Negative Patients Research Articles

Host Urinary Biomarkers in HIV positive and HIV negative patients with Tubercular uveitis and other uveitic diseases

Host Urinary Biomarkers in HIV positive and HIV negative patients with Tubercular uveitis and other uveitic diseases

Estimating Impacts of p16 Status on Tumor Radiosensitivity in Head and Neck Cancer using Predictive Models.

The intrinsic radiosensitivity index (RSI) and genomic-adjusted radiation dose (GARD) were reported to be able to predict the surviving fraction at 2 Gy and therapeutic effect when delivering actual treatment doses using the gene expression profiles of clinical cases. Given the impact of p16 status, a surrogate marker of the human papillomavirus (HPV) infection, on radiosensitivity, we attempted to apply the RSI and GARD to estimate p16-associated radiosensitivity in head and neck squamous cell carcinoma (HNSC). For this purpose, The Cancer Genome Atlas (TCGA) dataset was employed. In the GARD calculation, we assumed that p16-positive patients received 60 Gy in 30 fractions, while p16-negative patients received 70 Gy in 35 fractions. p16 positivity was associated with favorable characteristics compared to negative patients. The RSI and GARD analyses demonstrated increased radiosensitivity and high therapeutic effect in p16-positive patients, compared to p16-negative patients. Additionally, tumor microenvironmental conditions predicted by other models were also significantly affected by p16 status. Collectively, the models used in this study could be a promising tool for estimating p16-associated radiosensitivity in HNSC.

Genetic mutations in Parkinson's disease: screening of a selected population from North-Eastern Italy.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a multifactorial pathogenesis. Several genetic variants increase the risk of PD and about 5-10% of cases are monogenic. This study aims to define the genetic bases and clinical features of PD in a cohort of patients from Northeastern Italy, a peculiar geographical area previously not included in genetic screenings. Using an NGS multigenic panel, 218 PD patients were tested based on age at onset, family history and development of atypical features. A total of 133 genetic variants were found in 103 patients. Monogenic PD was diagnosed in 43 patients (20% of the cohort); 28 (12.8%) carried mutations in GBA1, 10 in LRRK2 (4.6%) and 5 in PRKN (2.3%). In 17% of patients the genetic defect remained of uncertain interpretation. The selection criterion "age of onset < 55years" was a significant predictor of a positive genetic test (OR 3.8, p 0.0037). GBA1 patients showed more severe symptoms and a higher burden of motor and non-motor complications compared to negative patients (dyskinesias OR 3, sleep disturbances OR 2.8, cognitive deficits OR 3.6; p < 0.05), with greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, p 0.03). Applying simple clinical criteria for genetic testing allows to increase the probability to identify patients with monogenic PD and better allocate resources. This process is critical to widen the understanding of disease mechanisms and to increase the individuation of patients potentially benefitting from future disease-modifying therapies.

Implementation of Choosing Wisely® Recommendations for Lymph Node Surgery in Male Breast Cancer.

The Choosing Wisely® (CW) campaign recommended de-implementation of surgical management of axillary nodes in specified patients. This study aimed to assess trends in the application of CW guidelines for lymph node (LN) surgery in males with breast cancer. The National Cancer Database was queried for males diagnosed with breast cancer from 2017 to 2020. Patients were categorized into two cohorts based on CW criteria. Cohort 1 included all T1-2, clinically node-negative patients who underwent breast-conserving therapy and with ≤ 2 positive nodes, and Cohort 2 included all T1-2, node-negative, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative patients aged ≥ 70 years. In Cohort 1, patients who underwent sentinel LN biopsy (SLNB) alone were compared with axillary LN dissection (ALND) or no LN surgery, while in Cohort 2, patients who underwent LN surgery were compared with those with no LN surgery. Of 617 patients who met the criteria for Cohort 1, 73.1% underwent SLNB alone compared with ALND (11.8%) or no LN surgery (15.1%). Those who received SLNB alone were younger (65 vs. 68 vs. 73years; p<0.001). The annual proportion of males who underwent SLNB alone remained stable from 2017 to 2020. Overall, 1565 patients met the criteria for Cohort 2, and 84.9% received LN surgery. LN surgery was omitted in older patients (81 vs. 77; p<0.001). The proportion of elderly males with early-stage breast cancer who underwent LN surgery increased from 2017 to 2020. This study demonstrates that CW recommendations are not being routinely applied to males. These findings reinforce the need for additional studies and subsequent recommendations for optimal application of axillary surgery de-implementation for males diagnosed with breast cancer.

