Expression of Sympathetic Nervous System Genes in Lamprey Suggests Their Recruitment for Specification of a New Vertebrate Feature

The sea lamprey is a basal, jawless vertebrate that possesses many neural crest derivatives, but lacks jaws and sympathetic ganglia. This raises the possibility that the factors involved in sympathetic neuron differentiation were either a gnathostome innovation or already present in lamprey, but serving different purposes. To distinguish between these possibilities, we isolated lamprey homologues of transcription factors associated with peripheral ganglion formation and examined their deployment in lamprey embryos. We further performed DiI labeling of the neural tube combined with neuronal markers to test if neural crest-derived cells migrate to and differentiate in sites colonized by sympathetic ganglia in jawed vertebrates. Consistent with previous anatomical data in adults, our results in lamprey embryos reveal that neural crest cells fail to migrate ventrally to form sympathetic ganglia, though they do form dorsal root ganglia adjacent to the neural tube. Interestingly, however, paralogs of the battery of transcription factors that mediate sympathetic neuron differentiation (dHand, Ascl1 and Phox2b) are present in the lamprey genome and expressed in various sites in the embryo, but fail to overlap in any ganglionic structures. This raises the intriguing possibility that they may have been recruited during gnathostome evolution to a new function in a neural crest derivative

Cardiac structural and functional profile of patients with delayed QRS transition zone and sudden cardiac death

Delayed QRS transition zone in the precordial leads of the 12-lead electrocardiogram (ECG) has been recently associated with increased risk of sudden cardiac death (SCD), but the underlying mechanisms are unknown. We correlated echocardiographic findings with ECG and clinical characteristics to investigate how alterations in cardiac structure and function contribute to this risk marker. From the ongoing population-based Oregon Sudden Unexpected Death Study (catchment population similar to 1 million), SCD cases with prior ECG available (n = 627) were compared with controls (n = 801). Subjects with delayed transition at V-5 or later were identified, and clinical and echocardiographic patterns associated with delayed transition were analysed. Delayed transition was present in 31% of the SCD cases and 17% of the controls. These subjects were older and more likely to have cardiovascular risk factors and history of myocardial infarction. Delayed transition was associated with increased left ventricular (LV) mass (122.7 +/- 40.2 vs. 102.9 +/- 33.7 g/m(2); P <0.001), larger LV diameter (53.3 +/- 10.4 vs. 49.2 +/- 8.0 mm; P <0.001), and lower LV ejection fraction (LVEF) (46.4 +/- 15.7 vs. 55.6 +/- 12.5%; P <0.001). In multivariate analysis, delayed transition was independently associated with myocardial infarction, reduced LVEF, and LV hypertrophy. The association between delayed transition and SCD was independent of the LVEF (OR 1.57; 95% CI 1.04-2.38; P = 0.032). The underpinnings of delayed QRS transition zone extend beyond previous myocardial infarction and reduced LVEF. Since the association with sudden death is independent of these factors, this novel marker of myocardial electrical remodelling should be explored as a potential risk predictor of SCD.Peer reviewe

Outcomes of Second Combination Antiretroviral Therapy Regimens Among HIV-Infected Persons in Clinical Care: A Multicenter Cohort Study

Data on the effectiveness of second-line combination antiretroviral therapy (cART) are limited. We evaluated virologic outcomes of second cART in a multicenter cohort collaboration. The study population initiated first and second modern cART between 1996 and 2010. The second cART required a switch in at least the anchor agent of first cART. We evaluated time to virologic failure of second cART and factors associated with greater risk of failure using multivariable Cox proportional hazards models. Of 488 patients who switched to second-line cART, 67% were black and 32% were women. The median HIV-1 RNA at second cART initiation was 9,565 copies/ml [interquartile range (IQR); 123, 94,108]. The time to virologic failure of second cART was longer if HIV-1 RNA was undetectable at switch (p=0.001), although 12% and 17% of patients with undetectable and detectable HIV-1 RNA experienced virologic failure within 6 months of second cART initiation, respectively. A lower CD4 cell count at second cART initiation was associated with a greater risk of virologic failure. Failure rates decreased in more recent calendar years [adjusted relative hazard of 0.40 comparing 2008 to 2010 with 1996 to 1998 (95% confidence interval; 0.15, 1.00)]; however, type of anchor agent was not associated with failure. In conclusion, virologic failure of second cART was less likely if patients switched with undetectable HIV-1 RNA, although risk of early failure was similar. The effectiveness of second cART regimens improved over calendar time and was independent of the anchor agent in the regimen

Artificial Intelligence Model Predicts Sudden Cardiac Arrest Manifesting With Pulseless Electric Activity Versus Ventricular Fibrillation

BACKGROUND: There is no specific treatment for sudden cardiac arrest (SCA) manifesting as pulseless electric activity (PEA) and survival rates are low; unlike ventricular fibrillation (VF), which is treatable by defibrillation. Development of novel treatments requires fundamental clinical studies, but access to the true initial rhythm has been a limiting factor. METHODS: Using demographics and detailed clinical variables, we trained and tested an AI model (extreme gradient boosting) to differentiate PEA-SCA versus VF-SCA in a novel setting that provided the true initial rhythm. A subgroup of SCAs are witnessed by emergency medical services personnel, and because the response time is zero, the true SCA initial rhythm is recorded. The internal cohort consisted of 421 emergency medical services-witnessed out-of-hospital SCAs with PEA or VF as the initial rhythm in the Portland, Oregon metropolitan area. External validation was performed in 220 emergency medical services-witnessed SCAs from Ventura, CA. RESULTS: In the internal cohort, the artificial intelligence model achieved an area under the receiver operating characteristic curve of 0.68 (95% CI, 0.61-0.76). Model performance was similar in the external cohort, achieving an area under the receiver operating characteristic curve of 0.72 (95% CI, 0.59-0.84). Anemia, older age, increased weight, and dyspnea as a warning symptom were the most important features of PEA-SCA; younger age, chest pain as a warning symptom and established coronary artery disease were important features associated with VF. CONCLUSIONS: The artificial intelligence model identified novel features of PEA-SCA, differentiated from VF-SCA and was successfully replicated in an external cohort. These findings enhance the mechanistic understanding of PEA-SCA with potential implications for developing novel management strategies

Preventing child drowning in the Philippines: the need to address the determinants of health

Drowning is a public health issue in the Philippines, with children at significantly increased risk. Determinants of health (DoH) such as education, socio-economic status, ethnicity, and urbanization are factors that impact drowning risk. As drowning is a multisectoral issue, a national drowning prevention plan can drive collaboration with relevant stakeholders. This study reports trends in unintentional child (0–14 years) drowning in the Philippines (incidence, rates, and trends over time for fatal and non-fatal (years lived with a disability (YLDs) and disability adjusted life years (DALYs) from 2008–2017 and conducts an analysis of the Philippines’ Multisector Action Plan (MSAP) on Drowning Prevention. From 2008–2017, 27,928 (95%UI [Uncertainty Interval]: 22,794–33,828) children aged 0–14 years died from drowning (52.7% aged 5–14 years old). Rates of drowning have declined among both age groups, with greater reductions seen among 0–4 year olds (y = −0.3368x + 13.035; R2 = 0.9588). The MSAP has 12 child drowning-specific activities and 20 activities were identified where DoH will need to be considered during development and implementation. The MSAP activities, and work done to prevent drowning more generally, must consider DoH such as education, urbanization, water and sanitation health, and safe water transportation. A national drowning surveillance system and investment in research in the Philippines are recommended

Syncope and risk of sudden cardiac arrest in coronary artery disease

Background: Syncope has been associated with increased risk of sudden cardiac arrest (SCA) in specific patient populations, such as hypertrophic cardiomyopathy, heart failure, and long QT syndrome, but data are lacking on the risk of SCA associated with syncope among patients with coronary artery disease (CAD), the most common cause of SCA. We investigated this association among CAD patients in the community. Methods: All cases of SCA due to CAD were prospectively identified in Portland, Oregon (population approximately 1 million) as part of the Oregon Sudden Unexpected Death Study 2002-2015, and compared to geographical controls. Detailed clinical information including history of syncope and cardiac investigations was obtained from medical records. Results: 2119 SCA cases (68.4 +/- 13.8 years, 66.9% male) and 746 controls (66.7 +/- 11.7 years, 67.0% male) were included in the analysis. 143 (6.8%) of cases had documented syncope prior to the SCA. SCA cases with syncope were > 5 years older and had more comorbidities than other SCA cases. After adjusting for clinical factors and left ventricular ejection fraction (LVEF), syncope was associated with increased risk of SCA (OR 2.8; 95%CI 1.68-4.85). When analysis was restricted to subjects with LVEF >= 50%, the risk of SCA associated with syncope remained significantly elevated (adjusted OR 3.1; 95%CI 1.68-5.79). Conclusions: Syncope was associated with increased risk of SCA in CAD patients even with preserved LV function. These findings suggest a role for this clinical marker among patients with CAD and normal LVEF, a large subgroup without any current means of SCA risk stratification. (C) 2016 Published by Elsevier Ireland Ltd.Peer reviewe

Left Ventricular Geometry and Risk of Sudden Cardiac Arrest in Patients With Severely Reduced Ejection Fraction

Background-Recent reports indicate that specific left ventricular (LV) geometric patterns predict recurrent ventricular arrhythmias in patients with implantable cardioverter-defibrillators and reduced left ventricular ejection fraction (LVEF). However, this relationship has not been evaluated among patients at risk of sudden cardiac arrest (SCA) in the general population. Methods and Results-Adult SCA cases from the Oregon Sudden Unexpected Death Study were compared with geographic controls with no prior history of SCA. Archived echocardiograms performed closest and prior to the SCA event were reviewed. LV geometry was defined as normal (normal LV mass index [LVMI] and relative wall thickness [RWT]), concentric remodeling (normal LVMI and increased RWT), concentric hypertrophy (increased LVMI and RWT), or eccentric hypertrophy (increased LVMI and normal RWT). Analysis was restricted to those with LVEF Conclusions-Eccentric LV hypertrophy was independently associated with increased risk of SCA in subjects with EFPeer reviewe

Possible Loss of the Chloroplast Genome in the Parasitic Flowering Plant Rafflesia lagascae (Rafflesiaceae)

Rafflesia is a genus of holoparasitic plants endemic to Southeast Asia that has lost the ability to undertake photosynthesis. With short-read sequencing technology, we assembled a draft sequence of the mitochondrial genome of Rafflesia lagascae Blanco, a species endemic to the Philippine island of Luzon, with ∼350× sequencing depth coverage. Using multiple approaches, however, we were only able to identify small fragments of plastid sequences at low coverage depth

Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects.To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen.Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r.Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping