Patan Hospital

ABSTRACT This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar Typhi strains collected in southern Vietnam, the proportion of multidrug resistance has remained high since 1993 (50% in 2004) and there was a dramatic increase in nalidixic acid resistance between 1993 (4%) and 2005 (97%). In a cross-sectional sample of 381 serovar Typhi strains from 8 Asian countries, Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, and central Vietnam, collected in 2002 to 2004, various rates of multidrug resistance (16 to 37%) and nalidixic acid resistance (5 to 51%) were found. The eight Asian countries involved in this study are home to approximately 80% of the world's typhoid fever cases. These results document the scale of drug resistance across Asia. The Ser83→Phe substitution in GyrA was the predominant alteration in serovar Typhi strains from Vietnam (117/127 isolates; 92.1%). No mutations in gyrB , parC , or parE were detected in 55 of these strains. In vitro time-kill experiments showed a reduction in the efficacy of ofloxacin against strains harboring a single-amino-acid substitution at codon 83 or 87 of GyrA; this effect was more marked against a strain with a double substitution. The 8-methoxy fluoroquinolone gatifloxacin showed rapid killing of serovar Typhi harboring both the single- and double-amino-acid substitutions.

Enteric fever, an infection caused by Salmonella enterica serovar Typhi and serovar Paratyphi A, is common and endemic in many areas of the Asian and African continents. In endemic areas, diagnostic tests are needed to diagnose acute cases for clinical management, to detect convalescent and chronic fecal carriage and for contact tracing. A suitable test may also allow an assessment of disease burden in a community to determine the need for vaccination programs. Each specific role may warrant a dedicated test, utilizing different samples, targets and methods to serve their respective purpose. Current diagnostic methods are poor. Blood culture is insufficiently sensitive and technically demanding, and bone marrow culture, although more sensitive, is infrequently performed. Antibody- and antigen-detection tests lend themselves to point-of-care format but remain insufficiently sensitive and specific for this role. There are concerns about the sensitivity of nucleic acid amplification tests and they have not become widely adopted. However, new approaches using genomics, proteomics, transcriptomics, in vivo-induced antigen and immunoaffinity proteomics-based technologies are being employed to identify new antigens, gene targets and metabolic products that could be used as a basis for more effective diagnostic tests. If novel tests are to be credible and widely used they require rigorous evaluation in endemic areas in studies with appropriate selection of patients, adequate sample sizes and proper attention to a gold standard reference. Here, we discuss the range of methods currently used for diagnosing enteric fever in endemic locations and we suggest new technologies which may improve enteric fever diagnostics over the coming years.

BACKGROUND: Typhi is a major cause of fever in children in low- and middle-income countries. A typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization was shown to be efficacious in a human challenge model, but data from efficacy trials in areas where typhoid is endemic are lacking. METHODS: In this phase 3, randomized, controlled trial in Lalitpur, Nepal, in which both the participants and observers were unaware of the trial-group assignments, we randomly assigned children who were between 9 months and 16 years of age, in a 1:1 ratio, to receive either a TCV or a capsular group A meningococcal conjugate vaccine (MenA) as a control. The primary outcome was typhoid fever confirmed by blood culture. We present the prespecified analysis of the primary and main secondary outcomes (including an immunogenicity subgroup); the 2-year trial follow-up is ongoing. RESULTS: A total of 10,005 participants received the TCV and 10,014 received the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 7 participants who received TCV (79 cases per 100,000 person-years) and in 38 who received MenA vaccine (428 cases per 100,000 person-years) (vaccine efficacy, 81.6%; 95% confidence interval, 58.8 to 91.8; P<0.001). A total of 132 serious adverse events (61 in the TCV group and 71 in the MenA vaccine group) occurred in the first 6 months, and 1 event (pyrexia) was identified as being vaccine-related; the participant remained unaware of the trial-group assignment. Similar rates of adverse events were noted in the two trial groups; fever developed in 5.0% of participants in the TCV group and 5.4% in the MenA vaccine group in the first week after vaccination. In the immunogenicity subgroup, seroconversion (a Vi IgG level that at least quadrupled 28 days after vaccination) was 99% in the TCV group (677 of 683 participants) and 2% in the MenA vaccine group (8 of 380 participants). CONCLUSIONS: Typhi bacteremia in children 9 months to 16 years of age. (Funded by the Bill and Melinda Gates Foundation; Current Controlled Trials number, ISRCTN43385161.).

BACKGROUND: Enteric fever is a major global problem. Emergence of antibacterial resistance threatens to render current treatments ineffective. There is little research or public health effort directed toward Salmonella enterica serovar Paratyphi A, because it is assumed to cause less severe enteric fever than does S. enterica serovar Typhi. There are few data on which to base this assumption, little is known of the serovar's antibacterial susceptibilities, and there is no readily available tolerable vaccination. METHODS: A prospective study was conducted of 609 consecutive cases of enteric fever (confirmed by blood culture) to compare the clinical phenotypes and antibacterial susceptibilities in S. Typhi and S. Paratyphi A infections. Variables independently associated with either infection were identified to develop a diagnostic rule to distinguish the infections. All isolates were tested for susceptibility to antibacterials. RESULTS: Six hundred nine patients (409 with S. Typhi infection and 200 with S. Paratyphi A infection) presented during the study period. The infections were clinically indistinguishable and had equal severity. Nalidixic acid resistance, which predicts a poor response to fluoroquinolone treatment, was extremely common (75.25% of S. Paratyphi A isolates and 50.5% of S. Typhi isolates; P < .001). S. Paratyphi A was more likely to be resistant to ofloxacin (3.6% vs. 0.5%; P = .007) or to have intermediate susceptibility to ofloxacin (28.7% vs. 1.8%; P < .001) or ciprofloxacin (39.4% vs. 8.2%; P < .001). MICs for S. Paratyphi A were higher than for S. Typhi (MIC of ciprofloxacin, 0.75 vs. 0.38 microg/mL [P < .001]; MIC of ofloxacin, 2.0 vs. 0.75 microg/mL [P < .001]). CONCLUSIONS: The importance of S. Paratyphi A has been underestimated. Infection is common, the agent causes disease as severe as that caused by S. Typhi and is highly likely to be drug resistant. Drug resistance and lack of effective vaccination suggest that S. Paratyphi A infection may become a major world health problem.

The objective of this study was to determine the efficacy of low-dose acetazolamide (125 mg twice daily) for the prevention of acute mountain sickness (AMS). The design was a prospective, double-blind, randomized, placebo-controlled trial in the Mt. Everest region of Nepal between Pheriche (4243 m), the study enrollment site, and Lobuje (4937 m), the study endpoint. The participants were 197 healthy male and female trekkers of diverse background, and they were evaluated with the Lake Louise Acute Mountain Sickness Scoring System and pulse oximetry. The main outcome measures were incidence and severity of AMS as judged by the Lake Louise Questionnaire score at Lobuje. Of the 197 participants enrolled, 155 returned their data sheets at Lobuje. In the treatment group there was a statistically significant reduction in incidence of AMS (placebo group, 24.7%, 20 out of 81 subjects; acetazolamide group, 12.2%, 9 out of 74 subjects). Prophylaxis with acetazolamide conferred a 50.6% relative risk reduction, and the number needed to treat in order to prevent one instance of AMS was 8. Of those with AMS, 30% in the placebo group (6 of 20) versus 0% in the acetazolamide group (0 of 9) experienced a more severe degree of AMS as defined by a Lake Louise Questionnaire score of 5 or greater (p = 0.14). Secondary outcome measures associated with statistically significant findings favoring the treatment group included decrease in headache and a greater increase in final oxygen saturation at Lobuje. We concluded that acetazolamide 125 mg twice daily was effective in decreasing the incidence of AMS in this Himalayan trekking population.

NDM-producing Klebsiella pneumoniae strains represent major clinical and infection control challenges, particularly in resource-limited settings with high rates of antimicrobial resistance. Determining whether transmission occurs at a gene, plasmid, or bacterial strain level and within hospital and/or the community has implications for monitoring and controlling spread. Whole-genome sequencing (WGS) is the highest-resolution typing method available for transmission epidemiology. We sequenced carbapenem-resistant K. pneumoniae isolates from 26 individuals involved in several infection case clusters in a Nepali neonatal unit and 68 other clinical Gram-negative isolates from a similar time frame, using Illumina and PacBio technologies. Within-outbreak chromosomal and closed-plasmid structures were generated and used as data set-specific references. Three temporally separated case clusters were caused by a single NDM K. pneumoniae strain with a conserved set of four plasmids, one being a 304,526-bp plasmid carrying bla(NDM-1). The plasmids contained a large number of antimicrobial/heavy metal resistance and plasmid maintenance genes, which may have explained their persistence. No obvious environmental/human reservoir was found. There was no evidence of transmission of outbreak plasmids to other Gram-negative clinical isolates, although bla(NDM) variants were present in other isolates in different genetic contexts. WGS can effectively define complex antimicrobial resistance epidemiology. Wider sampling frames are required to contextualize outbreaks. Infection control may be effective in terminating outbreaks caused by particular strains, even in areas with widespread resistance, although this study could not demonstrate evidence supporting specific interventions. Larger, detailed studies are needed to characterize resistance genes, vectors, and host strains involved in disease, to enable effective intervention.

We report two cases which highlight the fact how poor communication leads to dangerously poor health outcome. We present the case of a 50-year-old woman recently diagnosed with rheumatoid arthritis from Southern Nepal presented to Patan hospital with multiple episodes of vomiting and oral ulcers following the intake of methotrexate every day for 11 days, who was managed in the intensive care unit. Similarly, we present a 40-year-old man with ileo-caecal tuberculosis who was prescribed with anti-tubercular therapy (ATT) and prednisolone, who failed to take ATT due to poor communication and presented to Patan Hospital with features of disseminated tuberculosis following intake of 2 weeks of prednisolone alone. These were events that could have been easily prevented with proper communication skills. Improvement of communication between doctors and patients is paramount so that life-threatening events like these could be avoided.

The worldwide increase of multidrug resistance in both community- and health-care associated bacterial infections has impaired the current antimicrobial therapy, warranting the search for other alternatives. We aimed to find the in vitro antibacterial activity of ethanolic extracts of 16 different traditionally used medicinal plants of Nepal against 13 clinical and 2 reference bacterial species using microbroth dilution method. The evaluated plants species were found to exert a range of in vitro growth inhibitory action against the tested bacterial species, and Cynodon dactylon was found to exhibit moderate inhibitory action against 13 bacterial species including methicillin-resistant Staphylococcus aureus , imipenem-resistant Pseudomonas aeruginosa , multidrug-resistant Salmonella typhi , and S. typhimurium . The minimum inhibitory concentration (MIC) values of tested ethanolic extracts were found from 31 to &gt;25,000 μ g/mL. Notably, ethanolic extracts of Cinnamomum camphora, Curculigo orchioides , and Curcuma longa exhibited the highest antibacterial activity against S. pyogenes with a MIC of 49, 49, and 195 μ g/mL, respectively; whereas chloroform fraction of Cynodon dactylon exhibited best antibacterial activity against S. aureus with a MIC of 31 μ g/mL. Among all, C. dactylon, C. camphora, C. orchioides , and C. longa plant extracts displayed a potential antibacterial activity of MIC &lt; 100 μ g/mL.

This was a retrospective study in an urban hospital in Kathmandu, Nepal to determine the changing burden of salmonella septicaemia, the proportion of Salmonella paratyphi A, and the emergence of drug-resistant organisms. The participants were outpatients and inpatients over the period 1993-2003, and the main outcome measures were blood culture isolates and antibiotic sensitivity testing. The results showed that of 82467 blood cultures performed, a bacterium was isolated from 12252. Salmonella accounted for 9124 (74.5%) of the positive blood cultures: 6447 (70.7%) were Salmonella enterica serotype Typhi (S. typhi) and 2677 (29.3%) were Paratyphi A (S. paratyphi A). In comparing the period 1997-2000 to the period 2001-2003, we found that, as a proportion of total blood cultures taken, salmonella septicaemia more than doubled, from 6.2 to 13.6% (P<0.001). From the first half of the study (1993-1998) to the second half (1999-2003), S. paratyphi A as a proportion of all salmonella isolates rose from 23 to 34% (P<0.001), which paralleled its increased resistance to ciprofloxacin. Despite the introduction of new antibiotics, enteric fever continues to grow as a cause for hospital presentation in Nepal. Salmonella paratyphi A contributes an increasingly large proportion of cases, and ciprofloxacin resistance is also emerging more rapidly in S. paratyphi A.

Intrauterine growth retardation has long been recognized at high altitude. Since growth-retarded babies have a decreased chance of survival, intrauterine growth retardation would be expected to have been selected against in populations long resident at high altitude. We have previously reported that Tibetan babies born at 3,658 m weighed more than their North or South American altitude counterparts. This study sought to determine whether Tibetans were protected from altitude-associated intrauterine growth retardation. We compared birth weights in Tibetans living at low altitude in Kathmandu, Nepal (elevation 1,200 m), or at high altitude in Lhasa, Tibet Autonomous Region, China (elevation 3,658 m). Birth weights were similar in 45 low-altitude and 34 high-altitude Tibetan births regardless of whether all infants or only full-term births were considered, or whether birth weight was adjusted for variation in maternal parity, gestational age, and infant sex. In comparison with literature observations, the altitude-associated difference in birth weight was smallest in Tibetans, intermediate in South America, and greatest in North America. These data support the hypothesis that Tibetans are protected from altitude-associated intrauterine growth retardation and suggest that selection for optimization of birth weight at high altitude has occurred in Tibetans.

Patak, Lance MD, MBA, RN; Wilson-Stronks, Amy MPP, CPHQ; Costello, John MA, CCC-SLP; Kleinpell, Ruth M. PhD, RN, FAAN; Henneman, Elizabeth A. PhD, RN; Person, Colleen MMA, BSN, RN; Happ, Mary Beth PhD, RN Author Information

The Global Alliance for Infections in Surgery appreciates the great effort of the task force who derived and validated the Sepsis-3 definitions and considers the new definitions an important step forward in the evolution of our understanding of sepsis. Nevertheless, more than a year after their publication, we have a few concerns regarding the use of the Sepsis-3 definitions.

OBJECTIVE: To determine the incidence of high-altitude cerebral edema (HACE), acute mountain sickness (AMS), and high-altitude pulmonary edema (HAPE) in pilgrims. Although it is well known that western trekkers suffer from acute mountain sickness (AMS) in the Himalayas, not much is documented about the incidence of AMS in the local population of Nepal that go to high altitude. METHODS: The design was a randomized study set at a sacred high-altitude lake at 4300 m at Gosainkund in the Nepal Himalayas. There was a control study at 1300 m at Pashupatinath in Kathmandu, Nepal. The subjects were pilgrims of different ethnic Nepali backgrounds. The Lake Louise consensus for AMS, HACE, and HAPE was used, and oxygen saturation with a pulse oximeter was performed on HACE subjects. RESULTS: Out of 5000 pilgrims, 228 were randomly chosen. Sixty-eight percent had AMS, 31% had HACE, and 5% had HAPE. The mean oxygen saturation of HACE subjects at that altitude was 77%, 87% being normal for 4300 m altitude. Seventy-three percent of the study population were men, yet women had a significantly higher rate of AMS (odds ratio, 4.34; 95% confidence interval, 1.83-10.68), HACE (odds ratio 3.15, confidence interval 1.62-6.12), and HAPE (odds ratio, 5.2; 95% confidence interval, 1.24-24.73). CONCLUSIONS: Such a high incidence of HACE in an epidemiological study using the Lake Louise criteria has, to our knowledge, not been reported before. High-altitude pilgrims, especially women pilgrims in this study, seem to be a very susceptible group. Preventive measures in these pilgrims need to be adopted to avoid AMS, specifically life-threatening HACE and HAPE.

PURPOSE OF REVIEW: Increasing antimicrobial resistance in Salmonella Typhi is a serious public health concern, especially in industrializing countries. Here we review recent clinical and laboratory data concerning the evolution of antimicrobial resistance, with particular reference to the emergence resistance against fluoroquinolones, third generation cephalosporins, and azithromycin. RECENT FINDINGS: The last 40 years have witnessed the sequential emergence of resistance to all first-line antimicrobials used in the treatment of S. Typhi infections. Multidrug resistance (MDR), defined by resistance to chloramphenicol, amoxicillin, and co-trimoxazole, emerged in the 1990s, followed rapidly by reduced susceptibility to fluoroquinolones. In the current decade, high-level fluoroquinolone resistance has emerged in south Asia and threatens to spread worldwide. Increasing reliance is now being placed on the activity of third generation cephalosporins and azithromycin, but resistance against these agents is developing. Carbapenems and tigecycline may be alternatives, although clinical data are sparse, and in some settings reversion to chloramphenicol and co-trimoxazole susceptibility is occurring. Therefore, older drugs may yet have a role in the treatment of S. Typhi infections. SUMMARY: Good surveillance, improved diagnostics, more prudent use of antimicrobials, and effective vaccines will all be critical to reducing the burden of disease caused by S. Typhi.

BACKGROUND: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome. AIMS: To identify a causative gene for SOPH syndrome. METHODS: Genomewide homozygosity mapping was conducted in 33 patients in 30 families. RESULTS: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome. CONCLUSION: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.

The incidence of enteric (typhoid) fever in travelers is estimated to be approximately 3-30 cases per 100,000 travelers to developing countries. Recently, it is become clear that travelers who are visiting friends and relatives, especially travelers to the Indian subcontinent, seem to be the most vulnerable to enteric fever and require special attention for prevention. Recent concerns are the increasing incidence of paratyphoid fever in Asia, which is not covered by available typhoid vaccines, and the emergence of infections caused by antibiotic-resistant strains (including strains resistant to fluoroquinolones). Typhoid vaccination is recommended for most travelers to moderate- to high-risk countries. Because of the nonspecific clinical presentation of enteric fever, a high index of suspicion is important in febrile travelers who have traveled to areas of endemicity.

BACKGROUND: Drug resistant typhoid fever is a major clinical problem globally. Many of the first line antibiotics, including the older generation fluoroquinolones, ciprofloxacin and ofloxacin, are failing. OBJECTIVES: We performed a randomised controlled trial to compare the efficacy and safety of gatifloxacin (10 mg/kg/day) versus azithromycin (20 mg/kg/day) as a once daily oral dose for 7 days for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. METHODS: An open-label multi-centre randomised trial with pre-specified per protocol analysis and intention to treat analysis was conducted. The primary outcome was fever clearance time, the secondary outcome was overall treatment failure (clinical or microbiological failure, development of typhoid fever-related complications, relapse or faecal carriage of S. typhi). PRINCIPAL FINDINGS: We enrolled 358 children and adults with suspected typhoid fever. There was no death in the study. 287 patients had blood culture confirmed typhoid fever, 145 patients received gatifloxacin and 142 patients received azithromycin. The median FCT was 106 hours in both treatment arms (95% Confidence Interval [CI]; 94-118 hours for gatifloxacin versus 88-112 hours for azithromycin), (logrank test p = 0.984, HR [95% CI] = 1.0 [0.80-1.26]). Overall treatment failure occurred in 13/145 (9%) patients in the gatifloxacin group and 13/140 (9.3%) patients in the azithromycin group, (logrank test p = 0.854, HR [95% CI] = 0.93 [0.43-2.0]). 96% (254/263) of the Salmonella enterica serovar Typhi isolates were resistant to nalidixic acid and 58% (153/263) were multidrug resistant. CONCLUSIONS: Both antibiotics showed an excellent efficacy and safety profile. Both gatifloxacin and azithromycin can be recommended for the treatment of typhoid fever particularly in regions with high rates of multidrug and nalidixic acid resistance. The cost of a 7-day treatment course of gatifloxacin is approximately one third of the cost of azithromycin in Vietnam. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN67946944.