Effect of PR status on the prognosis of advanced ER-high HER2-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy

BackgroundThis study was designed to evaluate the effect of progesterone receptor (PR) status on the prognosis of advanced estrogen receptor (ER)-high human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy.MethodsAdvanced ER-high HER2-negative breast cancer patients who were admitted to Harbin Medical University Cancer Hospital and received cyclin-dependent kinase (CDK)4/6 inhibitor combined with endocrine as first-line therapy were included for analysis. Patients were divided into PR-high group (11-100%), PR-low group (1-10%), and PR-negative group (< 1%) according to the expression of PR. Chi-square test was used to analyze the correlation of variables between groups. COX regression analysis were used to analyze the risk factors of survival. Kaplan-Meier survival curve was used to analyze the differences of progression-free survival (PFS) and overall survival (OS) between groups.ResultsAmong the 152 patients, 72 were PR-high, 32 were PR-low, and 48 were PR-negative. Compared with PR-negative group, the proportions of disease-free survival (DFS) ≥ 5 years and Ki-67 index ≤ 30% in PR-low group and PR-high group were significant higher. PR-negative patients were more likely to occur first-line progression of disease within 24 months (POD24) than PR-high(P = 0.026). Univariate and multivariate analysis showed that PR-negative and first-line POD24 occurrence were risk factors for survival. Survival curve analysis showed that compared with PR-high group, the PFS and OS were significantly lower in PR-negative group (P = 0.001, P = 0.036, respectively). Patients with first-line POD24 had shorter OS in the overall population as well as in subgroups stratified by PR status.ConclusionsPR-negative and first-line POD24 occurrence were risk factors of advanced ER-high HER2-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. PR-negative patients had shortest PFS and OS. Regardless of PR status, first-line POD24 occurrence predicted shorter OS.

Targeting the tumor microenvironment to improve clinical outcomes in triple negative breast cancer patients and bridge the current disparity gap

Targeting the tumor microenvironment to improve clinical outcomes in triple negative breast cancer patients and bridge the current disparity gap

Clinicopathological phenotype and outcomes of NCAM-1+ membranous lupus nephritis.

No studies explored the long-term outcomes of neural cell adhesion molecule 1 (NCAM1) associated membranous lupus nephritis (MLN) patients. We performed immunohistochemical studies on kidney biopsy specimens against NCAM1 in consecutive MLN patients. The clinical and histopathological characteristics and outcomes of cases of NCAM1 associated MLN patients are described and compared with NCAM1 negative patients. In addition, we detected serum circulating anti-NCAM1 antibodies through western blotting and indirect immunofluorescence assays. Among 361 MLN cases, 18 (5.0%) were glomerular NCAM1-positive. NCAM1 positive MLN patients were older [35 years (IQR 27-43) versus 28 (22-37); P=0.050) and had lower systemic lupus erythematosus disease activity index [11 (IQR 8-12) versus 14 (10-18); P=0.007], serum creatinine [60 μmol/L (IQR 50-70) versus 70 (54-114); P=0.029], activity index [3 (IQR 2-6) versus 6 (3-9); P=0.045] at kidney biopsy compared with NCAM1 negative patients. The percentage of positive anti-Sjogren's syndrome related antigen A antibodies in NCAM1 positive patients was significantly greater (83.3% versus 58.2%; P=0.035) than in the NCAM1 negative patients. However, no evidence of neuropsychiatric disorders was found in these 18 patients. There were no significant differences in the treatment response and the risk of end stage renal diseases between NCAM1 positive and negative groups (P=0.668 and P=0.318, respectively). But the risk of death was much higher in the NCAM1 positive group than the NCAM1 negative group (27.8%vs. 8.1%, P=0.007). Moreover, the risk of death was also much higher in the NCAM1 positive group than the matched NCAM1 negative group (Log-rank P=0.013). Additionally, circulating anti-NCAM1 antibodies can be detected in 1/5 (20%) patients who had serum available. The prevalence of NCAM1 positivity was 5.0% in our cohort of MLN and the high mortality in these subgroup patients are needed to validate in future studies.

Impact of homologous recombination repair/BReast CAncer (BRCA) gene alterations on survival in a real-world setting of metastatic prostate cancer.

