Negative Subjects Research Articles

1377-P: Pramlintide Lowers Postprandial Glucagon Concentrations by Inhibiting Glucagon Secretion without Altering Clearance in Type 1 Diabetes: A [13C15N]-Glucagon Study

To determine the underlying mechanism of pramlintide effects on postprandial (PP) glucagon concentrations, we studied thirteen C-peptide negative T1D subjects (Age 35±yrs, BMI 27.6±2.2 kg/m2, fasting plasma glucose 9.4±4 mM, HbA1c 7.1±1%) on two occasions in random order, with and without 30 μg of sc pramlintide at the onset of a mixed meal (75 gm carb, 15% fat and 35% protein; 8 kcal/kg) . Subjects administered insulin bolus at meal onset. 13C15N glucagon tracer was infused intravenously to estimate PP glucagon turnover. Arterialized venous samples were drawn periodically for measurements of glucose (YSI) , 13C15N-glucagon (LC-MS/MS) and glucagon (Mercodia) concentrations. Systemic glucagon turnover was calculated using non-steady state Steele's equation after determining glucagon volume of distribution. Integrated PP glucagon concentrations were lower (p<0.01) in pramlintide (Pram) than without pramlintide (No Pram) . Integrated rates of glucagon appearance and glucagon disappearance were lower (p<0.01) in Pram vs. No Pram. When adjusted for plasma glucagon concentrations, glucagon clearance was not different (p=0.7) between Pram vs. No Pram. These data demonstrate that pramlintide lowers postprandial glucagon concentrations by lowering glucagon secretion without altering clearance in subjects with T1D. Disclosure F.Ruchi: None. D.Romeres: None. M.Schiavon: None. S.Renuse: None. A.Pandey: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. C.Cobelli: None. R.Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A.Basu: Speaker's Bureau; Zealand Pharma A/S. Funding National Institute of Health (DK 085516, DK 029953)

Viral Load Pattern and Virological Suppression Rate of a Cohort of Hiv-1 Patients in a Rural Community in Nigeria

HIV is a pandemic infection and remains a public health concern for many decades. This infection is associated with life threatening depletion of immune response, opportunistic infections and malignancies.  The aim of this study is to determine the viral load pattern and virological suppression rate of HIV-1 subjects in Irrua, Edo Central Senatorial District of Edo state, Nigeria. A total of three hundred and forty four (344) HIV-1 subjects aged between 17-60 years and of both sexes were recruited into the study. The HIV-1 subjects were divided into asymptomatic and symptomatic subjects. One hundred and fifty (150) apparently healthy HIV-1 negative subjects served as control. The viral load titre was determined using the COBAS Ampliprep/COBAS “Taqman” HIV-RNA test (PCR technology). Results obtained revealed that the mean viral loads of the asymptomatic and symptomatic HIV-1 subjects were 20,333.00±13,474.65 and 535,000.02±485,423.40 against control (20.00±0.00). Both asymptomatic and symptomatic groups revealed a statistical significant difference (P<0.05). Furthermore, there was no significant difference according to gender while comparison between viral load and age showed a statistically significant difference (P<0.05).The overall virological suppression rate of HIV-1 subjects on-ART was 81.6%. Sex-wise distribution revealed that more females (48.87%) were virally suppressed compared to their male counterparts (32.73%). According to age distribution, subjects belonging to the age bracket of 37-46 years recorded the highest frequency distribution of 37.96% while the least (5.70%) belonged to the age group of 17-26 years. In summary, there was a significant and progressive increase in the viral load titre of asymptomatic and symptomatic HIV-1subjects in relation to control. Also, the proportion of HIV-1 subjects who had viral load <1,000 RNA copies/ml was relatively high at 81.6% but falls short of UNAIDS’ 90% target for on-treatment viral suppression.  It re-emphasizes the need to test subjects and start treatment with antiretroviral drugs early.

