Social demographics determinants for resistome and microbiome variation of a multiethnic community in Southern Malaysia.

The prevalence of antibiotic-resistant bacteria in Southeast Asia is a significant concern, yet there is limited research on the gut resistome and its correlation with lifestyle and environmental factors in the region. This study aimed to profile the gut resistome of 200 individuals in Malaysia using shotgun metagenomic sequencing and investigate its association with questionnaire data comprising demographic and lifestyle variables. A total of 1038 antibiotic resistance genes from 26 classes were detected with a mean carriage rate of 1.74 ± 1.18 gene copies per cell per person. Correlation analysis identified 14 environmental factors, including hygiene habits, health parameters, and intestinal colonization, that were significantly associated with the resistome (adjusted multivariate PERMANOVA, p < 0.05). Notably, individuals with positive yeast cultures exhibited a reduced copy number of 15 antibiotic resistance genes. Network analysis highlighted Escherichia coli as a major resistome network hub, with a positive correlation to 36 antibiotic-resistance genes. Our findings suggest that E. coli may play a pivotal role in shaping the resistome dynamics in Segamat, Malaysia, and its abundance is strongly associated with the community's health and lifestyle habits. Furthermore, the presence of yeast appears to be associated with the suppression of antibiotic-resistance genes.

A report on quality-of-life outcomes following transmastoid plugging of superior semicircular canal dehiscence in a newly established service in a UK hospital.

OBJECTIVE: This study aimed to evaluate the quality-of-life outcomes following transmastoid plugging of semicircular canal dehiscence in a newly established service in a UK hospital. METHOD: Quality-of-life outcomes were measured using the Glasgow benefit Inventory score in three patients who underwent transmastoid plugging for superior semicircular canal dehiscence between September 2019 and March 2020. Patients also completed pre- and post-operative symptomatic questionnaires and vestibular-evoked myogenic potential testing. RESULTS: All three patients reported an improvement in overall quality-of-life outcomes with a mean overall Glasgow Benefit Inventory score of +37 (range, +22.2-66.6). There were no immediate post-operative complications and hearing was preserved in all patients. CONCLUSION: This study reported an initial successful experience with transmastoid plugging of superior semicircular canal dehiscence. In all patients, improvement in quality-of-life measures and symptoms was reported.

Ethnicity influences the gut microbiota of individuals sharing a geographical location: a cross-sectional study from a middle-income country.

No studies have investigated the influence of ethnicity in a multi-ethnic middle-income country with a long-standing history of co-habitation. Stool samples from 214 Malaysian community members (46 Malay, 65 Chinese, 49 Indian, and 54 Jakun) were collected. The gut microbiota of the participants was investigated using 16S amplicon sequencing. Ethnicity exhibited the largest effect size across participants (PERMANOVA Pseudo-F = 4.24, R2 = 0.06, p = 0.001). Notably, the influence of ethnicity on the gut microbiota was retained even after controlling for all demographic, dietary factors and other covariates which were significantly associated with the gut microbiome (PERMANOVA Pseudo-F = 1.67, R2 = 0.02, p = 0.002). Our result suggested that lifestyle, dietary, and uncharacterized differences collectively drive the gut microbiota variation across ethnicity, making ethnicity a reliable proxy for both identified and unidentified lifestyle and dietary variation across ethnic groups from the same community.

Epistaxis as a marker for severe acute respiratory syndrome coronavirus-2 status - a prospective study.

OBJECTIVE: To evaluate the prevalence of severe acute respiratory syndrome coronavirus-2 infection in patients presenting with epistaxis to a tertiary otolaryngology unit. METHODS: A prospective study was conducted of 40 consecutive patients presenting with epistaxis referred to our tertiary otolaryngology unit. A group of 40 age-matched controls were also included. All patients underwent real-time reverse transcriptase polymerase chain reaction testing for severe acute respiratory syndrome coronavirus-2. Symptoms of fever, cough and anosmia were noted in the study group. RESULTS: The mean age was 66.5 ± 22.4 years in the study group. There were 22 males (55 per cent) and 18 females (45 per cent). The mean age in the control group was 66.3 ± 22.4 years (p = 0.935). There were six positive cases for severe acute respiratory syndrome coronavirus-2 (15 per cent) in the epistaxis group and one case (2.5 per cent) in the control group. The difference was statistically significant (p = 0.05). CONCLUSION: Epistaxis may represent a presenting symptom of severe acute respiratory syndrome coronavirus-2 infection. This may serve as a useful additional criterion for screening patients.