To investigate alterations of homologous recombination repair (HRR) and especially BReast CAncer 1/2 (BRCA1/2) gene on overall survival (OS). Moreover, to explore the effect of inhibition of poly(ADP-ribose)-polymerase (PARPi) as systemic therapy for metastatic castration-resistant prostate cancer (mCRPC). Of all HRR-screened patients with metastatic prostate cancer, baseline characteristics were sampled. Kaplan-Meier estimates and multivariable Cox regression models predicted the effect of HRR/BRCA1/2 alterations on OS. Of 196 eligible patients, 61 (31%) harboured any HRR and 40 (20%) BRCA1/2 alterations. Of HRR alterations, 40 (66%) vs six (10%) vs five (8.2%) vs four (6.6%) vs two (3.3%) vs four (6.6%) were BRCA1/2 vs Ataxia-telangiectasia mutated kinase (ATM) vs checkpoint kinase 2 (CHEK2) vs cyclin-dependent kinase 12 (CDK12) vs Fanconi anaemia complementation Group A (FANCA) vs positive for other mutations. Of these, 30% received a PARPi. OS differed significantly between HRR-positive vs -negative patients. Specifically in hormone-sensitive prostate cancer, the median OS was 63 (HRR positive) vs 57 (BRCA1/2 positive) vs 113 months (HRR negative) (P ≤ 0.01). In mCRPC, OS was 42 (HRR positive) vs 41 (BRCA1/2 positive) vs 70 months (HRR negative) (P ≤ 0.01). HRR and BRCA1/2 alterations were associated with worse OS after multivariable adjustment. Finally, patients with mCRPC with BRCA1/2 mutation treated without PARPi harboured worse OS than patients with BRCA1/2 mutation and PARPi therapy (median OS: 33 vs 48 months, P < 0.03). Incidence of HRR alteration in a clinical real-world setting is high when using blood- and tissue-based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA-positive patients with mCRPC with and without PARPi usage vs HRR/BRCA-negative patients.

Clinical significance of circulating tumor cells in colorectal cancer with peritoneal metastases: a prospective cohort study using a novel method for monitoring treatment response, and assessing minimal residual disease.

The treatment for patients with colorectal cancer with metastases to the peritoneum is complex and may involve both surgery and chemotherapy. Circulating tumor cells (CTCs) have been poorly investigated in peritoneal metastatic colorectal cancer. The aim of the study is to examine the role of circulating tumor cells (CTCs) as a biomarker for monitoring disease progression, treatment response and residual disease using CellMate® - a new promising in vitro diagnostic platform technology. We prospectively followed clinical outcomes of 46 patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer with peritoneal metastases and examined whether CTCs were present the week of surgery. The CTC measurements were made with the CellMate® technology, which is a platform technology to detect CTCs based on the difference in biomechanical properties compared to blood resident cells. The study was registered online (ClinicalTrials.gov). CTCs were detected in 17 (37%) patients. The presence of CTCs was associated with shorter recurrence-free survival and overall survival after CRS and HIPEC. Both recurrence free survival (HR 4.00, 95%CI 1.15-13.9; P=0.029) and overall survival (HR 5.91; 95% CI 1.18-29.7; P=0.03) were significantly worse if CTCs were detected after neoadjuvant treatment. In the subgroup of patients with CTCs detected, adjuvant therapy tended to improve the prognosis while in CTC negative patients it did not. Pending a prospective multi-center trial to validate these findings, CTCs may in the future be used as a dynamic personalized biomarker for prognostication, predicting response to therapy, and for monitoring disease progression in colorectal cancer with metastases to the peritoneum.

Development and validation of machine learning models to predict MDRO colonization or infection on ICU admission by using electronic health record data