Comparison of different microbiological procedures for the diagnosis of Pneumocystis jirovecii pneumonia on bronchoalveolar-lavage fluid

BackgroundThe current diagnostic gold standard for Pneumocystis jirovecii is represented by microscopic visualization of the fungus from clinical respiratory samples, as bronchoalveolar-lavage fluid, defining “proven” P. jirovecii pneumonia, whereas qPCR allows defining “probable” diagnosis, as it is unable to discriminate infection from colonization. However, molecular methods, such as end-point PCR and qPCR, are faster, easier to perform and interpret, thus allowing the laboratory to give back the clinician useful microbiological data in a shorter time. The present study aims at comparing microscopy with molecular assays and beta-D-glucan diagnostic performance on bronchoalveolar-lavage fluids from patients with suspected Pneumocystis jirovecii pneumonia. Bronchoalveolar-lavage fluid from eighteen high-risk and four negative control subjects underwent Grocott-Gomori’s methenamine silver-staining, end-point PCR, RT-PCR, and beta-D-glucan assay.ResultsAll the microscopically positive bronchoalveolar-lavage samples (50%) also resulted positive by end-point and real time PCR and all, but two, resulted positive also by beta-D-glucan quantification. End-point PCR and RT-PCR detected 10 (55%) and 11 (61%) out of the 18 samples, respectively, thus showing an enhanced sensitivity in comparison to microscopy. All RT-PCR with a Ct < 27 were confirmed microscopically, whereas samples with a Ct ≥ 27 were not.ConclusionsOur work highlights the need of reshaping and redefining the role of molecular diagnostics in a peculiar clinical setting, like P. jirovecii infection, which is a rare but also severe and rapidly progressive clinical condition affecting immunocompromised hosts that would largely benefit from a faster diagnosis. Strictly selected patients, according to the inclusion criteria, resulting negative by molecular methods could be ruled out for P. jirovecii pneumonia.

Leucocyte Profiles of Asymptomatic and Symptomatic HIV-1 Subjects in Irrua, EDO State, Nigeria

HIV is pandemic and remains a public health concern for many decades. This infection is associated with life threatening opportunistic infections and malignancies. The aim of this study is to look at the leucocyte profiles of HIV-1 positive subjects in Irrua, Edo state, Nigeria. A total of three hundred and forty four (344) HIV-1 subjects aged 17-60 years and of both sexes were recruited into the study. The HIV-1 subjects were divided into asymptomatic and symptomatic subjects. One hundred and fifty (150) apparently healthy HIV-1 negative subjects served as control. The white blood cells total (WBC total) count and differential leucocyte count (DLC) were determined using an automated blood analyzer (Sysmex KX-2IN). Results obtained revealed that the mean WBC total count (x103/µL) of the asymptomatic HIV-1 subjects (5.04 ± 1.14) and that of the control subjects (5.09 ± 1.24) did not show any significant difference (P&gt;0.05). In contrast, the mean WBC total count of symptomatic HIV-1 subjects (4.14 ± 5.06) was significantly decreased (P&lt;0.05) in comparison to that of control. However, age and sex did not affect the WBC total counts of the subjects studied. With respect to DLC, the mean neutrophil % of asymptomatic HIV-1 subjects (43.53 ± 8.84) was not statistically significant (P&gt;0.05) in comparison to control (43.91 ± 5.91) .Whereas, symptomatic HIV-1 subjects (49.25±5.86) revealed a significantly higher (P&lt;0.05) difference in relation to control (43.91 ± 6.25) and asymptomatic HIV-1 subjects. The mean lymphocyte count % of asymptomatic HIV-1 subjects (42.19 ± 6.25) and that of symptomatic HIV-1 subjects (43.32 ± 6.92) were significantly lower (P&lt;0.05) compared to control (47.11 ± 8.33). Age and sex also did not affect the DLC of the study subjects. In conclusion, it has been revealed that the leucocyte profile of symptomatic HIV-1 subjects were significantly affected compared to asymptomatic and control subjects. It re-emphasizes the prognostic role of leucocyte counts (especially in low resource areas) in the diagnosis of symptomatic HIV-1 subjects in the study area.

Changes of small non-coding RNAs by severe acute respiratory syndrome coronavirus 2 infection

Abstract The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat. In the context of viral infections, sncRNAs have been shown to regulate the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK-RNA-seq, a modified next-generation sequencing (NGS), we found that nasopharyngeal swabs (NPS) samples from SARS-CoV-2 positive and negative subjects show a significant difference in sncRNA profiles. There are about 166 impacted sncRNAs. Among them, tRFs are the most significantly affected and almost all impacted tRFs are derived from the 5′-end of tRNAs (tRF5). Using qRT-PCR, we validated that tRF5s derived from tRNA GluCTC (tRF5-GluCTC), LysCTT (tRF5-LysCTT), ValCAC (tRF5-ValCAC), CysGCA (tRF5-CysGCA) and GlnCTG (tRF5-GlnCTG) are enhanced in NPS samples of SARS-CoV2 patients and SARS-CoV2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several sncRNAs derived from the virus (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3′-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs

A machine learning-based approach to determine infection status in recipients of BBV152 (Covaxin) whole-virion inactivated SARS-CoV-2 vaccine for serological surveys

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the vaccine effectiveness. Asymptomatic breakthrough infections have been a major problem in assessing vaccine effectiveness in populations globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines since whole virion vaccines generate antibodies against all the viral proteins. Here, we show how a statistical and machine learning (ML) based approach can be used to discriminate between SARS-CoV-2 infection and immune response to an inactivated whole virion vaccine (BBV152, Covaxin). For this, we assessed serial data on antibodies against Spike and Nucleocapsid antigens, along with age, sex, number of doses taken, and days since last dose, for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, our ensemble ML model classified 724 to be infected. For method validation, we determined the relative ability of a random subset of samples to neutralize Delta versus wild-type strain using a surrogate neutralization assay. We worked on the premise that antibodies generated by a whole virion vaccine would neutralize wild type more efficiently than delta strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, neutralization against Delta strain was more effective, indicating infection. We found 71.8% subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%–80.2%) over the same period. Our approach will help in real-world vaccine effectiveness assessments where whole virion vaccines are commonly used.

Association of P-glycoprotein expression and response to anthracycline-based neoadjuvant chemotherapy in locally advanced breast cancer

BACKGROUND Neoadjuvant chemotherapy (NACT) has been shown to improve the overall survival of locally advanced breast cancer (LABC) patients with pathological complete response. However, the efficacy may be reduced due to chemoresistance mediated by P-glycoprotein (Pgp). This study aimed to explore the association between Pgp expression and patients’ response to NACT.&#x0D; METHODS A prospective cohort study was carried out from May 2018 to October 2019 at Cipto Mangunkusumo Hospital and Koja Hospital. Treatment-naïve LABC patients were consecutively enrolled in the study. Immunohistochemistry analysis of the biopsy samples was done to semi-quantitatively measure Pgp expression. The clinical response was evaluated after 3 cycles of NACT, while the pathological response was evaluated for subjects who underwent surgery post-NACT.&#x0D; RESULTS Mean age of the subjects was 46.2 (9.6) years old, and most of the cases were invasive ductal (78%) and luminal B subtype (61%). Pgp was strongly expressed in 21/27 subjects (78%). There were no differences between Pgp-positive and -negative subjects for clinical response (relative risk [RR] 1.1, 95% confidence interval [CI] 0.33–4.01, p = 0.61) and pathological response (RR 1.3, 95% CI 0.8–1.9, p = 0.22). Other clinicopathologic variables were not associated with either clinical or pathological responses.&#x0D; CONCLUSIONS These results showed that Pgp is expressed in most LABC patients, but its role as a predictive factor could not be established. However, due to the limited subjects and a lack of standardized Pgp measurement, careful consideration must be done when interpreting these results.

The Difference in Serum Pepsinogen I, Pepsinogen II, Carcinoembryonic Antigen, and Carcinoma Antigen 72-4 Levels between Children with and without Helicobacter Pylori Infection

BACKGROUND: Helicobacter pylori (H. pylori) is a common infection in human. The infection is mainly acquired in childhood with global prevalence of 32.3%. Several markers such as pepsinogen I, pepsinogen II, carcinoembryonic antigen (CEA), and carcinoma antigen (CA) 72-4 are associated with H. pylori infection and its complications.&#x0D; OBJECTIVE: To determine the difference in serum pepsinogen I, pepsinogen II, CEA, and CA 72-4 levels in children with and without H. pylori infection.&#x0D; METHODS: A cross sectional study was conducted in Samosir Island, Indonesia. Inclusion criteria were children aged 2 to 18 years who did not take antibiotics, bismuth containing drugs, histamine-2 receptor antagonists, proton pump inhibitors, and immunomodulator for the last 4 weeks before the study. All subjects were divided into 2 groups: H. pylori positive and negative. Demographic and anthropometric data were gathered. Serum pepsinogen I, pepsinogen II, CEA, and CA 72-4 levels were evaluated. The differences were determined using Mann Whitney U-test.&#x0D; RESULTS: A total of 74 subjects were enrolled in this study. H. pylori positive and negative subjects were 38 and 36, respectively. Females were dominant in both groups. No difference was observed in gender, age, anthropometric characteristics, serum CEA level, and CA 72-4 level between both groups. Serum pepsinogen I and pepsinogen II levels were higher in H. pylori positive group compared to their counterparts (p= 0.013 and p= 0.001, respectively).&#x0D; CONCLUSION: There are significant differences in serum pepsinogen I and II levels between children with and without H. pylori infection.

