Clinical Testing Research Articles

Genetics and biology of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and stromal cells that sustains anabolic growth and suppresses tumor immunity. These conceptual advances have generated novel immunotherapy regimens, particularly cancer vaccines, which are now in clinical testing. We also highlight the advent of KRAS targeted therapy, a milestone advance that has transformed treatment paradigms and offers a platform for combined immunotherapy and targeted strategies. This review provides a perspective summarizing current scientific and therapeutic challenges as well as practice-changing opportunities for the PDAC field at this major inflection point.

Reference Speech-recognition curves for a German monosyllabic test in noise: effects of loudspeaker configuration and room acoustics

Objective Measurement of reference speech-recognition curves for a specific speech test in typical clinical testing environments and for different loudspeaker configurations. Design Speech-recognition scores were measured at four signal-to-noise ratios for five loudspeaker configurations in two anechoic rooms, and in four audiometric test rooms with low reverberation times. Study sample 240 young participants (aged 18–25 years) without hearing impairment participated in the measurements. Results Reference speech-recognition curves for speech and noise from the front (S0N0) were similar across rooms. Compared to S0N0, lower speech-recognition thresholds (SRTs) were observed for all other loudspeaker configurations in which speech and noise were spatially separated. This spatial release from masking was significantly reduced for the audiometric test rooms compared to the anechoic rooms. A binaural speech-intelligibility model was used to verify the influence of room acoustic properties and loudspeaker configuration on SRT. Conclusions Speech-recognition curves for spatially separated loudspeaker configurations depend on the room acoustic properties, even in audiometric test rooms with low reverberation times. This makes it more difficult to compare clinical measurements with reference speech-recognition curves, or even with data measured in a different test room. It is thus recommended to document the loudspeaker configuration and test room for each clinical measurement.

Exposure to the antiretroviral drug dolutegravir impairs structure and neurogenesis in a forebrain organoid model of human embryonic cortical development

IntroductionFor many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy. However, many antiretroviral drugs are approved for widespread use following clinical testing only in non-pregnant populations and there may be limited information on potential teratogenicity until pregnancy outcomes are evaluated. The integrase strand transfer inhibitor dolutegravir (DTG) is a frontline antiretroviral drug that is effective in viral suppression of HIV but was previously reported to be associated with a slight increase in the risk for neural tube defects in one study, although this has not been replicated in other cohorts.MethodsTo directly investigate the potential impact of DTG on human cortical neurogenesis, we measured the effects of daily drug exposure on the early stages of corticogenesis in a human iPSC-based forebrain organoid model. We quantified organoid size and structure and analyzed gene and protein expression to evaluate the impact of several doses of DTG on organoid development.ResultsWe observed deficits in organoid structure and impaired neurogenesis in DTG-treated organoids compared to vehicle-treated control organoids after 20 or 40 days in culture. Our highest dose of DTG (10 μM) resulted in significantly smaller organoids with a reduced density of neural rosette structures compared to vehicle-treated controls. Mechanistically, RNA-sequencing and immunohistological analysis suggests dysregulated amino acid transport and activation of the integrated stress response in the DTG-treated organoids, and functionally, a small molecule integrated stress response inhibitor (ISRIB) could partially rescue increased expression of proteins related to cell cycle regulation.DiscussionTogether, these results illustrate the potential for human iPSC-based strategies to reveal biological processes during neurogenesis that may be affected by therapeutic drugs and provide complementary data in relevant human cell types to augment preclinical investigations of drug safety during pregnancy.

Learning ballet technique modulates the stretch reflex in students with cerebral palsy: case series

