GABA release from interneurons in VTA, projections from the nucleus accumbens (NAc), and rostromedial tegmental nucleus (RMTg) was selectively activated in rat brain slices. The inhibition induced by ...μ-opioid agonists was pathway dependent. Morphine induced a 46% inhibition of IPSCs evoked from the RMTg, 18% from NAc, and IPSCs evoked from VTA interneurons were almost insensitive (11% inhibition). In vivo morphine treatment resulted in tolerance to the inhibition of RMTg, but not local interneurons or NAc, inputs. One common sign of opioid withdrawal is an increase in adenosine-dependent inhibition. IPSCs evoked from the NAc were potently inhibited by activation of presynaptic adenosine receptors, whereas IPSCs evoked from RMTg were not changed. Blockade of adenosine receptors selectively increased IPSCs evoked from the NAc during morphine withdrawal. Thus, the acute action of opioids, the development of tolerance, and the expression of withdrawal are mediated by separate GABA afferents to dopamine neurons.
•GABA pathways to dopamine neurons are selectively sensitive to μ-opioid agonists•GABA pathways to dopamine neurons are selectively sensitive to adenosine agonists•Pathways that are most sensitive to opioids and adenosine are different•Morphine withdrawal is expressed selectively at terminals from nucleus accumbens
Matsui et al. studied three opioid-sensitive GABA inputs to VTA dopamine neurons. The balance between initial sensitivity, development of tolerance, and expression of withdrawal were different for each pathway. Thus, different neuronal pathways regulate the three stages of opioid action.
Effective HIV prevention programs rely on accurate estimates of the per-act risk of HIV acquisition from sexual and parenteral exposures. We updated the previous risk estimates of HIV acquisition ...from parenteral, vertical, and sexual exposures, and assessed the modifying effects of factors including condom use, male circumcision, and antiretroviral therapy.
We conducted literature searches to identify new studies reporting data regarding per-act HIV transmission risk and modifying factors. Of the 7339 abstracts potentially related to per-act HIV transmission risk, three meta-analyses provided pooled per-act transmission risk probabilities and two studies provided data on modifying factors. Of the 8119 abstracts related to modifying factors, 15 relevant articles, including three meta-analyses, were included. We used fixed-effects inverse-variance models on the logarithmic scale to obtain updated estimates of certain transmission risks using data from primary studies, and employed Poisson regression to calculate relative risks with exact 95% confidence intervals for certain modifying factors.
Risk of HIV transmission was greatest for blood transfusion, followed by vertical exposure, sexual exposures, and other parenteral exposures. Sexual exposure risks ranged from low for oral sex to 138 infections per 10,000 exposures for receptive anal intercourse. Estimated risks of HIV acquisition from sexual exposure were attenuated by 99.2% with the dual use of condoms and antiretroviral treatment of the HIV-infected partner.
The risk of HIV acquisition varied widely, and the estimates for receptive anal intercourse increased compared with previous estimates. The risk associated with sexual intercourse was reduced most substantially by the combined use of condoms and antiretroviral treatment of HIV-infected partners.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiology of coronavirus disease 2019 (COVID-19), is readily transmitted person to person. Optimal control of COVID-19 depends on ...directing resources and health messaging to mitigation efforts that are most likely to prevent transmission, but the relative importance of such measures has been disputed.
To assess the proportion of SARS-CoV-2 transmissions in the community that likely occur from persons without symptoms.
This decision analytical model assessed the relative amount of transmission from presymptomatic, never symptomatic, and symptomatic individuals across a range of scenarios in which the proportion of transmission from people who never develop symptoms (ie, remain asymptomatic) and the infectious period were varied according to published best estimates. For all estimates, data from a meta-analysis was used to set the incubation period at a median of 5 days. The infectious period duration was maintained at 10 days, and peak infectiousness was varied between 3 and 7 days (-2 and +2 days relative to the median incubation period). The overall proportion of SARS-CoV-2 was varied between 0% and 70% to assess a wide range of possible proportions.
Level of transmission of SARS-CoV-2 from presymptomatic, never symptomatic, and symptomatic individuals.
The baseline assumptions for the model were that peak infectiousness occurred at the median of symptom onset and that 30% of individuals with infection never develop symptoms and are 75% as infectious as those who do develop symptoms. Combined, these baseline assumptions imply that persons with infection who never develop symptoms may account for approximately 24% of all transmission. In this base case, 59% of all transmission came from asymptomatic transmission, comprising 35% from presymptomatic individuals and 24% from individuals who never develop symptoms. Under a broad range of values for each of these assumptions, at least 50% of new SARS-CoV-2 infections was estimated to have originated from exposure to individuals with infection but without symptoms.