Morphological and Immunopathological Aspects of Lingual Tissues in COVID-19.

COVID-19, a recently emerged disease caused by SARS-CoV-2 infection, can present with different degrees of severity and a large variety of signs and symptoms. The oral manifestations of COVID-19 often involve the tongue, with loss of taste being one of the most common symptoms of the disease. This study aimed to detect SARS-CoV-2 RNA and assess possible morphological and immunopathological alterations in the lingual tissue of patients who died with a history of SARS-CoV-2 infection. Sixteen cadavers from 8 SARS-CoV-2 positive (COVID-19+) and 8 negative (COVID-19−) subjects provided 16 tongues, that were biopsied. Samples underwent molecular analysis through Real-Time RT-PCR for the detection of SARS-CoV-2 RNA. Lingual papillae were harvested and processed for histological analysis and for immunohistochemical evaluation for ACE2, IFN-γ and factor VIII. Real-Time RT-PCR revealed the presence of SARS-CoV-2 RNA in filiform, foliate, and circumvallate papillae in 6 out of 8 COVID-19+ subjects while all COVID-19− samples resulted negative. Histology showed a severe inflammation of COVID-19+ papillae with destruction of the taste buds. ACE2 and IFN-γ resulted downregulated in COVID-19+ and no differences were evidenced for factor VIII between the two groups. The virus was detectable in most COVID-19+ tongues. An inflammatory damage to the lingual papillae, putatively mediated by ACE2 and IFN-γ in tongues from COVID-19+ cadavers, was observed. Further investigations are needed to confirm these findings and deepen the association between taste disorders and inflammation in SARS-CoV-2 infection.

Tropheryma whipplei, Helicobacter pylori, and Intestinal Protozoal Co-Infections in Italian and Immigrant Populations: A Cross-Sectional Study.

Tropheryma whipplei (TW), Helicobacter pylori (HP), and intestinal protozoa (IP) are widespread pathogens with similar routes of transmission and epidemiological risk factors. Epidemiological data on co-infection between TW, HP, and IP are scarce. We aim to more deeply investigate the co-infection rate for these pathogens, evaluating the risk factors and symptoms. Methods: This is a cross-sectional study conducted at the IRCCS Sacro Cuore Don Calabria Hospital in Northern Italy, a referral center for tropical and Whipple’s disease (WD). Stored stool samples from 143 subjects previously tested for TW DNA by real-time PCR were explored for HP and IP DNA detection. The virulence factor cagA was investigated in HP-positive patients. Results: A history of migration was reported significantly more in TW-positive than in negative subjects (34.1% vs. 9.1%, p = 0.001) and in HP-infected than in those non-infected (59.1% vs. 9.1%, p < 0.001). The HP infection rate differed significantly between TW-infected and uninfected groups (31.8% vs. 8.1%, p = 0.001), while no difference was observed for IP infection. Significantly higher TW intestinal colonization was found in HP-infected patients than in non-infected (63.6% vs. 24.8%, p < 0.001). In addition, the proportion of Blastocysts positive finding was also significantly higher in HP-infected than in non-infected (40.9% vs. 17.4%, p = 0.018). Conclusions: The present study is the first to report a high TW and HP co-infection rate. To reduce the risk of morbidity from a chronic infection of either pathogen, clinicians may consider TW-HP molecular screening on the same stool sample for patients with suspected HP disease or WD, particularly in case of travel history.