BackgroundCerebral palsy (CP) is considered the most prevalent developmental motor disorder in children. There is a need for training programs that enhance motor abilities and normalize function from an early age. Previous studies report improved motor outcomes in dance interventions for CP. Investigating the neurophysiological mechanisms underlying such improvements is necessary for efficient and safe intervention design. This study reports changes in stretch reflex responses as the primary neurophysiological motor outcome of a targeted ballet class intervention.ResultsA case series of participants with mixed spastic and dyskinetic CP (n = 4, mean age = 12.5 years, SD = 6.9S years, three female, one male) who learned ballet technique in a course of one-hour classes twice per week for six weeks is presented. Changes in stretch reflex responses and in clinical motor tests as secondary outcomes were observed after the course and at one-month follow-up. Quantitative measures of elbow or ankle stretch reflex were obtained using electromyography and electrogoniometry. The joint angle of the stretch reflex onset varied across velocities of stretch, and its variability decreased after the intervention. Within-subject tests of the central tendency of stretch reflex angle coefficients of variation and frequency distribution demonstrated significant changes (p-values < 0.05). Secondary outcomes included the Quality of Upper Extremity Skills Test (QUEST), Pediatric Balance Scale (PBS), Modified Tardieu Scale (MTS), Dyskinesia Impairment Scale (DIS), and Selective Control Assessment of the Lower Extremity (SCALE). All the participants demonstrated improvements larger than the minimal clinical important difference (MCID) or the smallest detectable difference (SDD), as applicable.ConclusionsEvidence of changes in the stretch reflex responses in these four cases of mixed CP was observed. The observed variability in the stretch reflex responses may be due to the dyskinetic component of the mixed CP presentations. More studies with a larger sample size and longer duration of learning and practice of ballet technique are necessary to establish the extent of possible modulation and adaptation of the stretch reflex response as a neurophysiological basis for observed improvements in clinical measures.Trial registration: This study was registered in the Clinical Trials Protocol Registration and Results System (NCT04237506, January 17, 2020).

Predictive modeling of COVID-19 mortality risk in chronic kidney disease patients using multiple machine learning algorithms

The coronavirus disease 2019 (COVID-19) has a significant impact on the global population, particularly on individuals with chronic kidney disease (CKD). COVID-19 patients with CKD will face a considerably higher risk of mortality than the general population. This study developed a predictive model for assessing mortality in COVID-19-affected CKD patients, providing personalized risk prediction to optimize clinical management and reduce mortality rates. We developed machine learning algorithms to analyze 219 patients’ clinical laboratory test data retrospectively. The performance of each model was assessed using a calibration curve, decision curve analysis, and receiver operating characteristic (ROC) curve. It was found that the LightGBM model showed the most satisfied performance, with an area under the ROC curve of 0.833, sensitivity of 0.952, and specificity of 0.714. Prealbumin, neutrophil percent, respiratory index in arterial blood, half-saturated pressure of oxygen, carbon dioxide in serum, glucose, neutrophil count, and uric acid were the top 8 significant variables in the prediction model. Validation by 46 patients demonstrated acceptable accuracy. This model can serve as a powerful tool for screening CKD patients at high risk of COVID-19-related mortality and providing decision support for clinical staff, enabling efficient allocation of resources, and facilitating timely and targeted management for those who need the relevant interference urgently.

"The Brain as a Whole" Concept: Facilitating Approaches to Brain Death Understanding (Short Communication)

James Bernat claimed that "the formulation of whole-brain death provides the most congruent map for our correct understanding of death". However, the author has recently proposed the categorization of another phrase: "brain as a whole (BAAW)". This is because patients with primary brainstem lesions who otherwise meet the clinical criteria for BD may still have EEG, CBF, evoked potentials, and hypothalamic-pituitary neurosecretion.Bernat and colleagues suggested "tightening the clinical tests for brain death or loosening the whole-brain criterion of death". They emphasize that the BAAW criterion is an intermediate standard between the whole-brain and brainstem views, tolerating the irreversible cessation of critical brain functions, whereas the BD/DNC determination does not require the cessation of all brain functions or the death of every neuron.In this paper, we have revised the concept of BAAW, which is intuitive and facilitates a conceptual and practical approach, but requires further refinement to specify precisely which brain functions must cease at brain death and which may continue.

Comparative assessment of a COVID-19 vaccine after technology transfer to Iran from critical quality attributes to clinical and immunogenicity aspects