Foot and mouth disease virus serological study of dromedary camels in Oman.

The potential role of camels in the epidemiology of foot and mouth disease in Oman was investigated. Sera from local dromedaries (n = 151) that graze with animals (cattle and small ruminants) positive for foot and mouth disease virus (FMDV) non-structural protein antibody (NSP-Ab) were tested for the detection of FMDV NSP-Ab. The samples were tested using a commercial competitive enzyme-linked immunosorbent assay (cELISA) , a rapid immunochromatographic assay and a solid-phase cELISA for the detection of antibodies specific to FMDV serotype O. The results from all three assays were negative when tested with dromedary sera. This indicates that FMDV was not transmitted to dromedary camels kept with FMDV NSP-Ab-positive ruminants.

Une étude a été entreprise dans le but de déterminer le rôle potentiel joué par les camélidés dans l'épidémiologie de la fièvre aphteuse à Oman. À cette fin, des échantillons ont été prélevés à partir de dromadaires autochtones (n = 151) qui pâturaient sur les mêmes prairies que des bovins et des petits ruminants possédant des anticorps contre la protéine non structurale du virus de la fièvre aphteuse en vue de rechercher la présence de ces anticorps. Les sérums ont été soumis à trois tests sérologiques : une épreuve immuno-enzymatique de compétition (cELISA), un essai immunochromatographique rapide et une cELISA en phase solide pour la détection spécifique d'anticorps dirigés contre le sérotype O du virus de la fièvre aphteuse. Les sérums des dromadaires ont tous donné des résultats négatifs aux trois tests. Ces résultats indiquent qu'il n'y a pas eu transmission du virus de la fièvre aphteuse entre les ruminants possédant des anticorps contre la protéine non structurale du virus et les dromadaires.

Los autores describen un estudio encaminado a estudiar la posible función del dromedario en la epidemiología de la fiebre aftosa en Omán. Tras extraer suero de dromedarios locales (n = 151) que pastaban junto con animales (ganado vacuno y pequeños rumiantes) positivos para el anticuerpo contra la proteína no estructural del virus de la fiebre aftosa, se sometieron las muestras de suero a técnicas de detección de ese anticuerpo, empleando para ello: un ensayo inmunoenzimático (ELISA) de competición comercial; una prueba rápida de inmunocromatografía; y un ELISA de competición en fase sólida para la detección de anticuerpos específicos contra el serotipo O del virus. Las tres técnicas arrojaron resultado negativo ante los sueros de dromedario, hecho indicativo de que los rumiantes con anticuerpos contra la proteína no estructural del virus de la fiebre aftosa no habían transmitido el virus a los dromedarios con los que convivían.

Acquired Resistance to Poly (ADP-ribose) Polymerase Inhibitor Olaparib in BRCA2-Associated Prostate Cancer Resulting From Biallelic BRCA2 Reversion Mutations Restores Both Germline and Somatic Loss-of-Function Mutations.

PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in BRCA1/2 or ATM genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that revert the normal open reading frame rescuing homologous recombination. We describe a case of metastatic CRPC with germline BRCA2 mutation with acquired resistance to olaparib related to biallelic BRCA2 reversion mutations of both the germline and somatic loss of function alleles detected by circulating tumor DNA testing. We also summarize a retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis showing a 1.6% incidence of germline BRCA2 mutations. Within the germline BRCA2-positive cases exposed to platinum chemotherapy or PARP inhibition, the prevalence of reversion mutations was 40%. This report documents the frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations. It also shows the potential utility of ctDNA analyses for early detection of reversion mutation driving tumor resistance.

Sero-epidemiology of equine toxoplasmosis using a latex agglutination test in the three metropolises of Punjab, Pakistan.