In Patients with Covid-19, The Association of Diabetes Melltus and Impaired Glucose Tolerance

Objective: Patients with COVID-19 are being studied to assess the prevalence of diabetes mellitus and decreased glucose tolerance. Study Design: Cross-sectional study Place and Duration: THQ hospital Jaranwala, Punjab medical college Faisalabad. Dec 2020-Nov 2021 Methods: In this research, one hundred and sixty individuals, both males and females, who had coronavirus illness, were included. The ages of the patients varied from 20 to 75 years. Following the receipt of informed written consent, we gathered extensive demographic information on all of the enrolled patients, including their age, gender, BMI, educational achievement, and location of residence, as well as their medications. The blood of all of the patients was tested for corona disease using the RT-PCR method. The 75-g oral glucose tolerance test was performed after screening positive participants (fasting capillary glucose &gt;100 mg/dl and 200 mg/dl) and each sixth consecutive negative subject (fasting capillary glucose 100 mg/dl) for a total of seven consecutive days. For the purpose of data analysis, the SPSS 24.0 programme was used. Results: Patients included in the study were on average 62.8±10.35 years old, with a BMI of 30.10±17.35kg/m2. More over half of the people in the study were male 100 (62.5%), while the other were 60 (37.5%) female. Patients were illiterate in the majority of cases. Hypertension, hyperlipidemia, chronic renal disease, and coronary artery disease were the most prevalent co-morbidities. Diabetes mellitus was found in 56.3 % of the individuals studied, with the vast majority of cases being pre-existing. Impaired glucose tolerance was seen in 40% of the instances in which pancreatic cancer was the most common. Intubation was used in 37 (23.1%) studied. There were a total of 22 (13.8 %) deaths in this study. Conclusion: Covid-19 was discovered to be more common in persons with diabetes and impaired glucose metabolism. Another sign of primary infection that was previously misunderstood has been connected to an abnormality in glucose metabolism. To get to the bottom of the disease's pathogenesis, researchers need to look into how SARS-CoV-2 impacts glucose metabolism. Keywords: Mortality, IGT, Covid-19, Co-morbidities , DM,

Evaluation of Some Haematological Parameters in the Management of HBV Infection Treatment Outcome in Delta State, Nigeria

Aims: To evaluate Hepatitis B virus (HBV) infection treatment outcome using the levels of white blood cells, haemoglobin, platelets counts and other red cell indices of HBV positive treatment naïve, on treatment at 3- and 6-months subjects attending gastro-enterology clinic in Federal Medical Centre Asaba, Delta State, Nigeria&#x0D; Study Design: Cross-Sectional and longitudinal study.&#x0D; Place and Duration of Study: Federal Medical Centre Asaba (FMC) and Iykenson Medical and Diagnostic Co. Ltd, Awka. Federal Medical Centre, Asaba, between August 2019 and September 2020.&#x0D; Methodology: A total of one hundred and fifteen (115) adults aged 22 – 64 years participated in this study. The study sites for this work comprised of Federal Medical Centre Asaba (FMC) and Iykenson Medical and Diagnostic Co. Ltd, Awka. The cross-sectional study consists of fifty (50) confirmed hepatitis B negative subjects as negative controls whereas, the follow-up study consists sixty-five (65) treatment naïve HBV positive subjects which were followed-up at three and six months on treatment with tenovofir respectively. Four (4) of the participants (two in three months post treatment and two six months post treatment) dropped-out of the research due to time constraint. Blood samples were collected from the subjects in EDTA bottles and were used for the analysis of white blood cell (WBC count), haemoglobin concentration, packed cell volume (PCV), mean cell volume (MCV), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC) and platelet count (PLT). Statistical Package for social Science (SPSS) software version 26 was used in the analysis of data and P&lt;.05 was considered statistically significant.&#x0D; Results: There were no significant difference (P&gt;.05) in neutrophil, lymphocyte, eosinophil and monocyte in the study population among the four groups whereas, the level of total white blood cell counts was significantly lower in the HBV naïve, one month post treatment and three-month post treatment when compared with the control group. The levels of haemoglobin, packed cell volume, mean cell volume, mean cell haemoglobin and mean cell haemoglobin concentration were significantly lower in the HBV naïve, three months on treatment and six-months on treatment when compared with the control group (P&lt;.05).&#x0D; Conclusion: In conclusion, it is possible that HBV infection has effect on iron metabolism and production of haematological precursor cells which are reflected in low levels of haemoglobin, PCV, MCV, MCH and MCHC as such these parameters could be used as co – markers to viral load in monitoring the treatment outcome of HBV infection in Nigeria.

Clinical Relevance of Anti-Gliadin Seropositivity in the Ageing Population: A Long-term Follow-up Study.