BACKGROUND: Thousand of tourists trek in the Himalayas every season and risk acute mountain sickness (AMS). Prior studies have shown that the rate of ascent is one of the primary risk factors for the development of AMS but the role of body hydration, age, gender, alcohol and medication usage, body weight, and altitude of residence continues to be in question. This study estimates the incidence of AMS at 4234 m at Pheriche in the Everest region, explores a number of risk factors predisposing trekkers to a diagnosis of AMS and attempts to quantify the relationship between the Lake Louise AMS diagnostic criteria and oxygen saturation. METHODS: Demographic data and information about risk factors felt to place trekkers at increased risk of AMS was collected from 550 trekkers for 1 mo in the fall of 1996 at 4234 m in the Everest region. RESULTS: Diagnosis of AMS was made in 29.8% (159 trekkers) of the study population. Low water intake (odds ratio 1.57; 95% confidence interval,1.02-2.40), the presence of respiratory symptoms (odds ratio 2.21; 95% confidence interval, 1.43-3.40), and an oxygen saturation below 85% at 4243 m (odds ratio 2.35; 95% confidence interval, 1.55-3.56) were identified as independent risk factors for AMS diagnosis in this sample. In addition, AMS risk decreased 18.7% (95% confidence interval, 3.8-31.2%) for each additional night spent between Lukla (2804 m) and the study site at 4243 m. CONCLUSION: Increased reported fluid intake decreased the risk of AMS in this cross sectional prospective study. Further studies need to be done to confirm this finding before recommendations can be made. In addition the rise in the risk of AMS as the rate of ascent increased along this popular Everest trek was quantified for the first time. Finally, AMS was also associated with respiratory symptoms and with a lower oxygen saturation.

BACKGROUND: Typhoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up. METHODS: We did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing. FINDINGS: From Nov 20, 2017, to April 9, 2018, of 20 119 children screened, 20 019 participants were randomly assigned to receive TCV or MenA vaccine. There were 75 cases of blood culture-confirmed typhoid fever included in the analysis (13 in the TCV group and 62 in the MenA group) over the 2-year period. The protective efficacy of TCV against blood culture-confirmed typhoid fever at 2 years was 79·0% (95% CI 61·9-88·5; p<0·0001). The incidence of typhoid fever was 72 (95% CI 38-123) cases per 100 000 person-years in the TCV group and 342 (95% CI 262-438) cases per 100 000 person-years in the MenA group. Adverse events occurring within the first 7 days post-vaccination were reported previously. INTERPRETATION: The final results of this randomised, controlled trial are in keeping with the results of our published interim analysis. There is no evidence of waning protection over a 2-year period. These findings add further support for the WHO recommendations on control of enteric fever. FUNDING: Bill & Melinda Gates Foundation.

Monitoring and prediction of the climatic phenomenon are of keen interest in recent years because it has great influence in the lives of people and their environments. This paper is aimed at reporting the variation of daily and monthly solar radiation, air temperature, relative humidity (RH), and dew point over the year of 2013 based on the data obtained from the weather station situated in Damak, Nepal. The result shows that on a clear day, the variation of solar radiation and RH follows the Gaussian function in which the first one has an upward trend and the second one has a downward trend. However, the change in air temperature satisfies the sine function. The dew point temperature shows somewhat complex behavior. Monthly variation of solar radiation, air temperature, and dew point shows a similar pattern, lower at winter and higher in summer. Maximum solar radiation (331 Wm -2 ) was observed in May and minimum (170 Wm -2 ) in December. Air temperature and dew point had the highest value from June to September nearly at 29°C and 25°C, respectively. The lowest value of the relative humidity (55.4%) in April indicates the driest month of the year. Dew point was also calculated from the actual readings of air temperature and relative humidity using the online calculator, and the calculated value showed the exact linear relationship with the observed value. The diurnal and nocturnal temperature of each month showed that temperature difference was relatively lower (less than 10°C) at summer rather than in winter.