Toxoplasmosis is a serious threat for livestock in addition to being of zoonotic significance. In this study, serodiagnosis of equine toxoplasmosis was conducted in a randomly selected population from the 3 metropolises of Punjab, Pakistan. To this end, 272 draught equines were screened using a commercial latex agglutination assay kit. Association of probable risk factors of equine toxoplasmosis was also documented. A total of 91 (33.5%) equines were found sero-positive for Toxoplama (T.) gondii having antibody titers ranging between 1:32 to 1:612. The highest rates of seropositive cases were observed in donkeys (58.7%) followed by mules (28.6%) and horses (23.5%). Age, sex and species of draught equines were found not to be statistically (p>0.05) associated with the distribution of T. gondii antibodies. The results of the study provided a baseline data for the exposure of equine population in this area. In addition, it is recommended that the contiguous population of domestic ruminants and possible reservoirs such as feral cats should be screened in order to explore the potential risk for the human population in Pakistan.

High prevalence of West Nile virus in equines from the two provinces of Pakistan.

This study describes the first large-scale serosurvey on West Nile virus (WNV) conducted in the equine population in Pakistan. Sera were collected from 449 equids from two provinces of Pakistan during 2012-2013. Equine serum samples were screened using a commercial ELISA kit detecting antibodies against WNV and related flaviviruses. ELISA-positive samples were further investigated using virus-specific microneutralization tests (MNTs) to identify infections with Japanese encephalitis virus (JEV), WNV and tick-borne encephalitis virus (TBEV). Anti-WNV antibodies were detected in 292 samples by ELISA (seroprevalence 65.0%) and WNV infections were confirmed in 249 animals by MNT. However, there was no animal found infected by JEV or TBEV. The detection of WNV-seropositive equines in Pakistan strongly suggests a widespread circulation of WNV in Pakistan.

Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235).

OBJECTIVES: To determine the efficacy and tolerability of bicalutamide in patients with advanced prostate cancer with progression after conventional hormonal therapy. METHODS: Fifty-two patients received bicalutamide, 150 mg once daily, as second-line therapy after progressing following treatment with orchiectomy or luteinizing hormone-releasing hormone analogue or diethylstilbestrol, alone or in combination. Patients had measurable (n = 8) or assessable (n = 44) disease, a Southwest Oncology Group performance status of 0 to 2, and no prior antiandrogen therapy or chemotherapy. The objective response to treatment was assessed every 12 weeks; symptoms and pain were assessed monthly with questionnaires for 6 months. RESULTS: There was evidence of palliation with three measures of pain and, to a lesser extent, with a measure of overall symptom status after 3 months of taking bicalutamide. No complete or partial responses occurred. However, 9 (20%) of 44 subjects with adequate prostate-specific antigen data had a 50% or higher decrease in their prostate-specific antigen levels, which did not correlate with symptom improvement. The median survival time was 15 months. The most common side effects were hot flashes (23%) and nausea (21%). CONCLUSIONS: These data suggest that bicalutamide decreases pain and improves symptom status in patients with prostate cancer in whom first-line hormonal therapy failed.

A phase II trial of estramustine and etoposide in hormone refractory prostate cancer: A Southwest Oncology Group trial (SWOG 9407).

BACKGROUND: The combination of oral estramustine and oral etoposide has generated response rates of 40-50% in patients with hormone refractory prostate cancer in single institution trials. This study tested this regimen in a multi-institutional setting. METHODS: Fifty-five patients were accrued over a period of 4 months between 1 March 1996 and 1 July 1996. Two patients were not analyzable and two patients were ineligible. They were given an oral regimen consisting of estramustine 15 mg/kg/day (capped at 1120 mg per day) and etoposide 50 mg/M(2)/day, days 1-21 every 28 days. Patients received a median of two cycles of therapy. RESULTS: Toxicities included 11 patients (20%) with grades 3 or 4 granulocytopenia, 5 patients (10%) with grades 3 or 4 edema, and 3 patients (6%) with a thrombotic event. There were two treatment-related deaths, one as a result of anemia and the other as a result of a myocardial infarction. Of the 32 men who received at least 2 cycles of therapy, 7 men (22%) demonstrated a partial response to this regimen as measured by prostate-specific antigen (PSA) criteria of a 50% decline from pretreatment values. CONCLUSIONS: This trial demonstrates the toxicity of estramustine delivered in high dose. It also illustrates the difficulty of conducting phase II trials in prostate cancer in the cooperative group setting where the experience and comfort level of oncologists with new agents is less than that of the physicians at the institution where the therapy was developed. As the activity of this regimen with low-dose estramustine is defined, further multi-institutional studies may be warranted.

