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The reliability and accuracy of five portable blood lactate (BLa) analysers (Lactate Pro, Lactate Pro2, Lactate Scout+, Xpress™, and Edge) and one handheld point-of-care analyser (i-STAT) were compared to a criterion (Radiometer ABL90). Two devices of each brand of analyser were assessed using 22 x 6 mL blood samples taken from five subjects at rest and during exercise who generated lactate ranging ~1-23 mM. Each sample was measured simultaneously ~6 times on each device. Reliability was assessed as the within-sample standard deviation (wsSD) of the six replicates; accuracy as the bias compared with the ABL90; and overall error (the root mean squared error (√MSE)) was calculated as the square root of (wsSD(2) and bias(2)). The √MSE indicated that both the Edge and Xpress had low total error (~0-2 mM) for lactate concentrations <15 mM, whereas the Edge and Lactate Pro2 were the better of the portable analysers for concentrations >15 mM. In all cases, bias (negative) was the major contribution to the √MSE. In conclusion, in a clinical setting where BLa is generally <15 mM the Edge and Xpress devices are relevant, but for athlete testing where peak BLa is important for training prescription the Edge and Lactate Pro2 are preferred. Key pointsThe reliability of five common portable blood lactate analysers were generally <0.5 mM for concentrations in the range of ~1.0-10 mM.For all five portable analysers, the analytical error within a brand was much smaller than the biological variation in blood lactate (BLa).Compared with a criterion blood lactate analyser, there was a tendency for all portable analysers to under-read (i.e. a negative bias), which was particularly evident at the highest concentrations (BLa ~15-23 mM).The practical application of these negative biases would overestimate the ability of the athlete and prescribe a training intensity that would be too high.

Three portable blood lactate analysers, Lactate Pro (LP), Lactate Scout (LS) and Lactate Plus (L + ), were evaluated. Analyser reliability and accuracy was assessed. For reliability, intra- and inter-analyser comparisons demonstrated that the LP (intra-TE = 0.5 mM, inter-TE = 0.4 mM) and L + (intra-TE = 0.4, inter-TE = 0.4 mM) displayed greater overall reliability than the LS (intra-TE = 1.0, inter-TE = 0.8 mM). At BLa < 4.0 mM, the LP (intra-TE = 0.1 mM) demonstrated greater reliability than the LS (intra-TE = 0.5 mM) and L + (intra-TE = 0.4 mM). At BLa > 8.0 mM, the LP (intra-TE = 0.5 mM, inter-TE = 0.4 mM) and L + (intra- and inter-TE = 0.4 mM) displayed greater reliability than the LS (intra-TE = 1.1 mM, inter-TE = 0.9 mM). For accuracy, the L + (SEE = 0.6 mM) compared more favourably to the LP than the LS (SEE = 1.1 mM). At BLa ~1.0–18.0 mM, the LS produced values that were up to 0.9 mM higher than the LP; the L + produced BLa that were within ±0.1 mM. All portable analysers tended to under-read the ABL 700 analyser. The suitability of the LP and L + as accurate analysers is supported by strong correlations ( r  = 0.91 and r  = 0.94) and limits of agreement ≤2.1 mM. This study showed that the LP and L + , compared well to each other, displayed good reliability and accuracy when compared to a laboratory-based analyser. Although the LS also displayed relatively good reliability, it was not as reliable or accurate as the LP or L + .

