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To assess the impact of a newly developed Central-Line Insertion Site Assessment (CLISA) score on the incidence of local inflammation or infection for CLABSI prevention.
A pre- and postintervention, quasi-experimental quality improvement study.
Setting and participants:
Adult inpatients with central venous catheters (CVCs) hospitalized in an intensive care unit or oncology ward at a large academic medical center.
We evaluated CLISA score impact on insertion site inflammation and infection (CLISA score of 2 or 3) incidence in the baseline period (June 2014–January 2015) and the intervention period (April 2015–October 2017) using interrupted times series and generalized linear mixed-effects multivariable analyses. These were run separately for days-to-line removal from identification of a CLISA score of 2 or 3. CLISA score interrater reliability and photo quiz results were evaluated.
Among 6,957 CVCs assessed 40,846 times, percentage of lines with CLISA score of 2 or 3 in the baseline and intervention periods decreased by 78.2% (from 22.0% to 4.7%), with a significant immediate decrease in the time-series analysis (P < .001). According to the multivariable regression, the intervention was associated with lower percentage of lines with a CLISA score of 2 or 3, after adjusting for age, gender, CVC body location, and hospital unit (odds ratio, 0.15; 95% confidence interval, 0.06–0.34; P < .001). According to the multivariate regression, days to removal of lines with CLISA score of 2 or 3 was 3.19 days faster after the intervention (P < .001). Also, line dwell time decreased 37.1% from a mean of 14 days (standard deviation [SD], 10.6) to 8.8 days (SD, 9.0) (P < .001). Device utilization ratios decreased 9% from 0.64 (SD, 0.08) to 0.58 (SD, 0.06) (P = .039).
The CLISA score creates a common language for assessing line infection risk and successfully promotes high compliance with best practices in timely line removal.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Space Infrared Telescope for Cosmology and Astrophysics (SPICA), the cryogenic infrared space telescope recently pre-selected for a ‘Phase A’ concept study as one of the three remaining candidates for European Space Agency (ESA's) fifth medium class (M5) mission, is foreseen to include a far-infrared polarimetric imager [SPICA-POL, now called B-fields with BOlometers and Polarizers (B-BOP)], which would offer a unique opportunity to resolve major issues in our understanding of the nearby, cold magnetised Universe. This paper presents an overview of the main science drivers for B-BOP, including high dynamic range polarimetric imaging of the cold interstellar medium (ISM) in both our Milky Way and nearby galaxies. Thanks to a cooled telescope, B-BOP will deliver wide-field 100–350
m images of linearly polarised dust emission in Stokes Q and U with a resolution, signal-to-noise ratio, and both intensity and spatial dynamic ranges comparable to those achieved by Herschel images of the cold ISM in total intensity (Stokes I). The B-BOP 200
m images will also have a factor
30 higher resolution than Planck polarisation data. This will make B-BOP a unique tool for characterising the statistical properties of the magnetised ISM and probing the role of magnetic fields in the formation and evolution of the interstellar web of dusty molecular filaments giving birth to most stars in our Galaxy. B-BOP will also be a powerful instrument for studying the magnetism of nearby galaxies and testing Galactic dynamo models, constraining the physics of dust grain alignment, informing the problem of the interaction of cosmic rays with molecular clouds, tracing magnetic fields in the inner layers of protoplanetary disks, and monitoring accretion bursts in embedded protostars.
In 2016, imported Zika virus (ZIKV) infections and the presence of a potentially competent mosquito vector (Aedes albopictus) implied that ZIKV transmission in New York City (NYC) was possible. The NYC Department of Health and Mental Hygiene developed contingency plans for a urosurvey to rule out ongoing local transmission as quickly as possible if a locally acquired case of confirmed ZIKV infection was suspected. We identified tools to (1) rapidly estimate the population living in any given 150-m radius (i.e. within the typical flight distance of an Aedes mosquito) and (2) calculate the sample size needed to test and rule out the further local transmission. As we expected near-zero ZIKV prevalence, methods relying on the normal approximation to the binomial distribution were inappropriate. Instead, we assumed a hypergeometric distribution, 10 missed cases at maximum, a urine assay sensitivity of 92.6% and 100% specificity. Three suspected example risk areas were evaluated with estimated population sizes of 479–4,453, corresponding to a minimum of 133–1244 urine samples. This planning exercise improved our capacity for ruling out local transmission of an emerging infection in a dense, urban environment where all residents in a suspected risk area cannot be feasibly sampled.
We investigated risk factors for severe acute lower respiratory infections (ALRI) among hospitalised children <2 years, with a focus on the interactions between virus and age. Statistical interactions between age and respiratory syncytial virus (RSV), influenza, adenovirus (ADV) and rhinovirus on the risk of ALRI outcomes were investigated. Of 1780 hospitalisations, 228 (12.8%) were admitted to the intensive care unit (ICU). The median (range) length of stay (LOS) in hospital was 3 (1–27) days. An increase of 1 month of age was associated with a decreased risk of ICU admission (rate ratio (RR) 0.94; 95% confidence intervals (CI) 0.91–0.98) and with a decrease in LOS (RR 0.96; 95% CI 0.95–0.97). Associations between RSV, influenza, ADV positivity and ICU admission and LOS were significantly modified by age. Children <5 months old were at the highest risk from RSV-associated severe outcomes, while children >8 months were at greater risk from influenza-associated ICU admissions and long hospital stay. Children with ADV had increased LOS across all ages. In the first 2 years of life, the effects of different viruses on ALRI severity varies with age. Our findings help to identify specific ages that would most benefit from virus-specific interventions such as vaccines and antivirals.
Introduction: The optimal diagnostic strategy for children presenting to the Emergency Department (ED) with suspected appendicitis (SA), the most common non-traumatic surgical emergency in children, remains unclear. This study aims to identify which investigations and management priorities are preferred by Canadian surgeons prior to consultation from the ED. Methods: An internet survey was extended to practicing surgeons who are members of the Canadian Association of Pediatric Surgeons and Canadian Association of General Surgeons. Three case-based scenarios evaluated surgeons expected ED investigations and management for SA with varying severity of disease (simple - SA vs perforated - PA) and sex (male vs female). Differences across scenarios were determined by ANOVA and direct comparisons were reported using proportions and odds ratios with 95% confidence intervals. Results: Surveys were completed by 82 surgeons. Across the 3 cases, CBC (227/246, 92.3%) and urinalysis (188/246, 76.4%) were the sole investigations expected in >75% of responses. Expectations differed across cases for use of blood cultures (p<0.001), electrolytes (p<0.001), sexually transmitted infection testing (0.015) and ultrasound (US) (p<0.001). Blood cultures (26/82, 31.7% vs 4/82, 4.9%; OR 9.05 95%CI 2.88-37.33) and electrolytes (58/82, 70.7% vs 33/82, 40.2%; OR 3.59 95%CI 1.79-7.24) were expected more often in severe disease. US was expected more often in females (58/82,70.7% vs 25/82, 30.5%; OR 5.51, 95% CI 2.68-11.38). Expected management differed across cases for fluid boluses (p=0.01), intravenous (IV) analgesia (p<0.001) and antibiotics (p<0.001), with all differences attributed to severity of illness (fluids 73/82, 89.0% vs 59/82, 72.0% OR 3.16 95%CI 1.28-8.33; IV analgesia 66/82, 80.5% vs 42/82, 51.2% OR 3.93 95%CI 1.86-8.45; antibiotics 44/82, 53.7% vs 10/82, 12.2% OR 8.34 95%CI 3.59-20.44). Conclusion: Severity of illness and sex of the child impact the ED investigations and management expected by surgeons consulted for suspected appendicitis. Further research focusing on how these expectations influence patient outcomes should be conducted. Collaborative ED-surgery protocols for the diagnosis and management of acute appendicitis in children should be established.
A combination of better management and genetic selection for good health and fertility would provide a more effective long term solution for economic loss due to diseases and poor fertility. This would also help to address public concerns about the use of medical treatment in milk production. A balance in the genetic improvement of health and fertility together with milk production could be achieved through their inclusion in national genetic selection indices, for which genetic parameters are needed. One of the main objectives of this study was to estimate genetic parameters for various disease and fertility traits in the UK dairy cattle population, using records from a national recording scheme run by Livestock Services UK Ltd. Genetic analysis of traits recorded as present or absent (binary traits; e.g. diseases) requires the use of non-linear threshold models, because linear models require normality assumptions (e.g., Gianola 1982). The other objective of this study was to estimate genetic parameters for binary disease and fertility traits based on threshold animal models and to compare results with those from linear animal models.
Central nervous system infections (CNSI) are a leading cause of death and long-term disability in children. Using ICD-10 data from 2005 to 2015 from three central hospitals in Ho Chi Minh City (HCMC), Vietnam, we exploited generalized additive mixed models (GAMM) to examine the spatial-temporal distribution and spatial and climatic risk factors of paediatric CNSI, excluding tuberculous meningitis, in this setting. From 2005 to 2015, there were 9469 cases of paediatric CNSI; 33% were ⩽1 year old at admission and were mainly diagnosed with presumed bacterial CNSI (BI) (79%), the remainder were >1 year old and mainly diagnosed with presumed non-bacterial CNSI (non-BI) (59%). The urban districts of HCMC in proximity to the hospitals as well as some outer districts had the highest incidences of BI and non-BI; BI incidence was higher in the dry season. Monthly BI incidence exhibited a significant decreasing trend over the study. Both BI and non-BI were significantly associated with lags in monthly average temperature, rainfall, and river water level. Our findings add new insights into this important group of infections in Vietnam, and highlight where resources for the prevention and control of paediatric CNSI should be allocated.
Vitamin E and selenium have been reported to improve immune function across a range of species. Ewes lambing on poor-quality dry pasture in autumn in Western Australia are at risk of being deficient in vitamin E and selenium at lambing thus predisposing their lambs to deficiencies and increasing the risk of infection and disease. This study tested the hypotheses that (i) supplementation of autumn-lambing ewes with vitamin E plus selenium in late gestation will increase the concentrations of vitamin E and selenium in plasma in the ewe and lamb and (ii) that the increased concentrations of vitamin E and selenium in plasma in the lambs will improve their innate and adaptive immune responses and thus survival. Pregnant Merino ewes were divided into a control group (n=58) which received no supplementation or a group supplemented with vitamin E plus selenium (n=55). On days 111, 125 and 140 of pregnancy ewes in the vitamin E plus selenium group were given 4 g all-rac-α-tocopherol acetate orally. On day 111 the ewes were also given 60 mg of selenium as barium selenate by subcutaneous injection. The concentrations of α-tocopherol and selenium were measured in ewes and/or lambs from day 111 of pregnancy to 14 weeks of age±10 days (weaning). Immune function of the lamb was assessed by analysing the numbers and phagocytic capacities of monocytes and polymorphonuclear leucocytes and plasma IgG and anti-tetanus toxoid antibody concentrations between birth and 14 weeks of age±10 days. Maternal supplementation with vitamin E plus selenium increased the concentration of α-tocopherol in plasma (1.13 v. 0.67 mg/l; P<0.001) and selenium in whole blood (0.12 v. 0.07 mg/l; P<0.01) of the ewes at lambing compared with controls. Supplementation also increased the concentration of α-tocopherol (0.14 v. 0.08 mg/l; P<0.001) and selenium (0.08 v. 0.05 mg/l; P<0.01) in lambs at birth compared with controls. There was no significant effect of supplementation on immune function or survival in the lambs.
Two ice cores (118.4 and 214.7 m in length) were collected in 2000 from the Puruogangri ice cap in the center of the Tibetan Plateau (TP) in a joint US-Chinese collaborative project. These cores yield paleoclimatic and environmental records extending through the Middle Holocene, and complement previous ice-core histories from the Dunde and Guliya ice caps in northeast and northwest Tibet, respectively, and Dasuopu glacier in the Himalaya. The high-resolution Puruogangri climate record since AD 1600 details regional temperature and moisture variability. The post-1920 period is characterized by above-average annual net balance, contemporaneous with the greatest 18O enrichment of the last 400 years, consistent with the isotopically inferred warming observed in other TP ice-core records. On longer timescales the aerosol history reveals large and abrupt events, one of which is dated ∼4.7 kyr BP and occurs close to the time of a drought that extended throughout the tropics and may have been associated with centuries-long weakening of the Asian/Indian/African monsoon system. The Puruogangri climate history, combined with the other TP ice-core records, has the potential to provide valuable information on variations in the strength of the monsoon across the TP during the Holocene.
We have found that 4 new, bright IRAS quasars, out of 7 observed, have strong, non-variable, wavelength-dependent polarization. Three show degrees of polarization, pλ, increasing from infrared to UV wavelengths (Fig. 1), which implies a combination of a polarized, scattered spectrum and a much redder, unpolarized spectrum. Detailed IR and optical polarimetry and spectrophotometry of one, IRAS 13349+2438 (Wills et al.), shows a polarized flux spectrum, pλxFλ, (continuum and Pa α, Hα, and Hβ broad hydrogen lines) typical of unreddened, luminous quasars. This suggests that the path of scattered light from a central, luminous quasar is low in dust and that the polarization of the scattered spectrum is wavelength independent. The latter is most easily explained by electron scattering although the data do not exclude dust scattering. When this polarized flux spectrum is subtracted from the total spectrum, we are left with a very reddened line and continuum spectrum, E(B-V) = 0.3 to 0.7, which we attribute to the same luminous quasar seen through a thick dusty torus. The angle of polarization is parallel to the major axis of the r-band image, presumed to be that of the host galaxy. If the torus is in the plane of the galaxy, the axial ratio suggests a viewing angle of 40° to the plane of the torus. Fig. 2 illustrates the geometry. The appearance of the quasar at optical and UV wavelengths will depend strongly on viewing angle, suggesting that present samples of quasars selected by colours, optical flux density, or quasi-stellar appearance, may be seriously biased, with important consequences for studies of the space density and evolution of AGN.
Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.
This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).
Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (βstd = −0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.
Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.
During May 2015, an increase in Salmonella Agona cases was reported from western Sydney, Australia. We examine the public health actions used to investigate and control this increase. A descriptive case-series investigation was conducted. Six outbreak cases were identified; all had consumed cooked tuna sushi rolls purchased within a western Sydney shopping complex. Onset of illness for outbreak cases occurred between 7 April and 24 May 2015. Salmonella was isolated from food samples collected from the implicated premise and a prohibition order issued. No further cases were identified following this action. Whole genome sequence (WGS) analysis was performed on isolates recovered during this investigation, with additional S. Agona isolates from sporadic-clinical cases and routine food sampling in New South Wales, January to July 2015. Clinical isolates of outbreak cases were indistinguishable from food isolates collected from the implicated sushi outlet. Five additional clinical isolates not originally considered to be linked to the outbreak were genomically similar to outbreak isolates, indicating the point-source contamination may have started before routine surveillance identified an increase. This investigation demonstrated the value of genomics-guided public health action, where near real-time WGS enhanced the resolution of the epidemiological investigation.
This article aims to give a comprehensive view of the distribution patterns for natural and artifical radionuclides over Antarctica. We focus this study on 137Cs, 210Pb and tritium. Applying various statistical methods, we show that the deposition of radionuclides reveals a structured distribution, although local drift redistribution and the snow-surface roughness disturb the representativeness of samples and produce a “noise” effect. The deposition of 137Cs over Antarctica (885 TBq) represents 0.09% of the total deposition of this radionuclide in the world and the correlation between 137Cs fluxes and accumulation shows two sub-populations. For the stations with a mean annual temperature above −21° C, a strong correlation is found, whereas the correlation is lower for locations with temperatures below −21° C. The flux of 210Pb varies from 0.9 to 8.2 Bq m −1 a−1 with values strongly correlated with the accumulation and a well-defined spatial structure. The same mechanism governs the deposition of artificial and natural tritium but it clearly differs from that of other radionuclides associated with particulate material. The “dry fall-out” accounts for between 60 and 80% of the total fall-out for the artificial radionuclides and around 40% for 210Pb. This difference is likely related to a tropospheric fraction for 210Pb. Despite its isolated location, the radioactive fall-out of artificial long-lived radionuclides over Antarctica has been ten times greater than for natural radionuclides.
Introduction: The suboptimal management of children’s pain in the emergency department (ED) is well described. Although surveys of physicians show improvements in providing analgesia, institutional audits suggest otherwise. One reason may be patient refusal. Our objectives were to determine the proportion of caregivers that offered analgesia prior to arrival to the ED, accept analgesia in the ED, and identify reasons for withholding analgesia. Our results will inform knowledge translation initiatives to improve analgesic provision to children. Methods: A novel survey was designed to test the hypothesis that a large proportion of caregivers withhold and refuse analgesia. Over a 16-week period across two Canadian paediatric EDs, we surveyed caregivers of children aged 4-17 years with an acutely painful condition (headache, otalgia, sore throat, abdominal pain, or musculoskeletal injury). The primary outcome was the proportion of caregivers who offered analgesia up to 24 hours prior to ED arrival and accepted analgesia in the ED. Results: The response rate was 568/707 (80.3%). The majority of caregivers were female (426/568, 75%), aged 36 years or older (434/568, 76.4%), and had a post-secondary education (448/561, 79.9%). Their children included 320 males and 248 females with a mean age of 10.6 years. Most (514/564, 91.1%) reported being “able to tell when their child was in pain”. On average, children rated their maximal pain at 7.4/10. A total of 382/561 (68.1%) caregivers did not offer any form of analgesia prior to arrival. Common reasons included lack of time (124/561, 22.1%), fear of masking signs and symptoms (74/561, 13.2%) or the seriousness of their child’s condition (72/561, 12.8%), and lack of analgesia at home (71/561, 12.7%). Analgesia was offered to 328/560 (58.6%) children in the ED and 283/328 (72.6%) caregivers accepted. The most common reason for not accepting analgesia was child refusal (20/45, 44.4%). Conclusion: Most caregivers do not offer analgesia to their child prior to arriving in the ED despite high levels of pain and an awareness of it. Despite high rates of acceptance of analgesia in the ED, misconceptions are common. Knowledge translation strategies should dispel caregiver misconceptions, and highlight the impact of pain on children and the importance of analgesia at home.
We obtained simultaneous images of solar plage on 7 May 1991 with Goddard Space Flight Center’s Solar EUV Rocket Telescope and Spectrograph (SERTS), the Very Large Array (VLA), and the NASA/NSO spectromagnetograph at Kitt Peak. Using intensity ratios of Fe XVI to Fe XV emission lines, we find that the coronal plasma temperature is 2.5 ± 0.3 ×lO6 K throughout the region. The column emission measure ranges from 2.6 × 1027 to 1.3 × 1028 cm−5. The calculated structure and intensity of the 20 cm wavelength thermal bremsstrahlung emission from the hot plasma observed by SERTS is quite similar to the observed structure and intensity of the 20 cm microwave emission observed by the VLA. Using the revised coronal iron abundance of Meyer (1991, 1992), we find no evidence for either cool absorbing plasma or for contributions from thermal gyroemission. Combining the observed microwave polarization and the SERTS plasma parameters, we calculate a map of the coronal longitudinal magnetic field. The resulting values, ~ 30 – 60 Gauss, are comparable to extrapolated values of the potential field at heights of 5,000 and 10,000 km.
The fossil record displays remarkable stasis in many species over long time periods, yet studies of extant populations often reveal rapid phenotypic evolution and genetic differentiation among populations. Recent advances in our understanding of the fossil record and in population genetics and evolutionary ecology point to the complex geographic structure of species being fundamental to resolution of how taxa can commonly exhibit both short-term evolutionary dynamics and long-term stasis.
Attentional impairment is a core cognitive feature of major depressive disorder (MDD) and bipolar disorder (BD). However, little is known of the characteristics of response time (RT) distributions from attentional tasks. This is crucial to furthering our understanding of the profile and extent of cognitive intra-individual variability (IIV) in mood disorders.
A computerized sustained attention task was administered to 138 healthy controls and 158 patients with a mood disorder: 86 euthymic BD, 33 depressed BD and 39 medication-free MDD patients. Measures of IIV, including individual standard deviation (iSD) and coefficient of variation (CoV), were derived for each participant. Ex-Gaussian (and Vincentile) analyses were used to characterize the RT distributions into three components: mu and sigma (mean and standard deviation of the Gaussian portion of the distribution) and tau (the ‘slow tail’ of the distribution).
Compared with healthy controls, iSD was increased significantly in all patient samples. Due to minimal changes in average RT, CoV was only increased significantly in BD depressed patients. Ex-Gaussian modelling indicated a significant increase in tau in euthymic BD [Cohen's d = 0.39, 95% confidence interval (CI) 0.09–0.69, p = 0.011], and both sigma (d = 0.57, 95% CI 0.07–1.05, p = 0.025) and tau (d = 1.14, 95% CI 0.60–1.64, p < 0.0001) in depressed BD. The mu parameter did not differ from controls.
Increased cognitive variability may be a core feature of mood disorders. This is the first demonstration of differences in attentional RT distribution parameters between MDD and BD, and BD depression and euthymia. These data highlight the utility of applying measures of IIV to characterize neurocognitive variability and the great potential for future application.
We investigated the prevalence, diversity, and antimicrobial resistance (AMR) profiles of non-typhoidal Salmonella (NTS) and associated risk factors on 341 pig, chicken, and duck farms in Dong Thap province (Mekong Delta, Vietnam). Sampling was stratified by species, district (four categories), and farm size (three categories). Pooled faeces, collected using boot swabs, were tested using ISO 6575: 2002 (Annex D). Isolates were serogrouped; group B isolates were tested by polymerase chain reaction to detect S. Typhimurium and (monophasic) serovar 4,,12:i:- variants. The farm-level adjusted NTS prevalence was 64·7%, 94·3% and 91·3% for chicken, duck and pig farms, respectively. Factors independently associated with NTS were duck farms [odds ratio (OR) 21·2], farm with >50 pigs (OR 11·9), pig farm with 5–50 pigs (OR 4·88) (vs. chickens), and frequent rodent sightings (OR 2·3). Both S. Typhimurium and monophasic S. Typhimurium were more common in duck farms. Isolates had a high prevalence of resistance (77·6%) against tetracycline, moderate resistance (20–30%) against chloramphenicol, sulfamethoxazole-trimethoprim, ampicillin and nalidixic acid, and low resistance (<5%) against ciprofloxacin and third-generation cephalosporins. Multidrug resistance (resistance against ⩾3 classes of antimicrobial) was independently associated with monophasic S. Typhimurium and other group B isolates (excluding S. Typhimurium) and pig farms. The unusually high prevalence of NTS on Mekong Delta farms poses formidable challenges for control.