Human papillomavirus infection & anal cytological abnormalities in HIV-positive men in eastern India

Background

Oncogenic Human papillomavirus (HPV) infections are closely associated with anal cancer which is high among human immunodeficiency virus (HIV) infected males. There are no data regarding anal HPV infection and cytological abnormalities in HIV positive males receiving free therapy in the national program. Thus, this cross-sectional study was performed to assess the prevalence and risk factors of anal HPV infection and cytological abnormalities in HIV positive males.

Methods

We screened 126 HIV-positive male patients attending the antiretroviral treatment center (ART) between 2014 and 2015 with anal papanicolaou smear cytology and HPV-DNA testing. HPV-DNA was detected by using polymerase chain reaction (PCR) method with two consensus primer sets E6 and MY09/11 and further analyzed for the presence of various HPV genotype by Sanger sequencing. Risk factors associated with anal cytological abnormalities and HPV infection was analyzed by using univariate and multivariate logistic regression models.

Results

Out of 126, 52 were on antiretroviral therapy. 91% were married to female partners but during the study 48 (38%) gave positive history of anal intercourse with other men. Anal cytology was done in 95 patients, out of which 60 (63.15%) had cytological abnormalities. LSIL (low-grade squamous intraepithelial lesions) was present in 27 (45%), ASCUS (atypical squamous cells of undetermined significance) in 31 (52%) and ASC-H (atypical squamous cells cannot exclude a high-grade squamous intraepithelial lesion) in 2 (3.33%). In multivariate analysis, the risk factors for cytological abnormality were presence of history of anal intercourse (OR, 6.1; 95% CI, 2.0–18.7) and WHO stage III & IV (OR, 2.7; 95% CI, 1.1–7.5). HPV-DNA was detected in 33/119 (27.73%) patients. The most prevalent HPV type in the study was HPV-16 (10.08%), other HPV types detected were 18,31,35,17,66,72,52,68 and 107 (17.65%).

Conclusions

High prevalence of anal cytological abnormalities in our study suggests that regular anal Pap smear screening should be done in HIV positive males in the ART center.

     

Animal models of inflammatory bowel disease: a review

Inflammatory bowel disease (IBD) represents a group of idiopathic chronic inflammatory intestinal conditions associated with various areas of the GI tract, including two types of inflammatory conditions, i.e., ulcerative colitis (UC) and Crohn’s disease (CD). Both UC and CD are chronic inflammatory disorders of the intestine; in UC, inflammation starts in the rectum and generally extends proximally in a continuous manner through the entire colon. Bloody diarrhea, presence of blood and mucus mixed with stool, accompanied by lower abdominal cramping, are the characteristic symptoms of the disease. While in CD, inflammatory condition may affect any part of the GI tract from mouth to anus. It mainly causes abdominal pain, diarrhea, vomiting and weight loss. Although the basic etiology of IBD is unknown, there are several factors that may contribute to the pathogenesis of this disease, such as dysregulation of immune system or commensal bacteria, oxidative stress and inflammatory mediators. In order to understand these different etiological factors, a number of experimental models are available in the scientific research, including chemical-induced, spontaneous, genetically engineered and transgenic models. These models represent a major source of information about biological systems and are clinically relevant to the human IBD. Since there is less collective data available in one single article discussing about all these models, in this review an effort is made to study the outline of pathophysiology and various types of animal models used in the research study of IBD and other disease-related complications.     

Incremental role of three-dimensional transesophageal echocardiography in the assessment of mitral-aortic intervalvular fibrosa abscess

We report a case of an elderly patient in whom live/real time three-dimensional transesophageal echocardiography (3DTEE) provided definitive diagnosis of mitral-aortic intervalvular fibrosa abscess. This could not be done by two-dimensional transthoracic echocardiography (2DTTE) and two-dimensional transesophageal echocardiography (2DTEE). 3DTEE was also helpful in ruling out associated mitral valve endocarditis, which was initially suspected by 2DTEE leading to a mitral valve sparing surgery. Thus, 3DTEE provided incremental information over 2DTTE and 2DTEE in this patient.     

Incremental value of live/real time three-dimensional echocardiography in the diagnosis and evaluation of pericardial cyst

Pericardial cysts are rare anomalies of the pericardium that are usually asymptomatic and followed by two-dimensional (2D) echocardiography. Here we report a large pericardial cyst that could not be measured accurately by 2D echocardiography but three-dimensional (3D) echocardiography enabled measurements of the cyst that correlated well with computed tomography measurements. In addition, 3D echocardiography demonstrated the mono-trabeculated nature of the cyst further suggesting the incremental value of 3D echocardiography in the evaluation of pericardial cysts. The cyst was subsequently resected surgically.     