Dietary nitrate supplementation can enhance exercise performance in healthy people, but it is not clear if it is beneficial in COPD. We investigated the hypotheses that acute nitrate dosing would improve exercise performance and reduce the oxygen cost of submaximal exercise in people with COPD. We performed a double-blind, placebo-controlled, cross-over single dose study. Subjects were randomised to consume either nitrate-rich beetroot juice (containing 12.9 mmoles nitrate) or placebo (nitrate-depleted beetroot juice) 3 hours prior to endurance cycle ergometry, performed at 70% of maximal workload assessed by a prior incremental exercise test. After a minimum washout period of 7 days the protocol was repeated with the crossover beverage. 21 subjects successfully completed the study (age 68 ± 7 years; BMI 25.2 ± 5.5 kg/m2; FEV1 percentage predicted 50.1 ± 21.6%; peak VO2 18.0 ± 5.9 ml/min/kg). Resting diastolic blood pressure fell significantly with nitrate supplementation compared to placebo (-7 ± 8 mmHg nitrate vs. -1 ± 8 mmHg placebo; p = 0.008). Median endurance time did not differ significantly; nitrate 5.65 (3.90-10.40) minutes vs. placebo 6.40 (4.01-9.67) minutes (p = 0.50). However, isotime oxygen consumption (VO2) was lower following nitrate supplementation (16.6 ± 6.0 ml/min/kg nitrate vs. 17.2 ± 6.0 ml/min/kg placebo; p = 0.043), and consequently nitrate supplementation caused a significant lowering of the amplitude of the VO2-percentage isotime curve. Acute administration of oral nitrate did not enhance endurance exercise performance; however the observation that beetroot juice caused reduced oxygen consumption at isotime suggests that further investigation of this treatment approach is warranted, perhaps targeting a more hypoxic phenotype. ISRCTN Registry ISRCTN66099139.

Coccidioides is the fungal causative agent of Valley fever, a primarily pulmonary disease caused by inhalation of fungal arthroconidia, or spores. Although Coccidioides has been an established pathogen for 120 years and is responsible for hundreds of thousands of infections per year, little is known about when and where infectious Coccidioides arthroconidia are present within the ambient air in endemic regions. Long-term air sampling programs provide a means to investigate these characteristics across space and time. Here we present data from > 18 months of collections from 11 air sampling sites across the Phoenix, Arizona, metropolitan area. Overall, prevalence was highly variable across space and time with no obvious spatial or temporal correlations. Several high prevalence periods were identified at select sites, with no obvious spatial or temporal associations. Comparing these data with weather and environmental factor data, wind gusts and temperature were positively associated with Coccidioides detection, while soil moisture was negatively associated with Coccidioides detection. These results provide critical insights into the frequency and distribution of airborne arthroconidia and the associated risk of inhalation and potential disease that is present across space and time in a highly endemic locale.

In March 2020, US public buildings (including schools) were shut down because of the COVID-19 pandemic, and 42% of US workers resumed their employment duties from home. Some shutdowns remain in place, yet the extent of the needs of US working parents is largely unknown. To identify and address the career development, work culture, and childcare needs of faculty, staff, and trainees at an academic medical center during a pandemic. For this survey study, between August 5 and August 20, 2020, a Qualtrics survey was emailed to all faculty, staff, and trainees at University of Utah Health, an academic health care system that includes multiple hospitals, community clinics, and specialty centers. Participants included 27 700 University of Utah Health faculty, staff, and trainees who received a survey invitation. Data analysis was performed from August to November 2020. Primary outcomes included experiences of COVID-19 and their associations with career development, work culture, and childcare needs. A total of 5030 participants completed the entire survey (mean [SD] age, 40 [12] years); 3738 (75%) were women; 4306 (86%) were White or European American; 561 (11%) were Latino or Latina (of any race), Black or African American, American Indian, Alaska Native, and Native Hawaiian or Pacific Islander; and 301 (6%) were Asian or Asian American. Of the participants, 2545 (51%) reported having clinical responsibilities, 2412 (48%) had at least 1 child aged 18 years or younger, 3316 (66%) were staff, 791 (16%) were faculty, and 640 (13%) were trainees. Nearly one-half of parents reported that parenting (1148 participants [49%]) and managing virtual education for children (1171 participants [50%]) were stressors. Across all participants, 1061 (21%) considered leaving the workforce, and 1505 (30%) considered reducing hours. Four hundred forty-nine faculty (55%) and 397 trainees (60%) perceived decreased productivity, and 2334 participants (47%) were worried about COVID-19 impacting their career development, with 421 trainees (64%) being highly concerned. In this survey of 5030 faculty, staff, and trainees of a US health system, many participants with caregiving responsibilities, particularly women, faculty, trainees, and (in a subset of cases) those from racial/ethnic groups that underrepresented in medicine, considered leaving the workforce or reducing hours and were worried about their career development related to the pandemic. It is imperative that medical centers support their employees and trainees during this challenging time.