Combination cisplatin, 5-fluorouracil and radiation therapy for locally advanced unresectable or medically unfit bladder cancer cases: a Southwest Oncology Group Study.

PURPOSE: Patients with locally advanced bladder cancer or who are not medically fit for surgery are a therapeutic dilemma. Radiotherapy with or without single agent cisplatin has been the major therapeutic modality. A phase II Southwest Oncology Group trial investigated the efficacy and feasibility of 5-fluorouracil, cisplatin and radiation in this patient subset. MATERIALS AND METHODS: Eligible patients had muscle invasive bladder cancer (clinical stages T2-T4) with nodal involvement at or below the level of bifurcation of the iliac vessels, were medically or surgically inoperable, or refused cystectomy. Patients underwent pretreatment cystoscopy and detailed tumor mapping, and were treated with 75 mg. /m.2 cisplatin on day 1 and 1 gm./m.2 daily, 5-fluorouracil on days 1 to 4 and definitive radiotherapy. Chemotherapy was repeated every 28 days, twice during and twice after radiation. RESULTS: From October 1993 to April 1998, 60 patients were enrolled in study. Of the 56 eligible patients 34% had unresectable tumors, 21% were not medically fit for surgery and 45% refused cystectomy. Overall, 68% of the patients had clinical T3 tumors or greater and 22% had nodal metastasis. Treatment was completed as planned in 32 of 56 (57%) patients. The most frequent grade 3 or 4 toxicities were neutropenia, stomatitis or mucositis, diarrhea, neuropathy and nausea. There were 53 patients who were evaluable for response, although response was not determined for 18. The overall response rate was 51% (95% confidence interval [CI] 37 to 65) based on intent to treat with a complete response rate of 49% (95% CI 35 to 63). Estimated median survival of the 56 patients was 27 months (95% CI 21 to 40 months) with an overall 5-year survival of 32%. The 5-year survival of the 25 patients who refused surgery was 45%. CONCLUSIONS: Concurrent 5-fluorouracil, cisplatin and radiation therapy is feasible. Despite a promising complete response rate, the overall 5-year survival suggests the need for more effective systemic therapy. The 5-year survival of patients who refused cystectomy suggests that this combined modality may provide another alternative to cystectomy for these patients.

Continuous-infusion 5-fluorouracil and cisplatin for advanced/recurrent transitional cell cancer of the bladder: a Southwest Oncology Group trial.

Significant toxicities result from the use of MVAC (methotrexate, vinblastine, adriamycin, cisplatin) for advanced/ recurrent transitional cell carcinoma of the bladder (ARTCCB). An alternative regimen of 5-fluorouracil (5-FU) and cisplatin was evaluated by Southwest Oncology Group (SWOG). Thirty-eight patients with ARTCCB were treated with continuous infusion 5-FU 1,000 mg/m2/days 1-5 and cisplatin 100 mg/day 1, on a every-21-days schedule. There were two complete responses (CR) and eight partial responses (PR) among 36 eligible patients, for an overall response rate of 28% [95% confidence interval (CI) 14-45%]. Median duration of response was 6 months, and median duration of survival was 9 months. No toxic deaths occurred. Grade 4 leukopenia occurred in 5 patients. Other toxicities were mild. Only two documented infections occurred in 5 patients with neutropenia. The response rate of 28% is better than that achieved with cisplatin alone and not dissimilar to the range of response for MVAC. Toxicities were less and tolerable. This regimen will need further evaluation.

Southwest Oncology Group studies in hormone-refractory prostate cancer.

