. Newborns with cCMV infection (confirmed by urine CMV polymerase chain reaction [PCR] testing, obtained following a positive screening saliva and/or dried blood spot result) underwent a diagnostic evaluation that included a cranial ultrasound (cUS) exam, laboratory studies, ophthalmological, and audiological evaluation. Neuroimaging findings and cCMV disease classification were interpreted based on international consensus guidelines. Among 87 newborns with confirmed cCMV, 76 underwent cUS. Of these, 53/76 (70%) had normal examinations, while 23/76 (30%) exhibited cUS findings: for 5 infants, these were clearly cCMV disease-defining, while for 18 infants, there were findings of uncertain significance. Magnetic resonance imaging (MRI) results (n = 10 infants) aligned with cUS cCMV disease-defining findings in 2 infants, while cCMV-specific abnormalities were noted by MRI in 2 of 6 infants with nondiagnostic/incidental cUS findings. Of 9 infants who had both cUS and MRI examination, the average time interval between studies was 220 days (range, 2-1061). Excluding infants with cCMV CNS disease-defining cUS abnormalities, incidental findings were observed more commonly in infants with clinical/laboratory features described in cCMV disease classification guidelines (9/13) than in newborns with completely asymptomatic infections (9/58; P < .0001). Among infants with cCMV identified in a universal screening study, the majority had a normal cUS. CNS disease-defining abnormalities were present in 7%, while 24% had findings of uncertain significance. We propose that many cUS findings are incidental, and not diagnostic of symptomatic cCMV infection. Although these findings may not be sufficient to define the presence of symptomatic cCMV disease involving the CNS, in our study they were more commonly observed in infants with other clinical and/or laboratory findings associated with symptomatic cCMV infection.

Rational virtual screening, ADME, and molecular simulation studies of potential inhibitors of human superoxide dismutase 1 in a dysfunctional antioxidant system

Superoxide dismutase 1 (SOD1), a copper-dependent enzyme, facilitates the conversion of superoxide anions into hydrogen peroxide and oxygen, thereby regulating superoxide levels. Dysfunctions in SOD1 have been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis, as well as liver and lung cancers. This study aimed to identify SOD1 modulators using in silico rational virtual enrichment screening, pharmacokinetics, docking, and molecular dynamic simulation (MDS). The findings yielded 38 compounds, predominantly exhibiting high gastrointestinal absorption but mostly non-permeable across the blood&amp;ndash;brain barrier, with few exhibiting inhibitory effects on selected cytochrome P450s. Molecular docking revealed that compound 1 (PubChem CID: 36791369) exhibited the highest binding affinity (&amp;minus;6.771 kcal&amp;middot;mol-1), followed by compound 19 (PubChem CID: 30935) with &amp;minus;6.468 kcal&amp;middot;mol-1, and compound 20 (PubChem CID: 135744521) with &amp;minus;5.978 kcal&amp;middot;mol-1. MDS and molecular mechanics/generalized Born surface area analysis indicated that the compound CID 36791369 &amp;ndash; SOD1 complex and compound CID 30935 &amp;ndash; SOD1 complex remained stable and energetically favorable under simulated physiological conditions at 0 ns and 100 ns. In conclusion, this study identified 38 compounds, among which compounds SN5, SN6, SN7, SN12, and SN25 emerged as potential inhibitors of SOD1 based on overall analyses. Further, research will be necessary to investigate the therapeutic effectiveness of these top five compounds in vitro and in vivo against SOD1.

Choosing the Appropriate HPV Testing and Treatment Algorithm: What Works for Different Contexts?