BackgroundMultidrug-resistant organisms (MDRO) pose a significant threat to public health. Intensive Care Units (ICU), characterized by the extensive use of antimicrobial agents and a high prevalence of bacterial resistance, are hotspots for MDRO proliferation. Timely identification of patients at high risk for MDRO can aid in curbing transmission, enhancing patient outcomes, and maintaining the cleanliness of the ICU environment. This study focused on developing a machine learning (ML) model to identify patients at risk of MDRO during the initial phase of their ICU stay.MethodsUtilizing patient data from the First Medical Center of the People’s Liberation Army General Hospital (PLAGH-ICU) and the Medical Information Mart for Intensive Care (MIMIC-IV), the study analyzed variables within 24 h of ICU admission. Machine learning algorithms were applied to these datasets, emphasizing the early detection of MDRO colonization or infection. Model efficacy was evaluated by the area under the receiver operating characteristics curve (AUROC), alongside internal and external validation sets.ResultsThe study evaluated 3,536 patients in PLAGH-ICU and 34,923 in MIMIC-IV, revealing MDRO prevalence of 11.96% and 8.81%, respectively. Significant differences in ICU and hospital stays, along with mortality rates, were observed between MDRO positive and negative patients. In the temporal validation, the PLAGH-ICU model achieved an AUROC of 0.786 [0.748, 0.825], while the MIMIC-IV model reached 0.744 [0.723, 0.766]. External validation demonstrated reduced model performance across different datasets. Key predictors included biochemical markers and the duration of pre-ICU hospital stay.ConclusionsThe ML models developed in this study demonstrated their capability in early identification of MDRO risks in ICU patients. Continuous refinement and validation in varied clinical contexts remain essential for future applications.

Limbic Network and Papez Circuit Involvement in ALS: Imaging and Clinical Profiles in GGGGCC Hexanucleotide Carriers in C9orf72 and C9orf72-Negative Patients

Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.

The Utility of Serum Procalcitonin Level as an Early Diagnostic Biomarker For COVID in Patients Presenting with ST-Elevation Myocardial Infarction Post Primary Percutaneous Coronary Intervention

Abstract Aim and Objectives The aim of the study was to detect if serum procalcitonin could be used as an early diagnostic marker for COVID in asymptomatic patients presenting with ST-segment elevation Myocardial infarction and if procalcitonin is related to the extent of myocardial injury after the infarction. Patients and Methods The study was carried out on 150 patients (age 53.39 ± 13.16) presenting to Ain shams university hospitals with ST-segment elevation Myocardial Infarction and received the standard of care management which is Primary PCI. The patients were assessed regarding the demographic data, presence of any symptoms and signs of infection, risk factors, echocardiography and laboratory measures. COVID PCR and Procalcitonin were withdrawn from all patients. Results Out of all the asymptomatic patients presenting with STEMI whose COVID PCR turned out to be positive, the procalcitonin was positive 24 and 48 hours post presentation with P value 0.000. Procalcitonin had no statistical significance with any demographical data, risk factors and comorbidities for cardiovascular disease, extent of myocardial injury and most laboratory findings. There was high statistical significance between positive procalcitonin and TLC count where there was a drop from a median of 11/mm3 with range (4.5– 19) /mm3 in negative procalcitonin to a median of 3.7 /mm3 with range (1.4 –12) /mm3 in procalcitonin positive patients. There was high statistical significance between positive procalcitonin and rise of CRP value where there was a rise from CRP median value from 12 mg/dL range (2– 40) mg/dL in negative procalcitonin patients to 47 mg/dL range (14– 163) mg/dL in positive procalcitonin patients. Conclusion Procalcitonin as an inflammatory marker has no relationship to myocardial infarction nor extent of myocardial injury. There was a strong relationship between procalcitonin and COVID infection in asymptomatic patients thus procalcitonin can be used as an early diagnostic biomarker for covid infection in patients presenting with myocardial infarction.

O-201 Antinuclear antibodies in women with recurrent early pregnancy loss: prevalence and impact on subsequent pregnancy outcome