Virtually all patients with hormone-refractory prostate cancer will eventually succumb to their diseases with no demonstrable increase in survival with any second-line therapy, thus making the conventional approach to the treatment of this disease palliative. The Southwest Oncology Group (SWOG) Genitourinary Committee strategy in investigating therapy for hormone-refractory prostate cancer is focused on the application of biologically guided treatments targeting primary patients with limited prior hormonal therapy, taking into account evolving concepts regarding the definitions of "hormone-refractory" disease and response criteria. This report reviews data from selected SWOG studies conducted in the past 10 years, and outlines the rationale and design of current and future studies conducted by the Genitourinary Committee of the SWOG in hormone-refractory prostate cancer.

Antigenic similarity of central European encephalitis and louping-ill viruses.

Twenty isolates of Central European encephalitis (CEE) virus were compared with 20 isolates of louping-ill (LI) virus in indirect immunofluorescence test (IIFT), using a panel of 17 monoclonal antibodies (MoAbs) prepared against the prototype LI virus. Three Asian members of the tick-borne encephalitis (TBE) complex were also included in the comparison: Turkish sheep encephalitis (TSE), Russian spring-summer encephalitis (RSSE) and Langat (LGT) viruses. Antigenic relationships of the viruses were evaluated by Dice similarity coefficient and cluster analysis. The results revealed antigenic heterogeneity of LI isolates, antigenic homogeneity of CEE isolates, and indicated that CEE and LI are related varieties of Eurasian TBE flavivirus that also includes TSE and RSSE strains.

Oral etoposide in the treatment of hormone-refractory prostate cancer.

BACKGROUND: Hormone-refractory prostate cancer generally remains a chemotherapy-resistant tumor and therefore warrants the continued evaluation of promising agents. METHODS: Twenty-two eligible patients with hormone-refractory prostate cancer were treated with oral etoposide at a dosage of 50 mg/m2/day for 21 days in a 28-day cycle. Response was evaluated using standard solid tumor response criteria. RESULTS: There were two partial responses of 6 and 14 months' duration, respectively. Two patients had disease stabilization, one for 6 months and one for 12 months. Median survival was 31 weeks, with an overall 1-year survival of 30%. Reversible alopecia and myelosuppression were the primary toxicities noted. CONCLUSIONS: Single-agent oral etoposide has minimal activity in patients with hormone-refractory prostate cancer.

Identification of naturally occurring monoclonal antibody escape variants of louping ill virus.

Louping ill virus isolates from Great Britain, Ireland and Norway were compared antigenically by indirect immunofluorescence, haemagglutination-inhibition and neutralization tests using a panel of five envelope-specific and five non-structural protein NS1-specific monoclonal antibodies raised against louping ill virus. The viruses were grouped according to their reactivities with the antibodies. Group 1, members of which were isolated between 1931 and 1987, consisted of 13 viruses that reacted with all antibodies, whereas group 2, members of which were isolated after 1980, consisted of five viruses that were positive with only eight of the 10 monoclonal antibodies. The two monoclonal antibodies that did not react with the group 2 viruses are known to be neutralizing antibodies and the amino acids that they recognize in the viral envelope protein have been identified. We therefore refer to the group 2 viruses as naturally occurring monoclonal antibody escape variants. When compared with group 1 viruses, the escape variants showed reduced virulence for mice in terms of the time taken to kill and/or the proportion that died, following intraperitoneal inoculation. The nucleotide and deduced amino acid sequences of the envelope gene of one escape variant were compared with those of several group 1 viruses. A single amino acid substitution at residue 308 was detected in the envelope protein of the escape variant which corresponds precisely to the position in experimentally selected attenuated monoclonal antibody escape mutants. The importance and potential implications of these naturally occurring variants in louping ill epizootiology and vaccine-based control are discussed.

Flow cytometric DNA analysis of fresh prostatic resections. Correlation with conventional prognostic parameters in patients with prostate cancer.

