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Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a frequent cause of healthcare-associated infections (HAIs). The CDC Emerging Infections Program (EIP) conducted population and laboratory-based surveillance of CRPA in selected areas in 8 states from August 1, 2016, through July 31, 2018. We aimed to describe the molecular epidemiology and mechanisms of resistance of CRPA isolates collected through this surveillance. Methods: We defined a case as the first isolate of P. aeruginosa resistant to imipenem, meropenem, or doripenem from the lower respiratory tract, urine, wounds, or normally sterile sites identified from a resident of the EIP catchment area in a 30-day period; EIP sites submitted a systematic random sample of isolates to CDC for further characterization. Of 1,021 CRPA clinical isolates submitted, 707 have been sequenced to date using an Illumina MiSeq. Sequenced genomes were classified using the 7-gene multilocus sequence typing (MLST) scheme, and a core genome MLST (cgMLST) scheme was used to determine phylogeny. Antimicrobial resistance genes were identified using publicly available databases, and chromosomal mechanisms of carbapenem resistance were determined using previously validated genetic markers. Results: There were 189 sequence types (STs) among the 707 sequenced genomes (Fig. 1). The most frequently occurring were high-risk clones ST235 (8.5%) and ST298 (4.7%), which were found across all EIP sites. Carbapenemase genes were identified in 5 (<1%) isolates. Overall, 95.6% of the isolates had chromosomal mutations associated with carbapenem resistance: 93.2% had porinD-associated mutations that decrease membrane permeability to the drugs; 24.8% had mutations associated with overexpression of the multidrug efflux pump MexAB-OprM; and 22.9% had mutations associated with overexpression of the endogenous β-lactamase ampC. More than 1 such chromosomal resistance mutation type was present in 37.8% of the isolates. Conclusions: The diversity of the sequence types demonstrates that HAIs caused by CRPA can arise from a variety of strains and that high-risk clones are broadly disseminated across the EIP sites but are a minority of CRPA strains overall. Carbapenem resistance in P. aeruginosa was predominantly driven by chromosomal mutations rather than acquired mechanisms (ie, carbapenemases). The diversity of the CRPA isolates and the lack of carbapenemase genes suggest that this ubiquitous pathogen can readily evolve chromosomal resistance mechanisms, but unlike carbapenemases, these cannot be easily spread through horizontal transfer.
Refractory depression is a major contributor to the economic burden of depression. Radically open dialectical behaviour therapy (RO DBT) is an unevaluated new treatment targeting overcontrolled personality, common in refractory depression, but it is not yet known whether the additional expense of RO DBT is good value for money.
To estimate the cost-effectiveness of RO DBT plus treatment as usual (TAU) compared with TAU alone in people with refractory depression (trial registration: ISRCTN85784627).
We undertook a cost-effectiveness analysis alongside a randomised trial evaluating RO DBT plus TAU versus TAU alone for refractory depression in three UK secondary care centres. Our economic evaluation, 12 months after randomisation, adopted the perspective of the UK National Health Service (NHS) and personal social services. It evaluated cost-effectiveness by comparing the net cost of RO DBT with the net gain in quality-adjusted life-years (QALYs), estimated using the EQ-5D-3L measure of health-related quality of life.
The additional cost of RO DBT plus TAU compared with TAU alone was £7048 and was associated with a difference of 0.032 QALYs, yielding an incremental cost-effectiveness ratio (ICER) of £220 250 per QALY. This ICER was well above the National Institute for Health and Care Excellence (NICE) upper threshold of £30 000 per QALY. A cost-effectiveness acceptability curve indicated that RO DBT had a zero probability of being cost-effective compared with TAU at the NICE £30 000 threshold.
In its current resource-intensive form, RO DBT is not a cost-effective use of resources in the UK NHS.