Doctor reported outcomes: Real-world data from a tertiary eye cancer center

Purpose:To provide real-world data on the world-wide-web for patient and doctor awareness.Methods:From December 2017 to January 2020, consecutive patients with choroidal melanoma (CM), iris ciliary body melanoma (ICM), and ocular surface squamous carcinoma (OSSC) had specific outcomes recorded at each return visit. Each result was anonymized, entered in an online portal, and sent to a unique software program where it was used to create real-world data of number of patients, mean vision, local tumor control, eye salvage, systemic metastases, and length of follow-up for our eye cancer center.Results:A HIPAA compliant, internet-based software program was developed and linked to public access web page to collect and analyze near-real-time data pertaining to the treatment, vision, life, and follow-up time of patients. During this period, CM radiation plaque tumor control was 99.7%, median vision 20/25 (mean 20/50) and eye salvage 95.8%. ICM tumor control was 99.1% and the median vision 20/20 (mean 20/20). OSSC tumor control was 100% and the most common vision was 20/20 (mean 20/25). Rates of primary enucleation as treatment were 4.2% for CM, 2.8% for ICM, and 0% for OSSC. All patient results were updated by the ophthalmic oncology fellow at each patient visit as to reflect near-real-time outcomes at our center.Conclusion:Prospective data collection of returning patients was found to be a simple method to reflect patient care outcomes. This method of reporting doctor outcomes offers a measure of transparency for patients and an opportunity to compare results with other clinical practices.     

Evaluation of multikinase inhibitor LDN193189 induced hepatotoxicity in teleost fish Poecilia latipinna

Currently, scientists show keen interest in the drugs that inhibit multiple kinases, LDN193189, being an example. It combats certain cancers in vitro as well as in vivo, making it a prerequisite for researchers to study the toxic potential of this drug in animal models. As most of the drugs metabolized by liver cause hepatic injury, LDN193189-induced hepatotoxicity was examined using a teleost fish, Poecilia latipinna. As a prelude, calculation of LD₅₀ showed a value of 95.22?mg/kg body weight and three doses were decided based on it for further evaluations. All these groups were tested for antioxidant enzyme levels and were significantly raised for mid- and high-dose group. Similar trend was recorded for ALP, AST, and ALT levels. Furthermore, some key indicators of drug metabolism in liver were tested for their expression in response to LDN193189 treatment. Among these, Cyt-C, CYP3A4, CYP1B1 and CYP1A1 were elevated in mid- and high dose, except CYP21A1, which declined remarkably. Moreover, histological profile of the liver reflected high degree of inflammation due to drug treatment, but this was found only at high dose. In summary, LDN193189, at 2.5?mg/kg body weight, did not cause any adverse hepatotoxicity, rendering it safe for use as an anti-proliferative agent – an activity for which it has already shown promising results in the same animal model. The low-dose group previously studied for its anti-proliferative property showed no adverse effect in liver, whereas the mid- and high dose induced moderate or severe hepatotoxicity in P. latipinna.     

Evaluating the validity and reliability of a modified survey to assess patient satisfaction with mail-order and community pharmacy settings

The level of patient-pharmacist interactions and services provided varies across different distribution methods and could affect patient satisfaction with services. Determining patient satisfaction with these medication distribution methods is important for improving care of chronic disease patients. This study evaluated the validity and reliability of a modified survey to assess patient satisfaction with mail-order and community pharmacy settings. Exploratory cross-sectional design using a convenience sample of HIV-infected patients at a university clinic was used. Satisfaction scale was modified from previously validated instrument resulting in 21 items on the final survey. Data collection occurred for 7 months, and 178 surveys were completed. An exploratory factor analysis was conducted using principal components and varimax rotation. Reliability and item analyses were conducted. Factor analysis resulted in a 2-factor solution, namely "satisfaction with the efficient functioning of the pharmacy" and "satisfaction with the managing therapy role of the pharmacist," respectively. Cronbach's alpha for factors 1 and 2 with mail-order were .951 and .795, for independent were .977 and .965, and for chain were .841 and .823. The study provides a valuable tool to assess patient satisfaction with pharmacy services provided through different distribution methods.     

