Clinical and economic impact of school-based nonavalent human papillomavirus vaccine on women in Singapore: a transmission dynamic mathematical model analysis.

OBJECTIVE: To examine the epidemiological and economic impact of a nine-valent (nonavalent) human papillomavirus (HPV) 6/11/16/18/31/33/45/52/58 vaccine programme for young teenagers in Singapore. DESIGN: Mathematical modelling. SETTING: Pharmaco-economic simulation projection. POPULATION: Singapore demography. METHODS: Clinical, epidemiological and financial data from Singapore were used in a validated HPV transmission dynamic mathematical model to analyse the impact of nonavalent HPV vaccination over quadrivalent and bivalent vaccines in a school-based 2-dose vaccination for 11- to 12-year-old girls in the country. The model assumed routine cytology screening in the current rate (50%) and vaccine coverage rate of 80%. MAIN OUTCOME MEASURES: Changes over a 100-year time period in the incidence and mortality rates of cervical cancer, case load of genital warts, and incremental cost-effectiveness ratio (ICER). RESULTS: Compared with bivalent and quadrivalent HPV vaccination programmes, nonavalent HPV universal vaccination resulted in an additional reduction of HPV31/33/45/52/58 related CIN1 of 40.5%, CIN 2/3 of 35.4%, cervical cancer of 23.5%, and cervical cancer mortality of 20.2%. Compared with bivalent HPV vaccination, there was an additional reduction in HPV-6/11 related CIN1 of 75.7%, and genital warts of 78.9% in women and 73.4% in men. Over the 100 years, after applying a discount of 3%, disease management cost will be reduced by 32.5% (versus bivalent) and 7.5% (versus quadrivalent). The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year gained was SGD 929 compared with bivalent vaccination and SGD 9864 compared with quadrivalent vaccination. CONCLUSION: Universal two-dose nonavalent HPV vaccination for 11- to 12-year-old adolescent women is very cost-effective in Singapore. TWEETABLE ABSTRACT: Nonavalent HPV vaccination of 11- to 12-year-old girls is cost-effective in Singapore.

Stimulation of homology-directed repair at I-SceI-induced DNA breaks during the permissive life cycle of human cytomegalovirus.

Human cytomegalovirus (HCMV) selectively relocalizes many DNA repair proteins, thereby avoiding a potentially detrimental damage response. In the present study, we evaluated interactions between HCMV and the homology-directed repair (HDR) pathway. In permissive human foreskin fibroblasts, a fluorescence-based double-stranded break repair assay was used to determine that HCMV stimulated HDR. Repair of both stably integrated and extrachromosomal reporter substrates was observed to increase. HDR was also stimulated through individual expression of the viral immediate-early protein IE1-72, mimicking full virus infection. These experiments further demonstrate HCMV's role in modulating critical cellular processes during a permissive infection.

Monocationic surfactant induced ultra structural changes in antibiotic resistant Escherichia coli.

BACKGROUND & OBJECTIVES: Cetrimide is a monocationic surfactant, commonly used for disinfection of hospital floors, equipments, for cleansing of burns and wounds, hand wash, etc. We evaluated whether antibiotic resistant (AR) Escherichia coli isolates from hospital settings (nosocomial pathogens) show any evidence of significant reduction in their susceptibility to cetrimide. Also the response of AR E. coli (nosocomial pathogens) to the action of cetrimide was assessed by studying the ultra structural changes induced using transmission electron microscopy (TEM). METHODS: A total of 165 clinical samples were screened for isolation of E. coli. Eighty two (49.6%) samples were positive for E. coli. Antibiotic susceptibility testing of E. coli isolates was carried out by Kirby Bauer method to isolate AR E. coli. The randomly selected AR E. coli isolate was treated with different concentrations of cetrimide and minimum inhibitory concentration (MIC) of cetrimide was determined by broth micro dilution method. This same isolate was used for performing time kill assay and TEM study. RESULTS: The test E. coli isolate showed resistance to 12 different antibiotics. The MIC of cetrimide against AR E. coli was 312.5 microg/ml. The ultra cellular structural changes in cetrimide treated AR E. coli revealed vacuole formation, disaxilization of nuclear material, loss of cytoplasmic granularity, bleb formation and cell lysis. CONCLUSION: Ultra structural changes induced by the action of cetrimide revealed cell damaging changes in the AR E. coli to be dose and time dependent. The results showed that antibiotic resistance does not alter any change in susceptibility of E. coli to cetrimide, which was found to be still an effective disinfectant against a nosocomial pathogen E. coli.