BACKGROUND: DNA ploidy analysis has been investigated as a prognostic indicator in prostate cancer. Most of the data is derived from retrospective studies using paraffin-embedded tissue. This method has drawbacks related to the quality of DNA histograms and uncontrolled data collection. METHODS: DNA ploidy analysis of freshly resected prostatic tissue was prospectively compared with conventional prognostic variables in 97 men treated with radical prostatectomy for localized prostate cancer. RESULTS: Regarding the patients, 31.9% were African American and 66% had pathologic Stages C or D1 disease. Only 9.6% of patients with Stages A2 and B had a prostate-specific antigen (PSA) value greater than 10 ng/ml, whereas 97% of patients with PSA values greater than 20 ng/ml had pathologic Stages C and D1. PSA levels correlated with Gleason score (P = < 0.05); 51% and 100% of patients with Gleason score 5-7 and 8-10, respectively, had PSA values greater than 10 ng/ml. Twenty-two patients (23%) had DNA aneuploid tumors. Comparisons of mechanical to enzymatic cell suspensions indicated that DNA aneuploidy was better preserved in mechanical cell preparations. DNA ploidy correlated with pathologic stage (P = < 0.05) and Gleason score (P = < 0.05). Fifteen of 79 patients (18.9%) with Gleason score 5-7 had DNA aneuploid tumors versus 71.4% of patients with Gleason score 8-10. PSA groups correlated with ploidy status (P = 0.01). Although the majority of patients (19 of 22) with DNA aneuploid tumors had elevated preoperative PSA levels, none had a PSA value greater than 50 ng/ml. CONCLUSIONS: DNA ploidy analysis correlated with established prognostic indicators in prostate cancer; however, its independent correlation with natural history and treatment outcome must be established for it to have an effect on therapeutic decisions.

Classification of a new member of the TBE flavivirus subgroup by its immunological, pathogenetic and molecular characteristics: identification of subgroup-specific pentapeptides.

The antigenic, pathogenic and molecular characteristics of Turkish sheep encephalitis (TSE) virus, strain TTE80, were compared with other members of the tick-borne encephalitis (TBE) virus complex. Monoclonal antibodies with defined specificity for the flavivirus envelope glycoprotein distinguished TSE virus from louping ill (LI), western or far eastern TBE, Langat and Powassan virus in indirect immunofluorescence, haemagglutination-inhibition and neutralization tests. On the other hand, TSE virus, which produces an LI-like disease in sheep, resembled LI virus in mouse neurovirulence tests. Molecular homology data of all the structural genes of TSE virus compared with other tick-borne flaviviruses demonstrated that TSE virus is a distinct member in the TBE virus subgroup. The data are consistent with the conclusion that TSE virus has evolved by a separate evolutionary pathway as compared with the close antigenic relatives, western European, far eastern TBE viruses and LI virus. By aligning the encoded amino acids in the viral envelope glycoprotein of mosquito- and tick-borne flaviviruses, we have also identified subgroup-specific pentapeptide motifs for the tick-borne encephalitis, Japanese encephalitis and dengue subgroup viruses of the genus Flavivirus. These pentapeptides have important implications for the evolution, classification and diagnosis of flaviviruses.

Sequencing and antigenic studies of a Norwegian virus isolated from encephalomyelitic sheep confirm the existence of louping ill virus outside Great Britain and Ireland.

We have carried out an antigenic analysis and nucleotide sequence comparison of the envelope glycoprotein of recognized louping ill virus strains isolated from Scotland with that of a Norwegian virus known to cause encephalomyelitis in sheep. Monoclonal antibodies with defined specificity for the louping ill virus envelope glycoprotein failed to distinguish between the Norwegian virus and prototype louping ill virus in indirect immunofluorescence, haemagglutination inhibition and neutralization tests. Nucleotide sequencing of the envelope glycoprotein and alignment of the deduced amino acid sequence with other known sequences revealed that the Norwegian virus closely resembles (> 95% identity for nucleotide and > 98% identity for amino acid sequences) louping ill virus. Maximum variation in identities among four strains of louping ill virus were 4.4% and 1.8% respectively for nucleotide and amino acid alignments. We conclude that sheep encephalomyelitis in Norway is caused by louping ill virus. These results imply that other viruses present in Europe and known to cause encephalitis/encephalomyelitis of sheep could be caused by louping ill virus.