Abstract Study question What is the prevalence of antinuclear antibodies (ANAs) in women with recurrent early pregnancy loss (REPL) and do they affect subsequent pregnancy outcome? Summary answer The prevalence of ANAs in women with REPL was 13.0%, and their presence did not negatively impact subsequent pregnancy outcomes, including EPL and livebirth rates. What is known already An etiological factor cannot be identified in more than half of the couples experiencing REPL. Immunologic mechanisms could be involved, with the presence of autoimmune disease (AD) associated to lower reproductive outcomes. For the mere presence of ANAs, in the absence of AD, the evidence on the association with REPL is controversial, with most studies having a small sample size with important clinical and methodological heterogeneity. Study design, size, duration This is a single-centre, retrospective cohort study from a tertiary referral hospital including 960 women referred for REPL between January 2014 and December 2019. During the entire study period, maternal serum ANA detection was part of the routine diagnostic REPL work-up, defined as two or more pregnancy losses before the 10th week of gestation, including previous spontaneous conceptions and pregnancies following autologous IVF/ICSI treatment. Participants/materials, setting, methods Women under the age of 40 at ANA analysis were eligible for inclusion. Confirmed AD, uterine anomalies, parental chromosomal abnormalities and uncontrolled endocrine disorders were exclusion criteria. The prevalence of positive ANA titers and the impact of ANA positivity on the outcome of a subsequent pregnancy were investigated with EPL rate as the main outcome parameter and biochemical pregnancy rate, clinical miscarriage rate and live birth rate as secondary outcome measures. Main results and the role of chance Positive ANA screening at a titer of ≥ 1/80 was observed in 125/940 women (13.0%), a prevalence in line with previously published data in the general population not experiencing REPL. There were no statistically significant differences in maternal age, body mass index, ethnicity, or conception method between ANA-positive and -negative women. No higher number of previous EPLs was observed in ANA-positive compared to ANA-negative women (respectively 2.7 versus 2.8, p = 0.06). Women with ANAs had significantly more thyroid antibodies (21.6% versus 10.2%, p &amp;lt; 0.001). For a subsequent pregnancy, no association was observed between ANA positivity and reproductive outcome with an unadjusted EPL rate of 30/86 (34.9%, ANA-positive) versus 206/509 (40.5%, ANA-negative, p = 0.32). Logistic regression analysis did not identify ANAs as an independent predictive risk factor for additional EPL (OR 0.73, 95%CI 0.45-1.20, p = 0.22). Similarly, there was no significant difference in live birth rates between both groups (p = 0.5), with 54/86 (62.8%) in ANA-positive and 300/509 (58.9%) in ANA-negative patients. Limitations, reasons for caution The current data are limited by the absence of a formal control group without REPL, the retrospective nature of the study and potential bias due to unmeasured confounders. Wider implications of the findings These findings further questions systematic ANA measurement in the diagnostic work-up of REPL without AD. Furthermore, when ANAs are detected, patient counselling and treatment adaptations should be considered with caution, given our inability to eventually detect any significant differences in the pregnancy outcomes between ANA-positive and -negative REPL patients. Trial registration number not applicable

Severe CSF immune cell alterations in cryptococcal meningitis gradually resolve during antifungal therapy

Cryptococcal meningitis (CM) is a severe fungal disease in immunocompromised patients affecting the central nervous system (CNS). Host response and immunological alterations in the cerebrospinal fluid (CSF) after invasion of Cryptococcus neoformans to the central nervous system have been investigated before but rigorous and comprehensive studies examining cellular changes in the CSF of patients with cryptococccal meningitis are still rare. We retrospectively collected CSF analysis and flow cytometry data of CSF and blood in patients with CM (n = 7) and compared them to HIV positive patients without meningitis (n = 13) and HIV negative healthy controls (n = 7). Within the group of patients with CM we compared those with HIV infection (n = 3) or other immunocompromised conditions (n = 4). Flow cytometry analysis revealed an elevation of natural killer cells and natural killer T cells in the CSF and blood of HIV negative patients with CM, pointing to innate immune activation in early stages after fungal invasion. HIV positive patients with CM exhibited stronger blood-CSF-barrier disruption. Follow-up CSF analysis over up to 150 days showed heterogeneous cellular courses in CM patients with slow normalization of CSF after induction of antifungal therapy.

P-610 Elevated/high-normal TSH on day of beta-hCG in sub-clinical hypothyroid patients on levothyroxine associated with better odds of pregnancy in IVF cycles: a nested case-control study