TAE226 inhibits human neuroblastoma cell survival

Purpose. Neuroblastoma is one of the most devastating pediatric solid tumors and is unresponsive to many interventions. TAE226 is a novel small molecule FAK inhibitor. We investigated the effects of TAE226 on neuroblastoma cells in vitro. Materials and Methods. Human neuroblastoma cell lines were treated with varying concentrations of TAE226. Following treatment, cell viability, cell cycle, and apoptosis were evaluated. Results. Treatment of human neuroblastoma cell lines with TAE226 resulted in a concentration dependent decrease in FAK phosphorylation, decrease in cellular viability, cell cycle arrest, and an increase in apoptosis. Conclusions. Targeting FAK provides potential therapeutic options for the treatment of neuroblastoma and deserves further investigation.     

Suitable Disk Antimicrobial Susceptibility Breakpoints Defining Salmonella enterica Serovar Typhi Isolates with Reduced Susceptibility to Fluoroquinolones

Infections with Salmonella enterica serovar Typhi isolates that have reduced susceptibility to ofloxacin (MIC ≥ 0.25 μg/ml) or ciprofloxacin (MIC ≥ 0.125 μg/ml) have been associated with a delayed response or clinical failure following treatment with these antimicrobials. These isolates are not detected as resistant using current disk susceptibility breakpoints. We examined 816 isolates of S. Typhi from seven Asian countries. Screening for nalidixic acid resistance (MIC ≥ 16 μg/ml) identified isolates with an ofloxacin MIC of ≥0.25 μg/ml with a sensitivity of 97.3% (253/260) and specificity of 99.3% (552/556). For isolates with a ciprofloxacin MIC of ≥0.125 μg/ml, the sensitivity was 92.9% (248/267) and specificity was 98.4% (540/549). A zone of inhibition of ≤28 mm around a 5-μg ofloxacin disc detected strains with an ofloxacin MIC of ≥0.25 μg/ml with a sensitivity of 94.6% (246/260) and specificity of 94.2% (524/556). A zone of inhibition of ≤30 mm detected isolates with a ciprofloxacin MIC of ≥0.125 μg/ml with a sensitivity of 94.0% (251/267) and specificity of 94.2% (517/549). An ofloxacin MIC of ≥0.25 μg/ml and a ciprofloxacin MIC of ≥0.125 μg/ml detected 74.5% (341/460) of isolates with an identified quinolone resistance-inducing mutation and 81.5% (331/406) of the most common mutant (carrying a serine-to-phenylalanine mutation at codon 83 in the gyrA gene). Screening for nalidixic acid resistance or ciprofloxacin and ofloxacin disk inhibition zone are suitable for detecting S. Typhi isolates with reduced fluoroquinolone susceptibility.Enteric fever is an infection caused by Salmonella enterica serovars Typhi and Paratyphi A. These human restricted pathogens are transmitted by the fecal-oral route, and enteric fever is common in regions with poor standards of hygiene and sanitation. There are 27 million new enteric fever infections each year, of which approximately 200,000 are fatal (16). Antimicrobials are essential for appropriate clinical management of enteric fever, but antimicrobial resistance in S. Typhi and S. Paratyphi A have become a problem in regions where they are endemic (6, 8). Multiple-drug-resistant (MDR) S. Typhi and S. Paratyphi A (resistant to chloramphenicol, trimethoprim-sulfamethoxazole, and ampicillin) are particularly common in some locations in Asia and have led to large epidemics. An MDR S. Typhi strain was responsible for an outbreak in Tajikistan in the late 1990s, causing over 24,000 infections (39).The occurrence of MDR strains limits the options for antimicrobial therapy of enteric fever. The current WHO guidelines suggest that the fluoroquinolones are the optimal group of antimicrobials for the treatment of uncomplicated typhoid fever in adults (44). The fluoroquinolones, such as ciprofloxacin and ofloxacin, are comparatively inexpensive and well tolerated and in early randomized clinical trials were very effective. However, S. Typhi and S. Paratyphi A isolates with reduced susceptibility to fluoroquinolones have become common in Asia and are increasingly common in Africa (6, 8, 13, 26, 32, 37). Infections with S. Typhi strains with elevated MICs to ciprofloxacin and ofloxacin have been associated with the failure of treatment with these antimicrobials and increased disease severity (15, 30, 33, 36, 43).Investigations of S. Typhi with reduced susceptibility to fluoroquinolones has shown the association of elevated MIC with several single-base-pair mutations in the DNA gyrase gene, gyrA, and the topoisomerase gene, parC (4, 6, 33, 42). Furthermore, extensive genome sequencing and single nucleotide polymorphism (SNP) investigation of S. Typhi strains have further shown the dramatic impact of strains with gyrA mutations on the population structure of this monophyletic organism (35). Genotyping studies identified at least 15 independent gyrA mutations that have occurred within a decade and stimulated clonal expansion in Asia and Africa (6, 35). These data suggest that such strains have evolved rapidly and are maintained by a strong selective pressure.The laboratory detection and identification of strains with reduced susceptibility to fluoroquinolones are important for the treating clinician, but such strains are categorized as susceptible by the current interpretive guidelines for fluoroquinolone disk susceptibility testing (3, 11, 19). These isolates are invariably resistant to nalidixic acid, and susceptibility testing with a nalidixic acid disk has been suggested as a suitable screening method for reduced fluoroquinolone susceptibility (11, 19). The British Society for Antimicrobial Chemotherapy (BSAC) has recommended that for invasive isolates of Salmonella, an MIC for reduced susceptibility to fluoroquinolones should be determined (3).Here we have examined the relationship between gyrA and parC mutations, nalidixic acid resistance, ofloxacin and ciprofloxacin disk inhibition zone sizes, and MIC for a large number of S. Typhi clinical isolates from multiple locations in Asia over a 16-year period. We suggest disk susceptibility breakpoints for strains with reduced susceptibility to ciprofloxacin and ofloxacin, which may permit the diagnostic laboratory to detect such isolates and aid the clinical management of enteric fever.     