Declaration of interest
R.H. is co-owner and director of Radically Open Ltd, the RO DBT training and dissemination company. D.K. reports grants outside the submitted work from the National Institute for Health Research (NIHR). T.L. receives royalties from New Harbinger Publishing for sales of RO DBT treatment manuals, speaking fees from Radically Open Ltd, and a grant outside the submitted work from the Medical Research Council. He was co-director of Radically Open Ltd between November 2014 and May 2015 and is married to Erica Smith-Lynch, the principal shareholder and one of two directors of Radically Open Ltd. H.O'M. reports personal fees outside the submitted work from the Charlie Waller Institute and Improving Access to Psychological Therapy. S.R. provides RO DBT supervision through her company S C Rushbrook Ltd. I.R. reports grants outside the submitted work from NIHR and Health & Care Research Wales. M. Stanton reports personal fees outside the submitted work from British Isles DBT Training, Stanton Psychological Services Ltd and Taylor & Francis. M. Swales reports personal fees outside the submitted work from British Isles DBT Training, Guilford Press, Oxford University Press and Taylor & Francis. B.W. was co-director of Radically Open Ltd between November 2014 and February 2015.
Individuals with depression often do not respond to medication or psychotherapy. Radically open dialectical behaviour therapy (RO DBT) is a new treatment targeting overcontrolled personality, common in refractory depression.
To compare RO DBT plus treatment as usual (TAU) for refractory depression with TAU alone (trial registration: ISRCTN 85784627).
RO DBT comprised 29 therapy sessions and 27 skills classes over 6 months. Our completed randomised trial evaluated RO DBT for refractory depression over 18 months in three British secondary care centres. Of 250 adult participants, we randomised 162 (65%) to RO DBT. The primary outcome was the Hamilton Rating Scale for Depression (HRSD), assessed masked and analysed by treatment allocated.
After 7 months, immediately following therapy, RO DBT had significantly reduced depressive symptoms by 5.40 points on the HRSD relative to TAU (95% CI 0.94–9.85). After 12 months (primary end-point), the difference of 2.15 points on the HRSD in favour of RO DBT was not significant (95% CI –2.28 to 6.59); nor was that of 1.69 points on the HRSD at 18 months (95% CI –2.84 to 6.22). Throughout RO DBT participants reported significantly better psychological flexibility and emotional coping than controls. However, they reported eight possible serious adverse reactions compared with none in the control group.
The RO DBT group reported significantly lower HRSD scores than the control group after 7 months, but not thereafter. The imbalance in serious adverse reactions was probably because of the controls' limited opportunities to report these.
Programmatic surveillance of intestinal schistosomiasis during control can typically use four diagnostic tests, either singularly or in combination, but these have yet to be cross-compared directly. Our study assembled a complete diagnostic dataset, inclusive of infection intensities, from 258 children from five Ugandan primary schools. The schools were purposely selected as typical of the endemic landscape near Lake Albert and reflective of high- and low-transmission settings. Overall prevalence was: 44.1% (95% CI 38.0–50.2) by microscopy of duplicate Kato-Katz smears from two consecutive stools, 56.9% (95% CI 50.8–63.0) by urine-circulating cathodic antigen (CCA) dipstick, 67.4% (95% CI 61.6–73.1) by DNA-TaqMan® and 75.1% (95% CI 69.8–80.4) by soluble egg antigen enzyme-linked immunosorbent assay (SEA-ELISA). A cross-comparison of diagnostic sensitivities, specificities, positive and negative predictive values was undertaken, inclusive of a latent class analysis (LCA) with a LCA-model estimate of prevalence by each school. The latter ranged from 9.6% to 100.0%, and prevalence by school for each diagnostic test followed a static ascending order or monotonic series of Kato-Katz, urine-CCA dipstick, DNA-TaqMan® and SEA-ELISA. We confirm that Kato-Katz remains a satisfactory diagnostic standalone in high-transmission settings but in low-transmission settings should be augmented or replaced by urine-CCA dipsticks. DNA-TaqMan® appears suitable in both endemic settings though is only implementable if resources permit. In low-transmission settings, SEA-ELISA remains the method of choice to evidence an absence infection. We discuss the pros and cons of each method concluding that future surveillance of intestinal schistosomiasis would benefit from a flexible, context-specific approach both in choice and application of each diagnostic method, rather than a single one-size fits all approach.
