Morbidity and Mortality Associated with Typhoid Fever Among Hospitalized Patients in Hyderabad District,Pakistan, 2017-2018: Retrospective Record Review

BackgroundHyderabad, Pakistan, was the first city to witness an outbreak of extensively drug resistant (XDR) typhoid fever. The outbreak strain is resistant to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporin, thus greatly limiting treatment options. However, despite over 5000 documented cases, information on mortality and morbidity has been limited.ObjectiveTo address the existing knowledge gap, this study aimed to assess the morbidity and mortality associated with XDR and non-XDR Salmonella serovar Typhi infections in Pakistan.MethodsWe reviewed the medical records of culture-confirmed typhoid cases in 5 hospitals in Hyderabad from October 1, 2016, to September 30, 2018. We recorded data on age, gender, onset of fever, physical examination, serological and microbiological test results, treatment before and during hospitalization, duration of hospitalization, complications, and deaths.ResultsA total of 1452 culture-confirmed typhoid cases, including 947 (66%) XDR typhoid cases and 505 (34%) non-XDR typhoid cases, were identified. Overall, ≥1 complications were reported in 360 (38%) patients with XDR typhoid and 89 (18%) patients with non-XDR typhoid (P<.001). Ileal perforation was the most commonly reported complication in both patients with XDR typhoid (n=210, 23%) and patients with non-XDR typhoid (n=71, 14%) (P<.001). Overall, mortality was documented among 17 (1.8%) patients with XDR S Typhi infections and 3 (0.6%) patients with non-XDR S Typhi infections (P=.06).ConclusionsAs this first XDR typhoid outbreak continues to spread, the increased duration of illness before hospitalization and increased rate of complications have important implications for clinical care and medical costs and heighten the importance of prevention and control measures.     

Disposition and efficacy of alcuronium in young children undergoing elective surgery

Alcuronium pharmacokinetics and pharmacodynamics were studied in ten patients, aged between two and six years and weighing between 10 and 20 kg, who were undergoing elective surgery. Eight patients received a single dose of alcuronium quaternary base, 0.25 mg·kg^?1; two patients required an additional dose after a similar initial dose. Alcuronium concentrations were determined using a specific liquid chromatographic procedure. In all patients, alcuronium plasma concentrations decline in a bi-exponential fashion with time. Several significant differences were noted when the pharmacokinetic parameters in children were compared with those obtained previously in adults. Young children had shorter mean distribution (5 vs 14 min, P < 0.001) and elimination phase half-lives (131 vs 199 min, P < 0.05) and a faster clearance from the body when corrected for differences in body weight (2.7 vs 1.4 ml·min^?1·kg^?1, P < 0.005). Alcuronium volumes of distribution were smaller in children compared with adults in absolute (uncorrected) terms, but no differences were observed when these were expressed relative to body weight. Maximum paralysis achieved in children was similar to that in adults, but was observed to occur more rapidly (4 vs 10 min, P < 0.005). Alcuronium plasma concentrations, at peak paralysis, were not different to those in adults (1.8 vs 1.4 μg·ml^?1). Young children eliminate alcuronium more efficiently, but exhibit the same sensitivity to alcuronium during onset of paralysis as adults.     

PHARMACOKINETICS OF TUBOCURARINE ADMINISTERED BY COMBINED I.V. BOLUS AND INFUSION

Pharmacokinetic data were used to calculate an i.v. bolus doseand infusion regimen for tubocurarine (dtc). This produced continuousparalysis in 12 anaesthetized patients. In nine of the patientsthe duration of infusion was sufficient to achieve a "steady-state"dtc concentration in the plasma (mean 1.09µg ml^–1).At the completion of the infusion, twitch response had beenabolished in half of the group, but 30 mm later all had a measurableresponse. All plasma concentrations decreased rapidly afterinfusion, from a mean of 1.35µg ml^–1, in eithera mono- or a bi-exponential manner. In all Instances, a two-compartmentopen model was used to describe the plasma concentration-timedata. The pharmacokinetic parameters derived from this studydid not differ significantly from those reported for a singledose except that the plasma clearance was less.     

Cancer incidence and mortality in Ontario First Nations, 1968-1991 (Canada)

Objective: To determine cancer incidence and mortality rates in Ontario First Nations (FN) people (native Indians) during 1968–1991 and to compare these with rates in the Ontario population. Methods: A cohort of 141,290 Ontario FN was created from registration files maintained by the Canadian government. Cancers and deaths were ascertained by linkage to the provincial cancer registry and mortality file, which also provided general population comparison data. Results: Cancer incidence was significantly lower in FN compared to the general population for all cancer (rate ratio (RR) = 0.72 for females; 0.62 for males), breast cancer (RR = 0.54), lung cancer in men (RR = 0.68), prostate cancer (RR = 0.57) and colorectal cancer (RR = 0.58 and 0.57 in men and women, respectively). Rates were significantly higher in FN for cervical cancer (RR = 1.73) and gallbladder cancer (2.05 and 2.20 in men and women, respectively). Incidence rates increased significantly in FN people between 1968–1975 and 1984–1991 for all cancer and for the major cancers (breast, lung, prostate and colorectal). Colorectal cancer rate ratios were significantly higher in 1984–1991 than in 1968–1975, indicating converging incidence rates. Patterns of cancer mortality were similar. Conclusions: These trends are compatible with a population in epidemiologic transition to the Euro-American disease pattern which is dominated by chronic diseases.     