To explore if anti-gliadin antibody (AGA) positivity is associated with overall mortality or morbidity and especially with the development of coeliac disease during long-term gluten exposure. The study population comprised 130 persistently AGA-positive but transglutaminase-2 (anti- TG2) -negative and 52 persistently AGA- and anti-TG2 -negative subjects aged 64-88 years. HLA-typing for DQ2 and DQ8 (coeliac-type HLA) was performed on the AGA-positives. The medical records of the study population were reviewed to compare mortality and morbidity during a long-term follow-up of 12-13 years since the initial antibody analysis. Mortality or cumulative prevalence of gastroenterological, autoimmune, psychiatric, cardiovascular or any malignant diseases did not differ statistically between the AGA-positives and the AGA-negatives. Neurological diseases were more common in the AGA-negative group (p=0.017), but there was no statistical difference between the prevalence of any particular neurological diseases. Coeliac-type HLA in AGA-positive subjects did not influence mortality or morbidity. However, during the last six to seven years the incidence of immunological diseases was more common in the AGA-positive subjects without coeliac-type HLA than in those with coeliac-type HLA, or in the AGA-negative group (p=0.020). None of the persistently AGA-positive subjects developed clinically diagnosed coeliac disease. Gliadin antibody positivity without coeliac disease does not predict mortality or morbidity in the ageing population continuing to consume gluten for over ten years.

Impact of Artificial Intelligence on Miss Rate of Colorectal Neoplasia

Background & AimsArtificial intelligence (AI) may detect colorectal polyps that have been missed due to perceptual pitfalls. By reducing such miss rate, AI may increase the detection of colorectal neoplasia leading to a higher degree of colorectal cancer (CRC) prevention. MethodsPatients undergoing CRC screening or surveillance were enrolled in 8 centers (Italy, UK, US), and randomized (1:1) to undergo 2 same-day, back-to-back colonoscopies with or without AI (deep learning computer aided diagnosis endoscopy) in 2 different arms, namely AI followed by colonoscopy without AI or vice-versa. Adenoma miss rate (AMR) was calculated as the number of histologically verified lesions detected at second colonoscopy divided by the total number of lesions detected at first and second colonoscopy. Mean number of lesions detected in the second colonoscopy and proportion of false negative subjects (no lesion at first colonoscopy and at least 1 at second) were calculated. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted by endoscopist, age, sex, and indication for colonoscopy. Adverse events were also measured. ResultsA total of 230 subjects (116 AI first, 114 standard colonoscopy first) were included in the study analysis. AMR was 15.5% (38 of 246) and 32.4% (80 of 247) in the arm with AI and non-AI colonoscopy first, respectively (adjusted OR, 0.38; 95% CI, 0.23–0.62). In detail, AMR was lower for AI first for the ≤5 mm (15.9% vs 35.8%; OR, 0.34; 95% CI, 0.21–0.55) and nonpolypoid lesions (16.8% vs 45.8%; OR, 0.24; 95% CI, 0.13–0.43), and it was lower both in the proximal (18.3% vs 32.5%; OR, 0.46; 95% CI, 0.26–0.78) and distal colon (10.8% vs 32.1%; OR, 0.25; 95% CI, 0.11–0.57). Mean number of adenomas at second colonoscopy was lower in the AI-first group as compared with non-AI colonoscopy first (0.33 ± 0.63 vs 0.70 ± 0.97, P < .001). False negative rates were 6.8% (3 of 44 patients) and 29.6% (13 of 44) in the AI and non-AI first arms, respectively (OR, 0.17; 95% CI, 0.05–0.67). No difference in the rate of adverse events was found between the 2 groups. ConclusionsAI resulted in an approximately 2-fold reduction in miss rate of colorectal neoplasia, supporting AI-benefit in reducing perceptual errors for small and subtle lesions at standard colonoscopy. ClinicalTrials.gov, Number: NCT03954548.

Metabolic syndrome and its components among HIV/AIDS patients on Antiretroviral Therapy and ART-Naïve Patients at the University of Calabar Teaching Hospital, Calabar, Nigeria.