RationaleExercise participation remains low despite clear benefits. Rats engage in voluntary wheel running (VWR) that follows distinct phases of acquisition, during which VWR escalates, and maintenance, during which VWR remains stable. Understanding mechanisms driving acquisition and maintenance of VWR could lead to novel strategies to promote exercise. The two phases of VWR resemble those that occur during operant conditioning and, therefore, might involve similar neural substrates. The dorsomedial (DMS) dorsal striatum (DS) supports the acquisition of operant conditioning, whereas the dorsolateral striatum (DLS) supports its maintenance.ObjectivesHere we sought to characterize the roles of DS subregions in VWR. Females escalate VWR and operant conditioning faster than males. Thus, we also assessed for sex differences.MethodsTo determine the causal role of DS subregions in VWR, we pharmacologically inactivated the DMS or DLS of adult, male and female, Long-Evans rats during the two phases of VWR. The involvement of DA receptor 1 (D1)–expressing neurons in the DS was investigated by quantifying cfos mRNA within this neuronal population.ResultsWe observed that, in males, the DMS and DLS are critical for VWR exclusively during acquisition and maintenance, respectively. In females, the DMS is also critical only during acquisition, but the DLS contributes to VWR during both VWR phases. DLS D1 neurons could be an important driver of VWR escalation during acquisition.ConclusionsThe acquisition and maintenance of VWR involve unique neural substrates in the DS that vary by sex. Results reveal targets for sex-specific strategies to promote exercise.

Background For patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn’t worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. Methods ELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O 6 -methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m 2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life. Discussion ELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials. Trial registrations EudraCT Number: 2020-004771-41 (issued 01 October 2020); ISCRTN11398887 (registered 14 July 2021).