Pharmacokinetics of alcuronium in children with acyanotic and cyanotic cardiac disease undergoing cardiopulmonary bypass surgery

The aim of this study was to determine the pharmacokinetic parameters for alcuronium in children with cyanotic or acyanotic congenital cardiac disease undergoing cardiopulmonary bypass surgery and to compare these parameters with previously reported values in children and adults with normal cardiac function. Seven children with acyanotic disease and seven with cyanotic disease were studied. Alcuronium (base) was administered in an initial dosage of 0.25 mg·kg^?1 with additional doses as needed to maintain paralysis. Using time averaged data, cyanotic children had lower mean clearance, elimination half-life and volume of distribution at steady state than the acyanotic children; none of these differences was, however, statistically significant. In this study, children with acyanotic and cyanotic cardiac disease undergoing bypass, had a diminished clearance (P < 0.05) and a smaller volume of distribution (P < 0.05) than normal children and a shorter elimination half-life (P < 0.05) than adults. Onset of cardiopulmonary bypass caused an immediate marked decrease in alcuronium plasma concentrations which remained low in the acyanotic children at the completion of bypass.     

Gene-gene interactions in breast cancer susceptibility

There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation.     

In-vitro Interaction between H2 Antagonists and Vecuronium

Abstract— The interaction between histamine H₂ antagonists and the neuromuscular blocking drug vecuronium was investigated in the rat phrenic nerve-hemidiaphragm preparation. Cimetidine alone, in the concentration range 800–4000 μm produced between 14 and 74% neuromuscular paralysis with an EC50 (mean ± s.e.) of 2900 ± 100 μm . Ranitidine augmented the indirectly-evoked muscle response at concentrations between 30 and 160 μm but at higher concentrations, between 300 and 1800 μm , produced neuromuscular paralysis. Famotidine produced negligible and statistically insignificant (0–5%) neuromuscular paralysis at concentrations between 0·3 and 300 μm . Cimetidine (800 μm ) shifted the neuromuscular concentration-effect curve of vecuronium to the left in a parallel manner, while ranitidine (160 μm ) shifted it to the right. The potentiation ratio was 1·90 ± 0·14 for cimetidine and 0·62 ± 005 for ranitidine. Famotidine (30 μm ) did not alter the response to vecuronium. These data indicate that higher than clinically relevant concentrations of cimetidine and ranitidine produce neuromuscular paralysis and may potentiate the action of vecuronium. Low concentrations of ranitidine may antagonize the action of vecuronium. Famotidine, in contrast, lacks significant neuromuscular effects.     

DOSE-RESPONSE CURVES FOR FOUR NEUROMUSCULAR BLOCKERS USING CONTINUOUS I.V. INFUSION

Cumulative dose-response curves were constructed in man forrubocurarine, pancuronium, gallamine and alcuronium from dataobtained during barbiturate-narcotic-nitrous oxide anaesthesia.Fifty-six adult patients received one of these drugs, administeredby constant-rate infusion, a technique enabling full characterizationof the sigmoid curve for each patient. The individual curveswere solved for several response levels and the results pooledto derive a composite dose-response curve for each drug. Usingthe mechanical twitch response, the ED₅₀ for each neuromuscularblocking drug was: tubocurarine 0.236 mg kg^–1, pancuronium0.048 mg kg^–1, gallamine 1.3 mg kg^–1 and alcuronium0.161 mg kg^–1. The slopes of the composite curves forpancuronium and alcuronium were significantly steeper than thosefor tubocurarine and gallamine. In the alcuronium studies thesimultaneous compound electromyogram was recorded, and usuallythis was more depressed than the mechanical twitch response,giving an ED₅₀ of 0.135 mg kg^–1.     

In search of a healing place: Aboriginal women in Vancouver's Downtown Eastside

Research on general health service delivery in urban areas of Canada shows that Aboriginal people face formidable barriers in accessing culturally appropriate and timely care. Over the past decade, Urban Aboriginal Health Centres (UAHCs) have emerged to address the unmet health concerns of Aboriginal people living in metropolitan areas of the country. The purpose of this research was to address the gap in social science literature on how the health care concerns of Aboriginal women are being met by UAHCs. The research aimed to give voice to Aboriginal women by asking them whether the appropriate professional services and educational programs they need to address their health care needs were being provided in the inner city. A case-study approach was used whereby three separate focus groups were conducted with Aboriginal women who were clients of the Vancouver Native Health Society (VNHS), its sister organization, Sheway, or residents of Vancouver's Downtown Eastside (DTES). In addition, twenty-five semi-structured interviews were conducted with VNHS staff, health providers, government representatives, and community leaders in health care (total n=61). The findings indicate that despite efforts from various quarters to articulate the health and social concerns of the country's marginalized populations, such has not been the case for Aboriginal women living in one of Canada's most prosperous cities. Many Aboriginal women expressed a strong desire for a Healing Place, based on a model of care where their health concerns are addressed in an integrated manner, where they are respected and given the opportunity to shape and influence decision-making about services that impact their own healing.