Abstract Study question Is there an association between odds of achieving pregnancy and high-normal/elevated TSH levels in sub-clinical hypothyroid (SCH) patients on levothyroxine replacement who are undergoing IVF? Summary answer Odds of achieving pregnancy are significantly greater when TSH on day of beta-hCG is elevated/high-normal despite levothyroxine replacement in sub-clinical hypothyroid (SCH) patients undergoing IVF. What is known already TSH levels are known to increase following ovarian stimulation (OS). A 2023 Nature publication reported that in euthyroid patients undergoing fresh embryo transfer following OS and IVF, elevated/high-normal TSH levels (&amp;gt;2.5 mIU/mL) are associated with better pregnancy rates. Another recent study found no differences in IVF outcomes between SCH patients whose TSH was maintained=/&amp;lt; 4.2 mIU/mL on levothyroxine vs euthyroid controls. To the best of our knowledge, there are no prospective studies investigating possible association between pregnancy outcome and elevated TSH levels following OS within a cohort of SCH patients on levothyroxine replacement, using 2.5 mIU/mL as a strict cut-off. Study design, size, duration Nested case-control study performed between July-December 2023. PCOS and other endocrinopathies excluded. 100 SCH patients booked for fresh, blastocyst eSET cycles initially recruited after thyroxine replacement. 79 patients completed the study following 5 drop-outs and 16 cases of cycle cancellation/failure, cleavage-stage transfers and freeze-all. Odds of achieving pregnancy (‘cases’) in patients with elevated/high-normal TSH (‘exposure’) on day of beta-hCG determined by Odds Ratio, with beta-hCG negative patients serving as ‘controls’. First IVF cycle data analysed/presented. Participants/materials, setting, methods Study performed at an university-affiliated ART institute. Following institutional ethical clearance, patients with SCH (TSH&amp;gt;2.5 mIU/mL) recruited after informed consent. Levothyroxine replacement initiated to achieve TSH:0.5-2.5 mIU/mL and continued; followed by OS, antagonist IVF/ICSI cycles, hCG trigger and fresh blastocyst eSET. TSH measured again on day of beta-hCG (blinded). Odds Ratio calculated (IBM SPSS V.26) to determine odds of achieving pregnancy in high-normal/elevated group (TSH&amp;gt;2.5 mIU/mL) compared to low-normal group (TSH =/&amp;lt; 2.5 mIU/mL). Main results and the role of chance Baseline demographic characteristics of the single starting cohort of sub-clinical hypothyroid patients undergoing IVF/ICSI (n = 79) are summarized as mean±SD- age: 31.7±4.9 years, BMI: 27.9±14.2 kg/m2, AMH: 3.1±2.4 ng/mL, TSH before levothyroxine replacement: 5.5±2.7 mIU/mL. Data analysis showed that out of 63 patients in whom TSH level elevated &amp;gt; 2.5 mIU/mL on day of beta-hCG, 33 became pregnant (P.R- 52.4%); and out of 16 patients in whom TSH remained =/&amp;lt; 2.5 mIU/mL on day of beta-hCG, 3 became pregnant (P.R- 18.8%). Statistical analysis further revealed that odds of achieving pregnancy in elevated/high-normal TSH group was almost 5 times compared to odds of achieving pregnancy in low-normal TSH group (OR = 4.77, C.I= 1.24-18.37, at 95% confidence), considering TSH values on day of beta-hCG. Mean TSH in pregnant group (n = 36) was also found to be higher (4.2±1.6 mIU/mL) than mean TSH (3.9±1.9 mIU/mL) in those who did not get pregnant (n = 43). Limitations, reasons for caution Our study is limited by its modest sample size and adequately powered, larger prospective studies are needed before definite conclusions can be drawn from our data. Moreover, being an ongoing study, we do not yet have miscarriage and live-birth data for all patients and thus have not reported the same. Wider implications of the findings To our knowledge, this is the first prospective study documenting association between positive pregnancy outcome and high-normal TSH (using TSH&amp;gt;2.5 mIU/mL as cut-off) in SCH patients having fresh blastocyst eSET. Further investigation is required to determine if high-normal TSH following OS has protective impact on IVF, and its underlying mechanism. Trial registration number not applicable

The effect of the HMGB1/RAGE/TLR4/NF-κB signalling pathway in patients with idiopathic epilepsy and its relationship with toxoplasmosis.