Cervical cancer can be eliminated, and the global community intends to achieve this goal in the next century. For this to successfully occur, concerted efforts to implement and scale-up available, evidence-based strategies including human papillomavirus vaccination, screening and treatment of precancerous lesions, and early detection and treatment for invasive cancers is paramount. While the World Health Organization has offered technical guidance and recommendations on implementation, several questions remain unanswered and require urgent high-quality research to inform policy and practice. We discuss the findings from the Cervical Cancer Screening and Treatment Algorithms pilot study in the context of the evidence synthesis conducted for the second edition of the World Health Organization guidelines for screening and treatment of cervical precancer lesions for cervical cancer prevention. Policymakers at the national level must consider the weight of evidence with country-level resources to make decisions on screening, triage, and treatment approaches. See related article by Sebitloane et al., p. 779.

A Geographically Weighted Cost-effectiveness Analysis of Newborn Cytomegalovirus Screening.

Early identification of newborns with congenital cytomegalovirus (CMV) is necessary to provide antiviral therapy and other interventions that can improve outcomes. Prior research demonstrates that universal newborn CMV screening would be the most cost-effective approach to identifying newborns who are infected. CMV is not uniformly prevalent, and it is uncertain whether universal screening would remain cost-effective in lower-prevalence neighborhoods. Our aim was to identify geographic heterogeneity in the cost-effectiveness of universal newborn CMV screening by combining a geospatial analysis with a preexisting cost-effectiveness analysis. This study used the CMV testing results and zip code location data of 96 785 newborns in 7 metropolitan areas who had been tested for CMV as part of the CMV and Hearing Multicenter Screening study. A hierarchical bayesian generalized additive model was constructed to evaluate geographic variability in the odds of CMV. The zip code-level odds of CMV were then used to weight the results of a previously published model evaluating universal CMV screening vs symptom-targeted screening. The odds of CMV were heterogeneous over large geographic scales, with the highest odds in the southeastern United States. Universal screening was more cost-effective and afforded more averted cases of severe hearing loss than targeted testing. Universal screening remained the most cost-effective option even in areas with the lowest CMV prevalence. Universal newborn CMV screening is cost-effective regardless of underlying CMV prevalence and is the preferred strategy to reduce morbidity from congenital CMV.

Enhancing Injectivity in Lithuanian Hydrocarbon Reservoirs through Wettability-Altering Surfactant Injection

Improved and efficient recovery methods are investigated as possible candidates to arrest the production decline and to improve the injection capacity in hydrocarbon fields in Lithuania. The data show that the Cambrian reservoirs in Lithuania are mixed to oil-wet in nature, which results in poor water-flooding efficiency. Wettability alteration could help in improved water injection and, at the same time, it could help recover additional oil from the residual oil saturation zone of the reservoir. In this paper, a screening exercise is conducted to help alter reservoir wettability, improve water injection efficiency, and to improve oil recovery. Analytical and machine-learning supported methods are used for screening. Based on the screening results, dilute surfactant-based injection techniques are suggested as a potential method to improve injectivity and, thereby, recovery from the field. An initial experimental analysis targets the wettability of the rock from the field, followed by testing for wettability-altering surfactants. Based on the findings of the screening study and experimental analysis, it is recommended that we initiate a core flooding experimental program to investigate wettability changes and enhance injection and recovery from the field.

Cost-effectiveness of newborn screening for sickle cell disease: a systematic review protocol.

The purpose of this systematic review is to assess the cost-effectiveness of targeted/selective newborn screening compared with universal screening for sickle cell disease across various countries and settings. The incidence of sickle cell disease is a widespread and potentially fatal hematologic disorder that affects thousands of newborns worldwide. The cost of newborn screening creates a burden on households and the economy. Studies will be eligible for inclusion in the review if they focus on the cost-effectiveness of newborn screening for sickle cell disease, comparing targeted/selective screening with universal screening. A preliminary search of MEDLINE (PubMed) was undertaken using MeSH terms, such as sickle cell disease, newborn , and economic evaluations . Two reviewers will screen the titles, abstracts, and full text independently against the inclusion criteria. Disagreements will be resolved by discussion or with a third reviewer. To assess methodological quality, the JBI checklist for economic evaluation will be used. Data will be extracted by 2 reviewers using a modified JBI data extraction form. The JBI dominance ranking matrix for economic evaluations will be used to summarize and compare the results. Cost-effectiveness will be measured on the basis of cost per test/case detected, quality-adjusted life years gained, or disability-adjusted life years averted. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessment will be conducted to evaluate the certainty of economic evidence, such as use of resources and expenditures, and to incorporate the results into the decision-making process. PROSPERO CRD42017057963.