Evaluation of analogues of DRDE-07 as prophylactic agents against the lethality and toxicity of sulfur mustard administered through percutaneous route.

Sulfur mustard (SM), chemically bis (2-chloroethyl) sulfide is a bifunctional alkylating agent that causes serious blisters on contact with human skin. Although several antidotes have been reported for the systemic toxicity of SM in experimental animals none of them are approved so far and decontamination of SM immediately by physical or chemical means is recommended as the best protection. Two compounds amifostine [S-2(3-aminopropylamino) ethyl phosphorothioate] and DRDE-07 [S-2(2-aminoethylamino) ethyl phenyl sulfide] gave very good protection as an oral prophylactic agent against SM the in mouse model, but in the rat model the protection was only moderate. In the search for more effective and less toxic compounds, a number of analogues of DRDE-07 were synthesised and their protective efficacy was evaluated in mouse and rat models. The LD50 of S-aryl substitution was between 1 and 2 g kg(-1) and S-alkyl substitution was more than 2 g kg(-1). In the mouse model, DRDE-07, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 gave about 20 fold protection, and DRDE-23 and DRDE-38 gave less protection of 4.8 and 9.0 fold respectively, against percutaneously administered SM. In the rat model, DRDE-07, DRDE-09, DRDE-10 and DRDE-21 gave about two fold protection. Percutaneously administered SM (19.33 mg kg(-1)) significantly depleted the hepatic GSH content in mice. Pretreatment with DRDE-21 significantly elevated the levels. A 4.4 fold increase in % DNA fragmentation was observed 7 days after SM administration (19.33 mg kg(-1)) in mice. Pretreatment with DRDE-07, DRDE-09, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 significantly protected the mice from SM induced DNA damage. The histopathological lesions in liver and spleen induced by percutaneously administered SM was reduced by pretreatment with DRDE-07, DRDE-09, DRDE-10 and DRDE-21. These analogues may prove as prototypes for the designing of more effective prophylactic drug for SM.

Novel S-substituted aminoalkylamino ethanethiols as potential antidotes against sulfur mustard toxicity.

Sulfur mustard (SM) is a highly toxic chemical warfare agent. A satisfactory treatment regimen is not yet available for this toxicant. In a search for an effective antidote against SM, a series of novel S-2(omega-aminoalkylamino)ethyl alkyl/aryl thioethers [H(2)N(CH(2))(n)()NHCH(2)CH(2)SR], where R = alky, alicyclic, aryl, and heterocyclic substituents, have been designed and synthesized as candidate antidotes against SM toxicity. These compounds were screened for their protective efficacy through the oral route against dermally applied sulfur mustard in female mice measured on the basis of percent survival following percutaneous administration of SM. A number of compounds demonstrated significant protection.

In vivo protection by amifostine and DRDE-07 against sulphur mustard toxicity.