Although an increasing access to ART in sub-Saharan Africa has made it possible for HIV/AIDS patients to live longer, clinicians managing such patients are faced with the challenge of drug-related metabolic complications. A cross -sectional study was carried out at the University of Calabar Teaching Hospital, Nigeria, on three groups of participants; namely HIV patients on ART, ART-naïve patients and HIV negative subjects (n =75). Demographic and anthropometric data were collected using a well-structured questionnaire while biochemical parameters were measured using colorimetric methods. The highest prevalence of MS was associated with the HIV/AIDS patients on ART (i.e. 32.0 %, and 50.3% for NCEP-ATP III and IDF criteria respectively). Patients on ART had significant increases (p< 0.05) in waist to hip ratio, FPG, serum TG and LDL-c; and a significantly higher (p< 0.05) prevalence of hypertension, diabetes, low HDL-c and hypertriglyceridaemia compared to the ART-naïve patients. Low serum HDL-c was the most prevalent form of dyslipidaemia in all three groups and the most prevalent component of MS in HIV patients. ART increases the risk of MS and CVD. HIV/AIDS patients on ART should be advised on lifestyle modifications and undertake regular assessment of their cardiovascular risk factors.

Risk factors of latent tuberculosis among chronic kidney disease with routine haemodialysis patients

IntroductionSince immune system alteration occurs, chronic kidney disease (CKD) on routine haemodialysis (HD) patients have a greater risk for latent tuberculosis (LTB). LTB needs special attention so that it does not develop into an active form, because infection in CKD patients increases the mortality. This study aims to determine the risk factors that associated with LTB among CKD on routine HD patients. MethodsThis was a cross-sectional study conducted in Haemodialysis Unit, Hasan Sadikin General Hospital, Bandung. The subjects were recruited from March–May 2020. Subjects aged > 18 years at least have undergoing HD in 3 months and twice a week HD were included in this study. Patients with active tuberculosis (TB) suspected, malignancy, or immunocompromised were excluded. LTB was diagnosed using interferon-γ release assays (IGRA). All data including age, sex, CKD etiologies, smoking status, HD adequacy that assessed using KT/V and urea reduction ratio (URR), and contact status with TB patients were obtained and recorded in case report form. ResultsA total of 120 subjects were involved. LTB based on IGRA was occurred in 39.2% subjects, while 56.7% and 4.1% subjects had negative and indeterminate IGRA, respectively. Adequacy of HD based on KT/V value was not significantly different between positive and negative IGRA subjects. Positive IGRA subjects had lower URR (p = 0.042). Smoking status had significant association with LTB (OR = 2.5[95%CI 1.2–5.4, p = 0.017). Furthermore, URR < 73% also had significant association with LTB (OR = 2.6[1.2–5.6, p = 0.013). ConclusionSmoking status and HD adequacy based on URR < 73% are associated factors that contribute to LTB among CKD on HD patients.

Hematological Findings among COVID-19 Patients Attending King Khalid Hospital at Najran, Kingdom of Saudi Arabia.

COVID-19 is a global pandemic viral infection that has affected millions worldwide. Limited data is available on the effect of COVID-19 on hematological parameters in Saudi Arabia. This study is aimed at examining the role of hematological parameters among COVID-19 patients admitted to King Khalid Hospital in Najran, Saudi Arabia. This is a retrospective, hospital-based study of 514 cases who were recruited during August to October 2020. 257 COVID-19 patients formed the study group, and a further 257 negative subjects formed the control group. Anemia was significantly elevated in positive subjects over controls (respectively, 64.2% and 35.8%), with patients 2.5 times more likely to be anemic (p < 0.01). Thrombocytopenia was higher in patients over controls (respectively, 62% and 38%), with patients ~1.7 times more likely to be thrombocytopenic (p < 0.01). Moreover, leukopenia was significantly higher in patients over controls (respectively, 71% and 29%), with positive subjects ~2.6 times more likely to be leukopenic. Our study results indicate that mild anemia associated with leukopenia may have diagnostic value for COVID-19. Careful assessment of hematological parameters, at baseline and throughout the disease path, will assist physicians in formulating personalized approaches to treatment and promptly offer intensive care to those in greater need.

Abstract P5-16-13: Safety and efficacy of INT230-6, a potential first-in-class intratumoral therapy, in monotherapy and in combination with pembrolizumab: Results from the IT-01 study [KEYNOTE-A10] in subjects with locally advanced, unresectable and metastatic breast cancer