During COVID-19 pandemic, international pharmaceutical companies put effort to build global manufacturing networks for vaccines. Soberana Plus vaccine, a recombinant protein based vaccine (RBD dimer), with the trade name of PastoCovac Plus in Iran, is based on a protein subunit platform in Cuba and completed preclinical and toxicological assessments. This study aimed at presenting the steps of vaccine technology transfer from Cuba to Iran. This study provides the first practical comparability results in Iran to ensure the quality, safety and efficacy of a protein subunit vaccine against COVID-19 after a successful technology transfer from Cuba. PastoCovac Plus was transferred to Iran at the formulation stage. The assessment of the active ingredient pharmaceutical (API) was achieved through physicochemical and clinical data collection and tests to assure if there was any adverse impact on the vaccination results. In order to assess the quality of the vaccine product after technology transfer, we sought different properties including regulatory features, physicochemical quality, vaccine potency and stability as well as its immunogenicity and safety. Following the evaluation of the clinical quality attributes (CQAs) based on the standard protocols, the results showed that the two vaccines are highly similar and comparable, with no considerable effect on safety or efficacy profiles. The CQAs were all in the acceptance limits in terms of safety and efficacy as well as clinical evaluation results. The immunogenicity evaluation also confirmed no significant differences between the vaccines regarding reinfection (P = 0.199) or vaccine breakthrough (P = 0.176). Furthermore, the level of anti-spike and neutralizing antibodies in the both vaccine groups was not significantly different indicating the equality of performance between the two vaccines. According to the results of the quality and clinical assessment of this study, we achieved an acceptable quality attributes and acceptant limits in terms of safety and efficacy of the vaccines pre and post technology transfer.

A rare Coffin-Siris syndrome induced by SOX11: a de novo nonsense variant of short stature.

Coffin-Siris syndrome is a clinically elusive and rare genetic disease characterized by a wide range of clinical manifestations. This study deeply analyzed and identified the clinical phenotype and genetic variant location in a pediatric patient with Coffin-Siris syndrome, aiming to enhance the understanding of this syndrome and assist in its screening and diagnosis. A combination of advanced diagnostic tools, including high-throughput whole-exome sequencing (WES) and first-generation sequencing technologies, was employed to ascertain the etiology of the disease in the child. The clinical phenotype was characterized by stunted growth, reduced stature, spina bifida, enuresis, and a ventricular septal defect. WES revealed a de novo variant in the SOX11 gene locus (c.700G > T), identified as pathogenic. It is noteworthy that this variant has not been previously reported. The combination of clinical presentation and genetic testing results supports that the patient suffers from Coffin-Siris syndrome due to a genetic variant in the SOX11 gene. This de novo variant expands our understanding of human gene variation, which is conducive to genetic counseling and screening for early diagnosis of Coffin-Siris syndrome.

A Simple Test Ratio APRI (AST to Platelet Ratio Index) as a Useful Tool for Cirrhosis: A Study from Bir Hospital, Nepal

Background Liver cirrhosis is a leading cause of morbidity and mortality worldwide, including Nepal. Liver biopsy, the gold standard for fibrosis assessment, is invasive and carries risks. The Aspartate Aminotransferase to Platelet Ratio Index (APRI) offers a non-invasive, cost-effective alternative. However, data on its utility in Nepalese populations are limited.  Objective To evaluate the diagnostic performance of APRI as a non-invasive marker of cirrhosis in Nepalese patients, determining its sensitivity, specificity, and predictive values.  Methods This cross-sectional study enrolled 58 cirrhotic patients and 58 healthy controls at Bir Hospital from April 2019 to January 2020. Clinical examinations, laboratory tests, and ultrasonography were performed. APRI with a cut-off of 0.5 was evaluated using SPSS version 23, applying chi-square and ANOVA tests.  Results Among 116 participants, APRI at a 0.5 cut-off demonstrated 88.3% sensitivity, 82.5% specificity, 90.1% positive predictive value, and 70.2% negative predictive value (p = 0.002, 95% CI).  Conclusion APRI is a reliable non-invasive tool for diagnosing liver fibrosis in cirrhotic patients, offering high sensitivity and specificity. It is practical for bedside use, especially in resource-limited settings.

Increased FT3/FT4 ratio in a certain range is associated with decreased glycemic variability in patients with type 2 diabetes

Thyroid hormone (TH) plays a crucial role in regulating glucose metabolism. However, the potential impact of the FT3/FT4 ratio, which reflects peripheral sensitivity to thyroid hormones, on glycemic variability in patients with type 2 diabetes (T2DM), has not been previously reported. To investigate the correlation between the FT3/FT4 ratio and glycemic variability in individuals with T2DM. In this retrospective analysis, a total of 468 inpatients with T2DM underwent continuous glucose monitoring (CGM) systems for a period of 6–14 days. Baseline clinical characteristics, laboratory tests, and CGM parameters were documented to investigate the correlation between FT3/FT4 ratio and CGM parameters. The levels of HBA, MG, SD, CV, LAGE, MODD and TAR2Scale were all higher in FT3/FT4Q1 compared with FT3/FT4Q2, FT3/FT4Q3 and FT3/FT4Q4 (all P < 0.01). Additionally, TIR was lower in FT3/FT4Q1 compared with the other quartiles (P < 0.01). Smooth curve fitting and saturation effect analysis revealed that there are curve-like relationships between the FT3/FT4 ratio and SD, MAGE, MODD and TAR2Scale. The inflection points of the fitted curves were found to be at FT3/FT4 = 0.279, 0.237, 0.253 and 0.282 respectively (all P < 0.05). Prior to the inflection point, the FT3/FT4 ratio was negatively related to SD, MAGE, MODD and TAR2Scale (all P < 0.05). Furthermore, The FT3/FT4 ratio exhibits a negative linear correlation with HBA and MG, while demonstrating a positive linear relationship with TIR (all P < 0.05). Binary logistic regression demonstrated that the FT3/FT4 ratio was independently related to HBA (P = 0.001), MG (P = 0.01), TAR2Scale (P = 0.003), LAGE (P = 0.014) and MAGE (P < 0.001). The increased FT3/FT4 ratio within a certain range (FT3/FT4 ≤ 0.282) is associated with decreased blood glucose variability and increased TIR. The FT3/FT4 ratio may act as a potential independent protective factor for glycemic fluctuation and glycemic control in patients with T2DM when it increases within a specific range.

Plasma neurofilament light chain in fibromyalgia: A case control study exploring correlation with clinical and cognitive features.

Plasma neurofilament light chain (NFL) has been measured as a biomarker of neuronal damage in various neurological disorders. Elevated tau and β-amyloid levels have been found in patients with fibromyalgia (FM). The aim of the present study was to compare plasma neurofilament levels in fibromyalgia patients with normal controls and to investigate the correlation with clinical features and cognitive tests. Plasma NFL levels were assessed in 33 FM patients and compared with 22 age-matched controls. All patients were also assessed with clinical scales examining fibromyalgia disability, sleep quality and duration, fatigue, anxiety, and depression, and a neuropsychological battery examining executive function, verbal short-term memory, and working memory, as well as attentional executive function and selective attention, interference sensitivity, and inhibition of automatic responses. NFL levels were higher in FM patients (controls 6.19± 1.92; FM 17.28± 15.94 pg/mL ANOVA p 0.002). Working memory was the most impaired cognitive function significantly correlated with high NFL scores (Pearson p 0.034). Short sleep times also correlated with higher NFL scores (Pearson p 0.02) and poorer working memory performance (Pearson p 0.02). No correlation was found with indices of disease severity and duration. Plasma NFL levels are elevated in fibromyalgia patients, suggesting neuronal damage and correlating with a slight decrease in working memory and short sleep duration. Plasma neurofilament levels are elevated in patients with fibromyalgia, regardless of disease severity and duration. Neurofilament levels are higher in patients with mild working memory impairment and sleep disorders. Subgroups of patients with primary neuronal damage phenomena could be individualized for prospective evaluation with regard to the possible development of cognitive decline and sleep disturbances, which would justify a tailored therapeutic approach.

The Maturity-Onset Diabetes of the Young (MODY) Calculator Overestimates MODY Probability in Hispanic Youth.

The applicability of the MODY risk calculator (Shields et al) to non- White European populations remains unknown. We aimed to test its real-world application in Hispanic youth. We conducted a retrospective chart review of Hispanic youth (<23 years) with diabetes (n=2033) in a large pediatric tertiary care center in the U.S. We calculated MODY probability for all subjects, splitting them into two cohorts based on the original model: Individuals who were started on insulin within 6 months of diabetes diagnosis (Cohort 1) and those who were not (Cohort 2). Cohort 1 consisted of 1566 individuals (median age [25p, 75p]: 16 [13, 19] years, 49% female), while Cohort 2 comprised 467 youth (median age [25p, 75p]: 17 [15, 20] years, 62% female). The mean MODY probability was 5.9% and 61.9% in Cohort 1 and Cohort 2, respectively. The mean probability for both cohorts combined was 18.8% suggesting an expected 382 individuals with MODY, which is much higher than previous estimations (1-5%; i.e. 20-102 individuals in this cohort). A total of 18 individuals tested positive for MODY among the limited number of individuals tested based on clinical suspicion and genetic testing availability (n=44 out of 2033 tested, [2.2% of overall cohort]). The MODY risk calculator likely overestimates the probability of MODY in Hispanic youth, largely driven by an overestimation in those not early-insulin treated (predominantly young-onset type 2 diabetes). The calculator needs updating to improve its applicability in this population. In addition, further research to help better identify MODY in Hispanic youth.

Compact Digital Immunoassay Platform Integrating ELISA with a Lateral Flow Strip

Background/Objectives: On-site diagnosis of infection in their early stages requires assays with high sensitivities that are compact and easy to operate out of the laboratory and hospital environments. However, current assay technologies fall short of these requirements and require highly skilled technicians to set up, operate, and interpret the results. Methods: To address these challenges, we developed and evaluated a Point-of-Care-Testing (PoCT) immunoassay platform called the D-strip. The D-strip platform combines the capabilities of a digital enzyme-linked immunoassay (ELISA) with a lateral flow assay (LFA). The D-strip sample flow cell is composed of the same components found in conventional LFAs, and its high sensitivity is due to its efficient implementation of ELISA. The fully integrated platform is simple and requires minimal user intervention to operate. Results: The D-strip exhibited a sample-to-result time of 15 min with a limit of detection (LOD) of 1.7 × 103 copies/mL for severe acute respiratory syndrome coronavirus 2 (SARS-2-CoV) antigen. The LOD of the D-strip is 488-fold higher than that for conventional LFAs and is comparable to a clinical laboratory test. Conclusions: The D-strip is a compact and highly sensitive immunoassay platform with a strong potential for application as a confirmatory assay outside the clinical laboratory.

Phylogenetic evaluation and genotypic identification of burn-related Pseudomonas aeruginosa strains isolated from post-burn human infections during hospitalization.

Cutaneous burn trauma, compromise of dermal layers and immune defense system is a physical and fiscal burden on healthcare systems. Burn-wound infections are a serious complication of thermal-injury and contribute significantly to care burden. After burn-induced trauma, sepsis by Pseudomonas aeruginosa impairs patient recovery and contributes to mortality and morbidity. Past studies show positive correlation between detection of Pseudomonas species and healing-impaired traumatic wounds. P. aeruginosa is a resilient opportunistic human pathogen and a nosocomial agent involved in pathology of healing-impaired wounds, especially in burn-patients. Expansive array of virulence determinants have resulted in gentamicin- and silver-resistant P. aeruginosa outbreaks. Knowledge of molecular dynamics and phylogeny of P. aeruginosa associated with burn-wounds is limited. Therefore, we conducted whole-genome sequencing for genotyping and phylogenetic analysis of P. aeruginosa burn-associated strains (n=19) isolated from 7 burn cases during hospitalization. Comparison of genetic features in P. aeruginosa strains in the core genome and mobilome detected genetic variations within some clonal infections overtime. Genetic variations were observed among different burn cases, with some features identified in severe lung infections. Polyclonal infections were also observed, with differing genotypes and virulence potentials, highlighting the importance of reasoned sampling of isolates for clinical testing.

Fermented Gold Kiwi Improves Gastrointestinal Motility and Functional Constipation: An Animal Study and Human Randomized Clinical Test.

Constipation is a functional disorder of the gastrointestinal system characterized by difficult bowel movements, infrequent defecation, reduced water content, and hard stools. This study aims to evaluate the preventive effects of fermented gold kiwis (FGK) on loperamide-induced constipation in rats and investigate its efficacy in improving constipation symptoms in human patients through a randomized clinical trial. In the animal study, FGK was administered orally at doses of 50, 125, and 250 mg/kg to constipated rats for two weeks, resulting in significant improvements in constipation parameters. FGK increased serum serotonin and acetylcholine levels and suppressed increases in serum dopamine concentration. FGK also upregulated mRNA expression of the serotonin-synthesizing receptors 5-HT3R and 5-HT4R and suppressed the expression of the dopamine 2-receptor (D2R) in the duodenum. Furthermore, FGK inhibited inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. In the clinical trials, the improvement in constipation symptoms was evaluated using the gastrointestinal symptom rating scale (GSRS). Clinical trial participants reported significant improvements in constipation symptoms after receiving FGK. These findings suggest that FGK effectively relieves constipation in both animals and humans, indicating its potential as an effective dietary supplement.

Biomarkers of glucose-insulin homeostasis and incident type 2 diabetes and cardiovascular disease: results from the Vitamin D and Omega-3 trial

BackgroundDysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations.MethodsVITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD).ResultsWe identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints.ConclusionsEach of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile X syndrome

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5’ untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. These EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding post-period 1 of the study, participants who received BPN14770 in period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770 measured at the end of period 1. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Reduced penetrance BRCA1 and BRCA2 pathogenic variants in clinical germline genetic testing

Prior studies have suggested the existence of reduced penetrance pathogenic variants (RPPVs) in BRCA1 and BRCA2 (BRCA) which pose challenges for patient counseling and care. Here, we sought to establish RPPVs as a new category of variants. Candidate BRCA RPPVs provided by two large clinical diagnostic laboratories were compiled to identify those with the highest likelihood of being a RPPV, based on concordant interpretations. Sixteen concordant candidate BRCA RPPVs across both laboratories were systematically assessed. RPPVs included missense, splice site, and frameshift variants. Our study establishes RPPVs as a new class of variants imparting a moderately increased risk of breast cancer, which impacts risk-informed cancer prevention strategies, and provides a framework to standardize interpretation and reporting of BRCA RPPVs. Further work to define clinically meaningful risk thresholds and categories for reporting BRCA RPPVs is needed to personalize cancer risks in conjunction with other risk factors.

Limitations and Principles of Safety in the 3D Bioprinting Process

The importance of biological printing is in tissue structures that imitate the micro and real environment of human tissues and organs. This is very important in medicinal tests and clinical tests. In biological printing, cells or molecules are printed directly on a substrate in a particular pattern so that the cells can be kept together and formed the required 3D structure. This technology is widely used in medical science, including tissue regeneration, diagnosis of drugs, tissue transplantation, cosmetic surgery, and more. In this study, we have tried to point out existing damage and safety tips in this technology. Studies show the challenges facing this technology, such as high clarity in cell construction, lack of mechanical resistance and adequate integration of bio -printing structures made with soft hydrogel, material printing speed, recurreability and cell preservation. Also, work safety instructions with bio -printers including personal hygiene, printer cleaning, work room cleaning, ventilation system, periodic medical tests for operators are provided. Bioprinting technology is developing and requires further research to remove restrictions and reduce risk management

Clinical and Structural Results Following Arthroscopic and Open Repair of Isolated Subscapularis Tears.

Objective: With advances in techniques, arthroscopic repair of isolated subscapularis tendon tears has become increasingly popular in recent years. The aim of this study was to analyze the clinical and structural results of arthroscopic repair versus the gold standard of open repair. It is a prospective cohort study with a control group; evidence level III. Methods: In a prospective study performed at two centers, 18 patients with an isolated subscapularis tear were treated with arthroscopic repair (ARG) and 16 patients with open repair (ORG) using a uniform single-row suture anchor repair technique in both groups. The subscapularis function was assessed using specific clinical tests (belly-press and lift-off tests), strength testing and shoulder function with the use of the Constant-Murley score (CMS). Standardized magnetic resonance imaging (MRI) was used to evaluate the postoperative subscapularis muscle-tendon status. Results: At a minimum follow-up of 48 months, the CMS increased from a mean of 54 points preoperatively to a mean of 86 points postoperatively in the ARG (p < 0.01) and from 50 points to 85 points postoperatively in the ORG (p < 0.01). Specific subscapularis tests (belly-press test and lift-off test) were significantly improved from the preoperative to the postoperative status in both repair groups (p < 0.05). Despite a subscapularis tendon healing rate of over 90% on MRI scans in both repair groups, the incomplete correction of specific muscle tests was a frequent postoperative finding. Conclusions: Arthroscopic repair of isolated subscapularis tears achieved equivalent clinical and structural results compared to the gold standard of open repair.