Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations

Postoperative Nausea and Vomiting in Diagnostic Gynaecological Laparoscopic Procedures: Comparison of the Efficacy of the Combination of Dexamethasone and Metoclopramide with that of Dexamethasone and Ondansetron

BACKGROUND AND OBJECTIVE: This study was conducted in a tertiary hospital with the aim of comparing the efficacy of a combination of dexamethasone and metoclopramide with dexamethasone and ondansetron for the prophylaxis of postoperative nausea and vomiting [PONV] after diagnostic gynaecological laparoscopic procedures. SUBJECTS AND METHODS: In this prospective, randomised, double-blind study, 120 women received either saline I.V. [Group I, n=40]; a combination of dexamethasone [8 mg] with metoclopramide [10 mg] [Group II, n=40]; or a combination of dexamethasone [8 mg] with ondansetron [4 mg] [Group III, n=40] prior to induction of general anaesthesia. PONV was evaluated at regular intervals. The results were analysed using one-way ANOVA, post-hoc, Chi-square, Kruskal-Wallace tests and Z test for proportions where appropriate through a SPSS V.9 package. RESULTS: The 3 groups were well matched for demographic characteristics. The incidence of nausea and emesis was significantly lower in Group III {[17.5%, P <0.02] and [10%, P <0.01] respectively}. Nausea scores were also lower in Group III [P <0.02]. Rescue anti-emetic requirements were higher in Group I [P <0.05] as compared to Groups II and III. CONCLUSIONS: A combination of dexamethasone and ondansetron was more efficacious as compared to that of metoclopramide and dexamethasone. The combination of metoclopramide and dexamethasone seems to offer no additional benefit as compared to saline placeb

Original Article - Postoperative Nausea and Vomiting in Diagnostic Gynaecological Laparoscopic Procedures: Comparison of the Efficacy of the Combination of Dexamethasone and Metoclopramide with that of Dexamethasone and Ondansetron

BACKGROUND AND OBJECTIVE: This study was conducted in a tertiary hospital with the aim of comparing the efficacy of a combination of dexamethasone and metoclopramide with dexamethasone and ondansetron for the prophylaxis of postoperative nausea and vomiting [PONV] after diagnostic gynaecological laparoscopic procedures. SUBJECTS AND METHODS: In this prospective, randomised, double-blind study, 120 women received either saline I.V. [Group I, n=40]; a combination of dexamethasone [8 mg] with metoclopramide [10 mg] [Group II, n=40]; or a combination of dexamethasone [8 mg] with ondansetron [4 mg] [Group III, n=40] prior to induction of general anaesthesia. PONV was evaluated at regular intervals. The results were analysed using one-way ANOVA, post-hoc, Chi-square, Kruskal-Wallace tests and Z test for proportions where appropriate through a SPSS V.9 package. RESULTS: The 3 groups were well matched for demographic characteristics. The incidence of nausea and emesis was significantly lower in Group III {[17.5%, P <0.02] and [10%, P <0.01] respectively}. Nausea scores were also lower in Group III [P <0.02]. Rescue anti-emetic requirements were higher in Group I [P <0.05] as compared to Groups II and III. CONCLUSIONS: A combination of dexamethasone and ondansetron was more efficacious as compared to that of metoclopramide and dexamethasone. The combination of metoclopramide and dexamethasone seems to offer no additional benefit as compared to saline placebo

Percutaneous tracheostomy by guidewire dilating forceps technique: review of 98 patients.