Abstract Background: INT230-6 is a novel formulation of cisplatin and vinblastine with an amphiphilic cell penetration enhancer that has been shown to enhance dispersion of the drug throughout tumors and allow diffusion into cells when given intratumorally. INT230-6 is being evaluated in monotherapy and in combination with immune checkpoint inhibitors (ICIs) in subjects with various advanced solid tumors, including advanced breast cancer. Methods: This phase 1/2 study evaluated INT230-6 in superficial and deep tumors with INT230-6 Q2W intratumoral injections for 5 doses alone or in combination with 200mg pembrolizumab IV Q3W for 2 years. Total INT230-6 injected in a subject ranged from 0.89 to 649 mL over 5 INT230-6 dosing sessions in each subject, except one subject who had only 2 dosing sessions. Subjects who had completed treatment in dose escalation cohorts were eligible for retreatment; and one subject was retreated with INT230-6 in multiple arms of the study. Advanced breast cancer subjects with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or below who have failed one or more approved therapies, or have no alternate approved therapy, were enrolled. Subjects must have adequate organ function and measurable disease by RECIST 1.1 criteria including one target tumor for injection. Tumor response using RECIST 1.1 was evaluated at 12 weeks from the first INT230-6 dose and then every 8 weeks. Tumor biopsies were taken prior to INT230-6 dosing on day 0 and on day 28 post dose. Results: 7 advanced triple negative breast cancer subjects (4 monotherapy, 3 pembrolizumab combination) were evaluable as of June 1, 2021. The median age was 56 (range 46-82) years old, with a median of 8 (2, 17) prior systemic therapies for metastatic disease. The intratumoral INT230-6 dose was up to 164 mL (82 mg of CIS, 16.4mg VIN) to tumors in a single dosing session. With INT230-6, 133-200% more volume is injected into the tumor and pharmacokinetics (PK) analysis shows that 95% of INT230-6 active agents remain in the tumor. Accordingly, assessment of tumor response using RECIST principles may be challenging, and even stable disease may represent a large decrease in viable tumor cells as indicated by biopsy evaluations. The most common (&amp;gt;20%) related treatment related adverse events (AE) were localized tumor related pain (71%), nausea (57%), anemia (29%), fatigue (29%), neck pain (29%), and vomiting (29%). AEs were mostly low grade and only one subject experienced grade 3 anemia (13%). There were no related grade 4 or 5 AEs or serious AEs. Disease control rate (DCR), defined as the percent of patients with a complete response, partial response, or stable disease at the first radiologic assessment, was 57%. Median overall survival was 12 months. Pre- and post- biopsy at 28 days after two INT230-6 doses (n= 3 evaluable, monotherapy, and combination with pembrolizumab) showed a 55% decrease in Ki67 and 69% reduction in viable cancer cells. In addition, multiplex immunofluorescence (n= 3 evaluable, combination with pembrolizumab) showed an influx of activated CD4 and CD8 T cells and in some cases a reduction in FoxP3 T-reg cells.. Conclusion: INT230-6 is a potential first-in-class intratumoral therapy for advanced breast cancer being developed in monotherapy and in combination with ICIs. There is a favorable safety profile in this population, similar to the broader metastatic solid tumor population presented elsewhere. There are early signs of cancer cell death in injected tumors and immune activation in heavily pre-treated patients. A Phase 2 expansion cohort of INT230-6 in combination with ICIs is ongoing. In addition, INT230-6 in being studied in a separate randomized Phase 2 neoadjuvant breast cancer study. Citation Format: Philippe Bedard, Lillian L Siu, Jacob Thomas, Diana Hanna, Anthony J Olszanski, Nilofer Azad, Giles Whalen, Matthew Ingham, Syed Mahmood, Lewis H Bender, Ian B Walters, Anthony El-Khoueiry. Safety and efficacy of INT230-6, a potential first-in-class intratumoral therapy, in monotherapy and in combination with pembrolizumab: Results from the IT-01 study [KEYNOTE-A10] in subjects with locally advanced, unresectable and metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-13.

Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis.

Background and ObjectivesTo study human leukocyte antigen (HLA) allele associations in anti-leucine–rich glioma-inactivated 1 (LGI1) encephalitis.MethodsA multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable.ResultsDRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e−50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, p = 4.57 × 10−6 and OR = 8.93, p = 2.50 × 10−3, respectively). DRB1*04:02 was also independently associated with younger age at onset (β = −6.68, p = 9.78 × 10−3). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms.DiscussionIn addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.

Studying APOE ɛ4 Allele Dose Effects witha Univariate Morphometry Biomarker.

A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N = 30), heterozygotes (HT, N = 49) and non-carriers (NC, N = 61). Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-β (Aβ) positive AD patients and Aβ negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals.