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This single-center retrospective study of invasive fungal disease (IFD) enrolled 251 adult patients undergoing induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) from 2014–2019. Patients had primary AML (n = 148, 59%); antecedent myelodysplastic syndrome (n = 76, 30%), or secondary AML (n = 27, 11%). Seventy-five patients (30%) received an allogeneic hematopoietic cell transplant within the first year after induction chemotherapy. Proven/probable IFD occurred in 17 patients (7%). Twelve of the 17 (71%) were mold infections, including aspergillosis (n = 6), fusariosis (n = 3), and mucomycosis (n = 3). Eight breakthrough IFD (B-IFD), seven of which were due to molds, occurred in patients taking antifungal prophylaxis. Patients with proven/probable IFD had a significantly greater number of cumulative neutropenic days than those without an IFD, HR = 1.038 (95% CI 1.018–1.059), p = 0.0001. By cause-specific proportional hazards regression, the risk for IFD increased by 3.8% for each day of neutropenia per 100 days of follow up. Relapsed/refractory AML significantly increased the risk for IFD, HR = 7.562 (2.585–22.123), p = 0.0002, and Kaplan-Meier analysis showed significantly higher mortality at 1 year in patients who developed a proven/probable IFD, p = 0.02. IFD remains an important problem among patients with AML despite the use of antifungal prophylaxis, and development of IFD is associated with increased mortality in these patients.

We evaluated the performance of the (1,3)-β-d-glucan (BDG) assay on bronchoalveolar lavage fluid (BALF) as a possible aid to the diagnosis of Pneumocystis jirovecii pneumonia. BALF samples from 18 patients with well-characterized proven, probable, and possible Pneumocystis pneumonia and 18 well-matched controls were tested. We found that the best test performance was observed with a cut-off value of 128 pg/mL; receiver operating characteristic/area under the curve (ROC/AUC) was 0.70 (95% CI 0.52–0.87). Sensitivity and specificity were 78% and 56%, respectively; positive predictive value was 64%, and negative predictive value was 71%. The low specificity that we noted limits the utility of BALF BDG as a diagnostic tool for Pneumocystis pneumonia.

Detection of (1,3)-beta- d -glucan (BDG), a component of the cell wall of many fungi, was studied in bronchoalveolar lavage fluid (BALF) as a possible aid for the diagnosis of proven/probable invasive pulmonary aspergillosis (IPA). BDG was measured on stored BALF from 13 patients with EORTC/MSGERC defined proven/probable IPA and 26 matched control patients without IPA. The median BALF BDG was 80 pg/mL (range < 45–8240 pg/mL) in the IPA cohort and 148 pg/mL (range < 45–5460 pg/mL) in the non-IPA cohort. Using a positive cutoff of ≥ 80 pg/mL, sensitivity was 54% and specificity was 38%. Higher cutoff values led to improvement in specificity but a dramatic decrease in sensitivity. ROC/AUC analysis was unable to identify an optimal cutoff value at which test performance was enhanced: AUC 0.43, 95% CI 0.24–0.63. When the BDG assay was performed on BALF, neither sensitivity nor specificity was sufficient for use in the diagnosis of IPA.

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype–specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance. Integrated analysis of transcriptome, open chromatin region and chromatin conformation capture data from subjects with acute myeloid leukemia (AML) harboring defined transcription factor and signaling molecule alterations provide insights into the subtype-specific regulatory network in AML.

High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK-based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants' systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting. British Heart Foundation.

Background: Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson's disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Objectives: Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Methods: We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controlsrone case. Results: In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0-2.8] including rotenone (OR = 2.5; 95% CI, 1.3-4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2-3.6), including paraquat (OR = 2.5; 95% CI, 1.4-4.7). Conclusions: PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.

The reliability of surface electromyography (sEMG) has not been adequately demonstrated in the equine literature and is an essential consideration as a methodology for application in clinical gait analysis. This observational study investigated within-session, intra-subject (stride-to-stride) and inter-subject reliability, and between-session reliability of normalised sEMG activity profiles, from triceps brachii (triceps), latissimus dorsi (latissimus), longissimus dorsi (longissimus), biceps femoris (biceps), superficial gluteal (gluteal) and semitendinosus muscles in n = 8 clinically non-lame horses during in-hand trot. sEMG sensors were bilaterally located on muscles to collect data during two test sessions (session 1 and 2) with a minimum 24-hour interval. Raw sEMG signals from ten trot strides per horse and session were DC-offset removed, high-pass filtered (40 Hz), full-wave rectified, and low-pass filtered (25 Hz). Signals were normalised to peak amplitude and percent stride before calculating intra- and inter-subject ensemble average sEMG profiles across strides for each muscle and session. sEMG profiles were assessed using waveform similarity statistics: the coefficient of variation (CV) to assess intra- and inter-subject reliability and the adjusted coefficient of multiple correlation (CMC) to evaluate between-session reliability. Across muscles, CV data revealed that intra-horse sEMG profiles within- and between-sessions were comparatively more reliable than inter-horse profiles. Bilateral gluteal, semitendinosus, triceps and longissimus (at T14 and L1) and right biceps showed excellent between-session reliability with group-averaged CMCs > 0.90 (range 0.90–0.97). Bilateral latissimus and left biceps showed good between-session reliability with group-averaged CMCs > 0.75 (range 0.78–0.88). sEMG profiles can reliably describe fundamental muscle activity patterns for selected equine muscles within a test session for individual horses (intra-subject). However, these profiles are more variable across horses (inter-subject) and between sessions (between-session reliability), suggesting that it is reasonable to use sEMG to objectively monitor the intra-individual activity of these muscles across multiple gait evaluation sessions at in-hand trot.

New animal models of Zika virus (ZIKV) infection are imperative to accelerating efforts to treat or prevent disease in humans. Adams Waldorf et al . now report that ZIKV infection of a pregnant female pigtailed macaque caused brain lesions in the developing fetus, suggesting that this model may be useful for understanding ZIKV-associated congenital abnormalities in humans. We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital–parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.