The study was aimed at investigating the prophylactic efficacy of orally administered amifostine and a newly synthesized compound, S-2(2-amino-ethylamino)ethyl phenyl sulphide (DRDE-07), against dermally applied sulphur mustard (SM) in mice and rats. The LD50 values of amifostine and DRDE-07 were determined following oral and intraperitoneal routes and the LD50 of SM diluted in PEG-300 was determined following dermal route. Amifostine or DRDE-07 (equivalent to their 0.05 LD50, 0.10 LD50 and 0.20 LD50) dissolved in water was fed to mice and rats and, after 30 min, various doses of SM were applied to the hair-clipped area of the skin and were observed for 14 days for mortality. The protection index (PI) was calculated as a ratio of LD50 with treatment to LD50 without treatment. The estimated percutaneous LD50 of SM was found to be 8.1 and 2.4 mg/kg for female mice and male rats, respectively. A dose-related protection was observed with all the three doses of both compounds. Thirty minutes prior, the administration of amifostine in female mice offered a PI of 3.0 at the lowest pretreatment dose (52.5 mg/ kg) followed by PI of 6.7 and 9.5 at 105 and 210 mg/kg pretreatment doses, respectively. DRDE-07 offered better protection against SM in female mice, i.e., a PI of 4.8 at pretreatment dose of 62.5 mg/kg, a PI of 12.0 at the dose of 124.7 mg/kg and a PI of 27.0 at the dose of 249.4 mg/kg. In male rats, DRDE-07 gave a PI of about 3.0 at all the three pretreatment doses (80, 160 and 320 mg/kg), whilst amifostine offered a PI of 3.1 at the highest pretreatment dose (452 mg/kg). The present study showed that oral administration of both amifostine and DRDE-07 was effective as a prophylactic agent for protecting against SM toxicity, and that DRDE-07 offered better protection.

Unilateral choanal atresia in a young female.

Congenital choanal atresia is a rare anomaly with an incidence of one in five to ten thousand live births. It can be a bilateral or unilateral atresia; the former is a medical emergency while the later may remain unrecognized until later in life. Transpalatal or transnasal approaches are routinely followed for surgery with placement of stent or serial dilatations in the postoperative period.

Membrane-interaction QSAR analysis: application to the estimation of eye irritation by organic compounds.

PURPOSE: The purpose of this study was to explore a potential mechanism of eye irritation, and to construct a corresponding general quantitative structure-activity relationship (QSAR) model, in terms of diversity of irritant chemical structure, based on the Draize eye irritation ECETOC data set. METHODS: Molecular dynamic simulation (MDS) was used to generate intermolecular membrane-solute interaction properties. These intermolecular properties were combined with intramolecular physicochemical properties and features of the solute (irritant) to construct QSAR models using multi-dimensional linear regression and the Genetic Function Approximation (GFA) algorithm. RESULTS: Significant QSAR models for estimating eye irritation potential were constructed in which solute aqueous solvation free energy and solute-membrane interaction energies are the principle correlation descriptors. These physicochemical descriptors were selected from a trial set of 95 descriptors for 18 structurally diverse compounds fully representative of the ECETOC set of 38 compounds. CONCLUSIONS: Combining intermolecular solute-membrane interaction descriptors with intramolecular solute descriptors yields statistically significant eye irritation QSAR models. The resultant QSAR models support an eye irritation mechanism of the action in which increased aqueous solubility of the irritant and its strength of binding to the membrane both increase eye irritation.

Single dose therapy of ascariasis--a randomized comparison of mebendazole and pyrantel.

A multicentre, randomized trial was carried out to compare the efficacy of two single-dose treatments for ascariasis: mebendazole 200 mg, and pyrantel 10 mg/kg. Each centre enrolled 200 patients with a suspected diagnosis of ascariasis, 100 for each treatment, and the treatments were randomized for each centre. To confirm the diagnosis, stools were examined for eggs of Ascaris lumbricoides by Kato's thick smear method. Efficacy was evaluated by stool examination repeated three weeks after treatment by a "blind" technician using two methods, viz. Kato's thick smear method and the zinc sulfate flotation method. Cure was defined as absence of ascaris eggs in the stools by both methods. Of the 600 enrolled patients, 32 were excluded from analysis as their initial stool examination was negative, and 568 completed the trial: 284 on each treatment. The cure rate was 80 per cent in the mebendazole group and 90 per cent in the pyrantel group (P less than 0.01). Thus pyrantel was found to be significantly more efficacious than mebendazole for single-dose treatment of ascariasis.