Background Elevated ovarian hormones during fear extinction can enhance fear extinction memory retention and reduce fear renewal, but the mechanisms remain unknown. High levels of ovarian hormones are associated with heightened dopamine (DA) transmission, a key player in fear extinction. In males, stimulation of substantia nigra (SN) DA neurons during fear extinction reduces renewal; an effect mimicked by DA D1 receptor agonist administration into the dorsolateral striatum (DLS), a primary target of the SN. The current studies tested the role of the SN-DLS pathway in estrous cycle-modulation of fear extinction and relapse. Methods Male and female Long-Evans rats were used to investigate the effects of sex and ovarian hormone levels during fear extinction on later fear relapse and underlying mechanisms. Fear extinction-induced cFos in SN DA neurons was quantified with double-label immunohistochemistry. An intersectional chemogenetic approach was used to determine whether SN-DLS pathway activity during fear extinction is necessary and sufficient for observed effects of ovarian hormones on fear relapse. Finally, fast scan cyclic voltammetry revealed the effects of sex and ovarian hormones on electrically-evoked DA release in the DLS and verified the effectiveness of chemogenetic approaches. Results Female rats exposed to fear extinction during proestrus or estrus (Pro/Est; high hormones) had less relapse (renewal and spontaneous recovery) compared to males or females exposed to fear extinction during metestrus or diestrus (Met/Di; low hormones). Fear extinction-induced cFos within SN DA neurons and electrically-evoked DA release in the DLS was highest in female rats during Pro/Est. The behavioral and neurochemical effects of Pro/Est were mimicked by estradiol administration to ovariectomized female rats. Inhibition of the SN-DLS pathway suppressed electrically-evoked DA release in the DLS and restored fear renewal in females exposed to simultaneous fear extinction and SN-DLS inhibition during Pro/Est. Conversely, stimulation of the SN-DLS pathway during extinction reduced fear renewal in males. Conclusions Results indicate that ovarian hormones present during fear extinction reduce later fear relapse through a SN-DLS dopamine pathway. Data suggest the SN-DLS DA pathway is a novel target for the reduction of fear relapse in both sexes. Plain Language summary Women are at higher risk than men for common psychiatric disorders such as post-traumatic stress disorder. Exposure therapy is used to treat these disorders whereby subjects learn that cues previously paired with trauma no longer predict danger. However, the efficacy of exposure therapy is limited by the return of fear (relapse), even after successful fear extinction. Research is needed to better understand sex differences in the processes governing fear extinction learning and relapse. Levels of ovarian hormones present during fear extinction can influence the strength of fear extinction memory and relapse, but the mechanisms underlying the effect of ovarian hormones remain unknown. Due to an emerging role for dopamine (DA) and the substantia nigra-to-dorsolateral striatum (SN-DLS) DA pathway in relapse-resistant fear extinction, we investigated the involvement of the SN-DLS DA pathway in ovarian hormone-modulation of fear extinction and relapse. We observe that females with elevated ovarian hormones during fear extinction have less fear relapse compared to males and females with low ovarian hormones, an effect attributable to estradiol. Elevated ovarian hormones potentiated DA neural activity during fear extinction in the SN and DA release in the DLS, while inhibition of the SN-DLS pathway during fear extinction restores fear relapse in females exposed to fear extinction in the presence of high ovarian hormones. Additionally, stimulation of the SN-DLS pathway during fear extinction reduces relapse in males. The results of this study implicate the SN-DLS pathway as a novel target for the reduction of relapse in both sexes. Highlights High levels of ovarian hormones during fear extinction is associated with low levels of fear relapse in adult, female rats. Electrically-evoked dopamine release in the dorsolateral striatum is potentiated by estradiol and is highest in phases of the estrous cycle characterized by high levels of ovarian hormones. Activity of substantia nigra dopamine neurons during fear extinction is greatest in females exposed to fear extinction during estrous cycle phases associated with high levels of ovarian hormones. Inhibition of the substantia nigra-to-dorsolateral striatum pathway during fear extinction restores fear relapse in females exposed to extinction during conditions of high ovarian hormones. Stimulation of the substantia nigra-to-dorsolateral striatum pathway during fear extinction reduces fear relapse in males.

RationaleDietary nitrate supplementation has been proposed as a strategy to improve exercise performance, both in healthy individuals and in people with COPD. We aimed to assess whether it could enhance the effect of pulmonary rehabilitation (PR) in COPD.MethodsThis double-blind, placebo-controlled, parallel group, randomised controlled study performed at four UK centres, enrolled adults with Global Initiative for Chronic Obstructive Lung Disease grade II–IV COPD and Medical Research Council dyspnoea score 3–5 or functional limitation to undertake a twice weekly 8-week PR programme. They were randomly assigned (1:1) to either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate), or placebo nitrate-deplete BRJ, consumed 3 hours prior to undertaking each PR session. Allocation used computer-generated block randomisation.MeasurementsThe primary outcome was change in incremental shuttle walk test (ISWT) distance. Secondary outcomes included quality of life, physical activity level, endothelial function via flow-mediated dilatation, fat-free mass index and blood pressure parameters.Results165 participants were recruited, 78 randomised to nitrate-rich BRJ and 87 randomised to placebo. Exercise capacity increased more with active treatment (n=57) than placebo (n=65); median (IQR) change in ISWT distance +60 m (10, 85) vs +30 m (0, 70), estimated treatment effect 30 m (95% CI 10 to 40); p=0.027. Active treatment also impacted on systolic blood pressure: treatment group −5.0 mm Hg (−5.0, –3.0) versus control +6.0 mm Hg (−1.0, 15.5), estimated treatment effect −7 mm Hg (95% CI 7 to −20) (p<0.0005). No significant serious adverse events or side effects were reported.ConclusionsDietary nitrate supplementation appears to be a well-tolerated and effective strategy to augment the benefits of PR in COPD.Trial registration number ISRCTN27860457.