BACKGROUND: Percutaneous tracheostomy to a large extent has replaced conventional surgical tracheostomy by virtue of its low incidence of complications and the rapidity with which the procedure can be performed at the bedside avoiding transport of critically ill patients to the operating rooms. Since it is a blind approach, bronchoscopic guidance has been suggested which might not always be possible due to logistic reasons. METHODS: A retrospective study of 98 patients who had guide wire dilating forceps technique of percutaneous tracheostomy without the aid of a bronchoscope was undertaken. By ensuring the free mobility of the guide wire at each step of the procedure, a safe placement of the tracheostomy tube was achieved. RESULTS: The mean operating time was 3.05 mins [S.D:2.20]. Two patients had peristomal bleeding as an early complication. 34 patients could be decannulated with good primary approximation of the stomal tissues [mean: 3.92days, S.D: 1.46]. There were no deaths or life threatening complications attributable to this technique. CONCLUSIONS: In the absence of bronchoscopic guidance, adopting the simple but effective precaution of free movement of guide wire at each step of the procedure, a safe tracheostomy tube placement is possible

Brief Report - Percutaneous Tracheostomy by Guidewire Dilating Forceps Technique: Review of 98 Patients

BACKGROUND: Percutaneous tracheostomy to a large extent has replaced conventional surgical tracheostomy by virtue of its low incidence of complications and the rapidity with which the procedure can be performed at the bedside avoiding transport of critically ill patients to the operating rooms. Since it is a blind approach, ponchoscopic guidance has been suggested which might not always be possible due to logistic reasons. METHODS: A retrospective study of 98 patients who had guide wire dilating forceps technique of percutaneous tracheostomy without the aid of a ponchoscope was undertaken. By ensuring the free mobility of the guide wire at each step of the procedure, a safe placement of the tracheostomy tube was achieved. RESULTS: The mean operating time was 3.05 mins [S.D:2.20]. Two patients had peristomal bleeding as an early complication. 34 patients could be decannulated with good primary approximation of the stomal tissues [mean: 3.92days, S.D: 1.46]. There were no deaths or life threatening complications attributable to this technique. CONCLUSIONS: In the absence of ponchoscopic guidance, adopting the simple but effective precaution of free movement of guide wire at each step of the procedure, a safe tracheostomy tube placement is possible

Are there dangers in biologic dose reduction strategies?

Biologic dose reduction strategies, for patients with inflammatory rheumatic diseases, have been assessed in multiple studies to assess outcomes compared to ongoing maintenance dosing. Whilst cessation in established disease usually leads to disease flare, dose tapering approaches for those achieving low disease activity often appear to be successful in the short term. However, tapering can be associated with a higher risk of losing disease control and rates of recapture of disease control using the original biologic dose vary between studies.Over relatively short periods of follow-up, a number of studies have shown no statistical difference in radiographic progression in patients tapering or discontinuing biologics. However, a Cochrane review found that radiographic and functional outcomes may be worse after TNF inhibitor discontinuation, and over long-term disease follow-up flares have been associated with radiographic progression and worse patient reported outcomes. To date, no studies of biological therapy dose reduction have specifically investigated the risk of increased immunogenicity or the effects on cardiovascular risk and other co-morbidities, although these remain important potential risks. In addition, whether there are greater dangers in certain dose reduction approaches such as a reduction in dose at the same frequency or a spacing of doses is not established

Brief Report - Percutaneous Tracheostomy by Guidewire Dilating Forceps Technique: Review of 98 Patients

BACKGROUND: Percutaneous tracheostomy to a large extent has replaced conventional surgical tracheostomy by virtue of its low incidence of complications and the rapidity with which the procedure can be performed at the bedside avoiding transport of critically ill patients to the operating rooms. Since it is a blind approach, ponchoscopic guidance has been suggested which might not always be possible due to logistic reasons. METHODS: A retrospective study of 98 patients who had guide wire dilating forceps technique of percutaneous tracheostomy without the aid of a ponchoscope was undertaken. By ensuring the free mobility of the guide wire at each step of the procedure, a safe placement of the tracheostomy tube was achieved. RESULTS: The mean operating time was 3.05 mins [S.D:2.20]. Two patients had peristomal bleeding as an early complication. 34 patients could be decannulated with good primary approximation of the stomal tissues [mean: 3.92days, S.D: 1.46]. There were no deaths or life threatening complications attributable to this technique. CONCLUSIONS: In the absence of ponchoscopic guidance, adopting the simple but effective precaution of free movement of guide wire at each step of the procedure, a safe tracheostomy tube placement is possible