This study aims to investigate the relationship between toxoplasmosis and this pathway, which may be effective in the formation of epilepsy by acting through the HMGB1/RAGE/TLR4/NF-κB signalling pathway in patients with idiopathic epilepsy. In the study, four different experimental groups were formed by selecting Toxoplasma gondii IgG positive and negative patients with idiopathic epilepsy and healthy controls. Experimental groups were as follows: Group 1: Epilepsy+/Toxo- (E+, T-) (n = 10), Group 2: Epilepsy-/Toxo- (E-, T-) (n = 10), Group 3: Epilepsy-/Toxo+ (E-, T+) (n = 10), Group 4: Epilepsy+/Toxo+ (E+, T+) (n = 10). HMGB1, RAGE, TLR4, TLR1, TLR2, TLR3, IRAK1, IRAK2, IKBKB, IKBKG, BCL3, IL1β, IL10, 1 L8 and TNFα mRNA expression levels in the HMGB/RAGE/TLR4/NF-κB signalling pathway were determined by quantitative simultaneous PCR (qRT-PCR) after collecting blood samples from all patients in the groups. Statistical analysis was performed by one-way ANOVA followed by LSD post-hoc tests, and p < 0.05 was considered to denote statistical significance. The gene expression levels of HMGB1, TLR4, IL10, IL1B, IL8, and TLR2 were significantly higher in the G1 group than in the other groups (p < 0.05). In the G3 group, RAGE and BCL3 gene expression levels were significantly higher than in the other groups (p < 0.05). In the G4 group, however, IRAK2, IKBKB, and IKBKG gene expression levels were significantly higher than in the other groups (p < 0.05). HMGB1, TLR4, IRAK2, IKBKB, IL10, IL1B, IL1B, and IL8 in this signalling pathway are highly expressed in epilepsy patients in G1 and seizures occur with the stimulation of excitatory mechanisms by acting through this pathway. The signalling pathway in epilepsy may be activated by HMGB1, TLR4, and TLR2, which are considered to increase the level of proinflammatory cytokines. In T. gondii, this pathway is activated by RAGE and BCL3.

Extending the role of tryptase in perioperative anaphylaxis: Predicting positive results in basophil activation tests

BackgroundBasophil activation tests (BAT) are useful in identifying culprits of perioperative anaphylaxis (PA), but its utility remains limited due to technical limitations, cost and availability. Being able to prioritize patients with likely higher yields for BAT would be useful in reducing costs and manpower. ObjectiveTo investigate if tryptase levels and clinical parameters may be useful for selecting patients for BAT. MethodsWe performed a ten-year retrospective study in Hong Kong to investigate the performance of BAT associated with tryptase levels (taking during PA) and other clinical parameters. ResultsOut of 90 patients, 70 (77.8%) showed significant tryptase elevation and 37 (41.1%) had positive BAT. BAT-positive patients presented with significantly higher absolute levels (15.9 μg/L vs 9.1 μg/L, p=0.018), absolute elevation (12.8μg/L vs 7.1 μg/L, p=0.012) and fold elevation (5.6- vs 4.1-fold, p=0.014) of acute tryptase; than negative BAT patients. Among patients with positive BAT, 94.6% (35/37) demonstrated elevated acute tryptase, significantly more than the BAT-negative group (66.0%, p<0.001). In regression analysis, tryptase elevation was the sole significant factor correlated to BAT positivity (OR=10.14 [95% CI=2.15-47.85], p=0.003). Overall, elevated acute tryptase demonstrated a sensitivity of 94.7% and a negative predictive value of 90.0% in predicting positive results with BAT. ConclusionWe observed that tryptase elevation is a very sensitive predictor of BAT positivity among patients with identified culprits of PA. Acute elevation of tryptase would not only aid in confirming anaphylaxis, but may also help guide the decision towards selecting labour-intensive and costly in vitro tests such as BAT.

Landscape of Clinically Relevant Genomic Alterations in the Indian Non-small Cell Lung Cancer Patients

BackgroundThe genomic landscape of non-small cell lung cancer (NSCLC) in the Indian patients remains underexplored. We revealed distinctive genomic alterations of Indian NSCLC patients, thereby providing vital molecular insights for implementation of precision therapies. MethodsWe analyzed the genomic profiles of 325 lung adenocarcinoma and 81 lung squamous carcinoma samples from Indian patients using targeted sequencing of 50 cancer related genes. Correlations between genomic alterations and clinical characteristics were computed using statistical analyses. Additionally, we identified distinct features of Indian NSCLC genomes by comparison across different ethnicities. ResultsOur genomic analysis revealed several noticeable features of Indian NSCLC patients. Alterations in EGFR (45.8%), TP53 (27.4%), ALK (11.4%) and KRAS (10.2%) were predominant in adenocarcinoma, with 68% eligible for targeted therapies. Squamous carcinoma exhibited prevalent alterations in TP53 (40.7%), PIK3CA (17.3%), and CDKN2A (8.6%). We observed higher frequency of EGFR alterations (18.5%) in lung squamous carcinoma patients, significantly distinct from other ethnicities reported till date. Beyond established correlations, we observed 60% of PD-L1 negative squamous patients harbored TP53 alterations, suggesting intriguing therapeutic implications. ConclusionsOur data revealed unique genomic variations of adenocarcinoma and squamous carcinoma patients, with significant indications for precision medicine and clinical practice of lung cancers. The study emphasizes the importance of clinical utility of NGS for routine diagnostics.Micro Abstract: The objective of the study was to provide a comprehensive genomic landscape of Indian lung cancer patients. Our findings highlight a high prevalence of actionable alterations in lung adenocarcinoma and the novel discovery of frequent EGFR alterations in lung squamous carcinoma. Thus, this study underscores the potential for implementation of precision medicine and the need for novel therapeutic strategies tailored to Indian population.