Synthesis, characterization, antimicrobial screening and in-silico studies of thiadiazole derivatives

In light of the growing concern surrounding antimicrobial resistance (AMR), there is an urgent need for novel antimicrobial agents with enhanced efficacy and reduced susceptibility to resistance mechanisms. Heterocyclic compounds, particularly those incorporating sulfur and oxygen heteroatoms, have emerged as promising candidates due to their diverse pharmacological properties and potential to overcome resistance mechanisms. In the present study, a novel class of thiadiazole derivatives were amalgamated having functionalities of benzimidazole and pyridine ring structures. Spectral techniques including proton NMR, 13C NMR, FTIR, mass spectroscopy, and elemental characterization were used to ascertain the molecular structure. The antibacterial and antifungal activity of the derivatives was assessed using the disc diffusion technique against selected bacterial and fungal strains. The derivatives showed significant antimicrobial activity compared to the standard drugs with MIC in the range of 25–100 μg/ml. The outcome of the structure-function analysis showed that para-positional substitution of an electronegative substituent at the phenyl ring enhances antimicrobial activity. Molecular dynamic simulations study was conducted against the receptor protein dihydrofolate reductase (DHFR). The compounds 3c and 3e demonstrated the highest binding energies against the selected target. The correlation between experimental and computational results was found to be robust. Moreover, the chloro and nitro group substituent were identified as the key contributors to the enhanced antimicrobial activity of the derivatives. Additionally, the thiadiazole derivatives demonstrated promising ADMET profile, excellent oral bioavailability, and favorable drug-likeness, and were also found to be “Lipinski's rule of five compliant”.

Cancer screening and first-time visits to oncology services during and after COVID-19 pandemic in Uruguay.

e23016 Background: On March 13, 2020, Uruguay confirmed the first cases of COVID-19 and the same day the government declared a Public Health Emergency that was extended until April 4, 2022. The measures implemented to mitigate the transmission included, among others, postponing screening studies and in-person consultations. Added to these measures was the fear of going to health centers and the consequences of the economic crisis, with the increasing difficulties in traveling and facing the co-payments necessary to access health services. This study aims to evaluate the impact of the COVID-19 pandemic on cancer screening and first time- visits to oncology services during the public health emergency and following its lifting. Methods: We compare the number of PAP test, mammograms and fecal immunochemical test (FIT) reported by the same comprehensive health providers during 3 periods: pre-pandemic (2018-2019), public health emergency period (March 13, 2020- April 4, 2022) and post-public health emergency (April 5 2022-June 30,2023). Cancer screening data was obtained from the screening registry of the Honorary Commission to Fight Cancer (CHLCC) and first oncology visits from the Oncology Electronic Health Record (HCEO). Health providers that report PAP, mammograms, and FIT cover around 90%, 30%, and 40% of health system users, respectively, and those that use HCEO, 40%. Results: After two years of COVID-19 public health emergency, the number of reported PAP smears test, mammography and fecal occult blood test, decreased by 26%, 46% and 33% respectively (Table 1). The reduction was greater during the first months of the pandemic and during the peak of the first wave (April-June 2021: PAP -50%, mammography -58%, occult blood test: -70%). Likewise, the number of first-time visits to oncology services decreased by 37%, reaching a 56% decline during the first wave. As shown in Table 1, these declines continued after the health emergency was lifted. Conclusions: Our results show an important decline of cancer screening and first-time visits to oncology services during the pandemic in Uruguay. After emergency was lifted, reported PAP test showed a partial recovery but mammography, occult fecal blood test and first-time visits to oncology services remain well below pre-pandemic levels. [Table: see text]