Undifferentiated Febrile Illness in Kathmandu,Nepal

Undifferentiated febrile illnesses (UFIs) are common in low- and middle-income countries. We prospectively investigated the causes of UFIs in 627 patients presenting to a tertiary referral hospital in Kathmandu, Nepal. Patients with microbiologically confirmed enteric fever (218 of 627; 34.8%) randomized to gatifloxacin or ofloxacin treatment were previously reported. We randomly selected 125 of 627 (20%) of these UFI patients, consisting of 96 of 409 (23%) cases with sterile blood cultures and 29 of 218 (13%) cases with enteric fever, for additional diagnostic investigations. We found serological evidence of acute murine typhus in 21 of 125 (17%) patients, with 12 of 21 (57%) patients polymerase chain reaction (PCR)-positive for Rickettsia typhi. Three UFI cases were quantitative PCR-positive for Rickettsia spp., two UFI cases were seropositive for Hantavirus, and one UFI case was seropositive for Q fever. Fever clearance time (FCT) for rickettsial infection was 44.5 hours (interquartile range = 26–66 hours), and there was no difference in FCT between ofloxacin or gatifloxacin. Murine typhus represents an important cause of predominantly urban UFIs in Nepal, and fluoroquinolones seem to be an effective empirical treatment.Undifferentiated febrile illnesses (UFIs) are a common clinical problem in south Asia.^1,2 Defined as a fever without a focus of infection on initial physical examination or in basic laboratory tests, UFIs represent a considerable burden of disease with diagnostic and therapeutic challenges. Empirical broad-spectrum antimicrobials are generally prescribed but with little evidence-based guidance on likely etiologies or potential treatment responses. Previous studies on UFIs, including those originating from our research group in Nepal,^3–5 have been limited by a lack of molecular testing, little convalescent serological testing, and few data on treatment outcomes.We sought to address this knowledge gap by expanding investigations to determine further causes and treatment outcomes of Nepalese patients with UFIs. Diagnostic tests were performed for scrub typhus, murine typhus, Spotted Fever Group (SFG) rickettsiosis, Q fever, leptospirosis, Hantavirus, Brucella, and dengue (3 Briefly, patients were eligible to enter if they were > 2 years old, had an untreated UFI for > 3 days, and could be treated in the community. Each patient was randomly assigned to 7 days of treatment with either gatifloxacin (10 mg/kg per day in a single oral dose) or ofloxacin (20 mg/kg per day in two divided oral doses). All patients were managed as outpatients, with assessment of fever clearance time (FCT) and collection of acute (day 1) and convalescent (day 30) blood samples by trained community medical auxiliaries. Approval for the study was obtained from the Nepal Health Research Council and the Oxford Tropical Research Ethics Committee. The trial was registered as ISRCTN 63006568. Written informed consent was obtained from all study participants.

Table 1

Diagnostic tests used for the study