Periodic Fasting and Acute Cardiac Events in Patients Evaluated for COVID-19: An Observational Prospective Cohort Study.

Periodic fasting was previously associated with greater longevity and a lower incidence of heart failure (HF) in a pre-pandemic population. In patients with coronavirus disease 2019 (COVID-19), periodic fasting was associated with a lower risk of death or hospitalization. This study evaluated the association between periodic fasting and HF hospitalization and major adverse cardiovascular events (MACEs). Patients enrolled in the INSPIRE registry from February 2013 to March 2020 provided periodic fasting information and were followed into the pandemic (n = 5227). Between March 2020 and February 2023, N = 2373 patients were studied, with n = 601 COVID-positive patients being the primary study population (2836 had no COVID-19 test; 18 were excluded due to fasting <5 years). A Cox regression was used to evaluate HF admissions, MACEs, and other endpoints through March 2023, adjusting for covariables, including time-varying COVID-19 vaccination. In patients positive for COVID-19, periodic fasting was reported by 180 (30.0% of 601), who periodically fasted over 43.1 ± 19.2 years (min: 7, max: 83). HF hospitalization (n = 117, 19.5%) occurred in 13.3% of fasters and 22.1% of non-fasters [adjusted hazard ratio (aHR) = 0.63, CI = 0.40, 0.99; p = 0.044]. Most HF admissions were exacerbations, with a prior HF diagnosis in 111 (94.9%) patients hospitalized for HF. Fasting was also associated with a lower MACE risk (aHR = 0.64, CI = 0.43, 0.96; p = 0.030). In n = 1772 COVID-negative patients (29.7% fasters), fasting was not associated with HF hospitalization (aHR = 0.82, CI = 0.64, 1.05; p = 0.12). In COVID-positive and negative patients combined, periodic fasting was associated with lower mortality (aHR = 0.60, CI = 0.39, 0.93; p = 0.021). Routine periodic fasting was associated with less HF hospitalization in patients positive for COVID-19.

Infratentorial hypoperfusion in multiple sclerosis

AbstractObjectivesLong‐term disability in patients with multiple sclerosis (MS) results from axonal degeneration in the central nervous system, which might follow hypoperfusion in neurodegenerative diseases. This study aimed to clarify the distribution and clinical significance of brain hypoperfusion in patients with MS.MethodsWe measured brain hypoperfusion in eight patients with relapsing–remitting MS using N‐isopropyl‐p‐iodine‐123‐iodoamphetamine single‐photon emission computed tomography with three‐dimensional stereotactic surface projection and stereotactic extraction estimation; moreover, we examined its clinical relevance.ResultsWe detected marked hypoperfusion in the brainstem and cerebellum relative to that in the cerebrum. Each infratentorial segment, the midbrain, pons, and cerebellar anterior and posterior lobes, showed more severe hypoperfusion than the frontal and parietal lobes (n = 8). This was attributed mainly to oligoclonal band (OCB)‐negative patients (n = 3), even when OCB‐positive patients (n = 5) showed a similar trend. Consistently, OCB‐negative patients had lower blood flow at the pons, and cerebellar anterior and posterior lobes than OCB‐positive patients; however, both groups showed comparable hypoperfusion in the cerebral lobes. Hypoperfusion at the posterior cerebellar lobe and pons was correlated with poor performance in the Trail Making Test Part B (n = 6), indicating cognitive cerebellar dysfunction and cerebrocerebellar conductive disturbances.ConclusionsPatients with relapsing–remitting MS had lower infratentorial perfusion, which strongly links to OCB‐negativity. The distribution of brain hypoperfusion detected by N‐isopropyl‐p‐iodine‐123‐iodoamphetamine single‐photon emission computed tomography indicated pathological heterogeneity in relapsing–remitting MS. The infratentorial hypoperfusion is possibly associated with neurodegeneration.