Research into the gut microbiota of human infants is necessary in order to better understand how inter-species interactions and ecological succession shape the diversity of the gut microbiota, and in turn, how the specific composition of the gut microbiota impacts on host health both during infancy and in later years. Blastocystis is a ubiquitous intestinal protist that has been linked to a number of intestinal and extra-intestinal diseases. However, emerging data show that asymptomatic carriage is common and that Blastocystis is prevalent in the healthy adult gut microbiota. Nonetheless, little is known about the prevalence and diversity of this microorganism in the healthy infant gut, including when and how individuals become colonized by Blastocystis. Here, we surveyed the prevalence and diversity of Blastocystis in an infant population (n = 59) from an industrialized country (Ireland) using Blastocystis-specific primers at three or more time-points up to 24 months old. Only three infants were positive for Blastocystis (prevalence = 5%) and this was only noted for samples collected at month 24. This rate is comparatively low relative to previously reported prevalence rates in the contemporaneous adult population. These data suggest that infants in Westernized countries that are successfully colonized by Blastocystis most likely acquire this microorganism via horizontal transfer.
n-3 PUFA are lipids that play crucial roles in immune-regulation, cardio-protection and neurodevelopment. However, little is known about the role that these essential dietary fats play in modulating caecal microbiota composition and the subsequent production of functional metabolites. To investigate this, female C57BL/6 mice were assigned to one of three diets (control (CON), n-3 supplemented (n3+) or n-3 deficient (n3−)) during gestation, following which their male offspring were continued on the same diets for 12 weeks. Caecal content of mothers and offspring were collected for 16S sequencing and metabolic phenotyping. n3− male offspring displayed significantly less % fat mass than n3+ and CON. n-3 Status also induced a number of changes to gut microbiota composition such that n3− offspring had greater abundance of Tenericutes, Anaeroplasma and Coriobacteriaceae. Metabolomics analysis revealed an increase in caecal metabolites involved in energy metabolism in n3+ including α-ketoglutaric acid, malic acid and fumaric acid. n3− animals displayed significantly reduced acetate, butyrate and total caecal SCFA production. These results demonstrate that dietary n-3 PUFA regulate gut microbiota homoeostasis whereby n-3 deficiency may induce a state of disturbance. Further studies are warranted to examine whether these microbial and metabolic disturbances are causally related to changes in metabolic health outcomes.
Within the World Health Organization 2012–2020 roadmap for control and elimination of schistosomiasis, the scale-up of mass drug administration with praziquantel is set to change the epidemiological landscape across Africa and Arabia. Central in measuring progress is renewed emphasis upon diagnostics which operate at individual, community and environmental levels by assessing reductions in disease, infections and parasite transmission. However, a fundamental tension is revealed between levels for present diagnostic tools, and methods applied in control settings are not necessarily adequate for application in elimination scenarios. Indeed navigating the transition from control to elimination needs careful consideration and planning. In the present context of control, we review current options for diagnosis of schistosomiasis at different levels, highlighting several strengths and weaknesses therein. Future challenges in elimination are raised and we propose that more cost-effective diagnostics and clinical staging algorithms are needed. Using the Kingdom of Saudi Arabia as a contemporary example, embedding new diagnostic methods within the primary care health system is discussed with reference to both urogenital and intestinal schistosomiasis.
The fetal and early postnatal environment can have a long-term influence on offspring growth. Using a pig model, we investigated the effects of maternal body condition (thin or fat) and maternal gestation feeding level (restricted, control or high) on maternal stress, milk composition, litter size, piglet birth weight and pre-weaning growth. A total of sixty-eight thin (backfat depth about 8 mm) and seventy-two fat (backfat depth about 12 mm) gilts were selected at about 22 weeks. This backfat difference was then accentuated nutritionally up to service at about 32 weeks. During gestation, individual gilts from within each group were randomly allocated to a gestation diet at the following feed allowances: 1·8 kg/d (restricted); 2·5 kg/d (control) and 3·5 kg/d (high) until day 90 of gestation. During gestation restricted gilts had higher levels of cortisol than high and control fed animals. Piglets born to fat gilts had higher average daily gain during the lactation period and higher weaning weights at day 28 than piglets born to thin gilts. Gilts on a high feed level had heavier piglets than those provided with restricted and control allocations. Fat gilts had less saturated fat in their milk at day 21 of lactation and higher unsaturated fat levels. No differences were found in the n-6:n-3 PUFA ratio in the milk between thin and fat gilts. In conclusion, maternal body condition influenced the daily weight gain of offspring up to weaning (day 28) and milk fat composition. Furthermore, maternal feed level during gestation alters maternal cortisol levels and milk fat composition.
Conjugated linoleic acid (CLA) reduces mammary milk fat synthesis in a dose-dependent manner. Our objective was to determine the effects of lipid-encapsulated CLA (LE-CLA) supplementation on milk production, reproductive performance and metabolic responses in lactating dairy cows fed a grass silage-based diet. Seventy-two Holstein-Friesian cows (32 primiparous and 40 multiparous) were used in a completely randomized block design. Cows received either 80 g of LE-CLA daily or 60 g of calcium salts of palm fatty acids daily (control) from parturition until 60 days in milk. LE-CLA contained a 50:50 mix of cis-9,trans-11 CLA and trans-10,cis-12 CLA, resulting in a daily intake of 6 g of each isomer. Milk production and dry matter intake were recorded daily, and blood samples were collected 3-times a week. Blood samples were analysed for circulating concentrations of glucose, non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHBA), insulin and insulin-like growth factor-I (IGF-I). Progesterone was measured in blood samples collected after the first post-partum insemination. Ovarian ultrasound examinations commenced at 8–10 d post partum and were carried out 3-times a week until first ovulation. LE-CLA treatment resulted in decreased milk fat concentration, with consequent improvements in energy balance and body condition score (BCS). The peak concentration of NEFA in blood was reduced by LE-CLA, but circulating concentrations of insulin, glucose, IGF-I, BHBA and progesterone were not affected. There was no effect of LE-CLA supplementation on the post-partum interval to first ovulation. Services per conception tended to be reduced. The reduction in milk energy output and improvement in energy status and BCS in LE-CLA-supplemented cows provides a strong rationale for further studies with greater cow numbers to test effects on reproductive performance.
It was hypothesized that differences in starch degradability account for observed differences in rumen vaccenic acid (t11-18:1) and milk rumenic acid (RA) concentrations. To test this hypothesis, starch degradability was varied through grain source and by processing. Eight Holstein cows in mid-lactation were assigned to two 4 × 4 Latin squares with four 21-day periods and four diets: dry rolled barley, ground barley, dry rolled corn and ground corn. Diets contained similar starch content and were supplemented with whole sunflower seed to provide similar total polyunsaturated fatty acid (PUFA) (18:2n-6 + 18:3n-3) contents. Forage/concentrate ratios of all diets were 42 : 58. Rumen, plasma and milk samples were collected in the third week of each period. In situ degradation rates (%/h) for rolled corn, ground corn, rolled barley and ground barley were 5.4, 8.9, 17.0 and 19.4, respectively, for dry matter (DM) and 6.3, 10.8, 25.3 and 43.8, respectively, for starch. DM intakes were greater for corn-based diets (CBD) than for barley-based diets (BBD) with no difference between rolled and ground diets. Daily minimum rumen pH was less (5.2 v. 5.5) and pH duration <5.8 (h/d) was greater (7.4 v. 4.3) for BBD than for CBD. Milk fat content and yield were less for BBD than for CBD with greater values observed for rolling compared with grinding. Variability in milk fat yield was strongly related (R2 = 0.55; P < 0.01) to total starch intake (45%) and milk c9t11-CLA (10%) and none of the t-18:1 isomers or CLA isomers that are typically associated with milk fat depression entered the model. The concentrations (%) of t10-18:1 and t11-18:1 were greater for BBD than for CBD in rumen contents (t10-18:1, 3.5 v. 1.3; t11-18:1, 3.2 v. 1.9), plasma (t10-18:1, 1.2 v. 0.2; t11-18:1, 0.97 v. 0.58) and milk (t10-18:1, 3.8 v. 1.0; t11-18:1, 2.6 v. 1.7) despite greater total PUFA intakes for CBD. Milk RA concentration was greater for BBD than for CBD (1.46 v. 0.89) but was not influenced by the method of grain processing. This study clearly demonstrated that the milk content and profile of t-18:1 and CLA isomers were more strongly influenced by the source of grain starch (barley > corn) than by the method of grain processing indicating that factors inherent in the source of starch were responsible for the observed differences and these factors could not be modified by the processing methods used in this study.
This chapter summarizes various imaging modalities in the workup of male infertility with emphasis on indications and outcome interpretation. The conditions outlined in this chapter are commonly identified causes for oligospermia and azoospermia, and are the usual targets for imaging investigations. Color Doppler ultrasound (CDUS) has become the most frequently used imaging modality for varicocele detection. Ultrasound studies of spermatic veins have suggested that the presence of multiple large veins. In CBAVD the diagnosis is established clinically by the absence of the two vasa deferentia on palpation. Intratesticular cysts include cysts of the tunica albuginea, tubular ectasia of the rete testis, and testicular cysts. Testicular microlithiasis (TM) is characterized by the presence of numerous punctate calcifications within the testis. Transrectal ultrasound (TRUS)-guided echo-enhanced seminal vesiculography in combination with transurethral resection of the ejaculatory duct (TURED) is considered the best imaging method when treating ejaculatory duct obstruction (EDO).
To audit the number of patients attending an ENT emergency clinic more than twice in the same clinical episode.
A completed audit cycle. The inclusion criterion for the retrospective arm was patients who had attended the ENT emergency clinic more than twice between 1 September to 30 November 2007. Data were analysed and interventions implemented. The re-audit, using the same inclusion criteria, was done between 1 March to 31 May 2008.
The initial audit found that 38 patients were seen more than twice in the ENT emergency clinic, giving rise to 81 ‘excess’ clinic appointments. After intervention, the re-audit identified 19 patients who were seen more than twice in the ENT emergency clinic, giving rise to 24 ‘excess’ clinic appointments.
By insisting that patients seen more than twice in the ENT emergency clinic were reviewed by a senior clinician, and by introducing a management guideline for acute otitis externa, we reduced excess clinic appointments by 70 per cent.
Methods of perceptual voice evaluation have yet to achieve satisfactory consistency; complete acceptance of a recognised clinical protocol is still some way off.
Materials and methods:
Three speech and language therapists rated the voices of 43 patients attending the problem asthma clinic of a teaching hospital, according to the grade-roughness-breathiness-asthenicity-strain (GRBAS) scale and other perceptual categories.
Results and analysis:
Use of the GRBAS scale achieved only a 64.7 per cent inter-rater reliability and a 69.6 per cent intra-rater reliability for the grade component. One rater achieved a higher degree of consistency. Improved concordance on the GRBAS scale was observed for subjects with laryngeal abnormalities. Raters failed to reach any useful level of agreement in the other categories employed, except for perceived gender.
These results should sound a note of caution regarding routine adoption of the GRBAS scale for characterising voice quality for clinical purposes. The importance of training and the use of perceptual anchors for reliable perceptual rating need to be further investigated.