In this decision analytical model of multiple scenarios of proportions of asymptomatic individuals with COVID-19 and infectious periods, transmission from asymptomatic individuals was estimated to account for more than half of all transmissions. In addition to identification and isolation of persons with symptomatic COVID-19, effective control of spread will require reducing the risk of transmission from people with infection who do not have symptoms. These findings suggest that measures such as wearing masks, hand hygiene, social distancing, and strategic testing of people who are not ill will be foundational to slowing the spread of COVID-19 until safe and effective vaccines are available and widely used.
In this study we compared 3.7 million rawinsonde observations from 232 stations over Europe and North America with proximal vertical profiles from ERA5 and MERRA-2 to examine how well reanalysis ...depicts observed convective parameters. Larger differences between soundings and reanalysis are found for thermodynamic theoretical parcel parameters, low-level lapse rates, and low-level wind shear. In contrast, reanalysis best represents temperature and moisture variables, mid-tropospheric lapse rates, and mean wind. Both reanalyses underestimate CAPE, low-level moisture, and wind shear, particularly when considering extreme values. Overestimation is observed for low-level lapse rates, midtropospheric moisture, and the level of free convection. Mixed-layer parcels have overall better accuracy when compared to most-unstable parcels, especially considering convective inhibition and lifted condensation level. Mean absolute error for both reanalyses has been steadily decreasing over the last 39 years for almost every analyzed variable. Compared to MERRA-2, ERA5 has higher correlations and lower mean absolute errors. MERRA-2 is typically drier and less unstable over central Europe and the Balkans, with the opposite pattern over western Russia. Both reanalyses underestimate CAPE and CIN over the Great Plains. Reanalyses are more reliable for lower elevation stations and struggle along boundaries such as coastal zones and mountains. Based on the results from this and prior studies we suggest that ERA5 is likely one of the most reliable available reanalyses for exploration of convective environments, mainly due to its improved resolution. For future studies we also recommend that computation of convective variables should use model levels that provide more accurate sampling of the boundary layer conditions compared to less numerous pressure levels.
Nonmotor symptoms (NMS) are common in patients with established Parkinson disease (PD) but their frequency in early PD has not been extensively studied. Our aim was to determine the frequency of NMS ...in a cohort of patients with newly diagnosed PD.
A total of 159 patients with early PD and 99 healthy controls participated in this study. NMS were screened for using the nonmotor symptom questionnaire. Other assessments included measures of motor disability (Movement Disorders Society-revised unified Parkinson's disease rating scale MDS-UPDRS), disease severity (Hoehn & Yahr staging), depression (geriatric depression scale), and global cognitive function (Mini-mental state examination and Montreal cognitive assessment).
The PD group reported a significantly greater number of NMS compared with controls (8.4 4.3 vs. 2.8 2.6). In the PD group, the most commonly experienced NMS were excessive saliva, forgetfulness, urinary urgency, hyposmia, and constipation. Patients with higher MDS-UPDRS III scores and those with the postural instability gait subtype experienced a greater number of NMS.
NMS are common in early PD and reflect the multisystem nature of the disorder. Even in the earliest stages of PD, NMS may be detrimental to patients' functional status and sense of well-being.
In this study we investigate convective environments and their corresponding climatological features over Europe and the United States. For this purpose, National Lightning Detection Network (NLDN) ...and Arrival Time Difference long-range lightning detection network (ATDnet) data, ERA5 hybrid-sigma levels, and severe weather reports from the European Severe Weather Database (ESWD) and Storm Prediction Center (SPC) Storm Data were combined on a common grid of 0.25° and 1-h steps over the period 1979–2018. The severity of convective hazards increases with increasing instability and wind shear (WMAXSHEAR), but climatological aspects of these features differ over both domains. Environments over the United States are characterized by higher moisture, CAPE, CIN, wind shear, and midtropospheric lapse rates. Conversely, 0–3-km CAPE and low-level lapse rates are higher over Europe. From the climatological perspective severe thunderstorm environments (hours) are around 3–4 times more frequent over the United States with peaks across the Great Plains, Midwest, and Southeast. Over Europe severe environments are the most common over the south with local maxima in northern Italy. Despite having lower CAPE (tail distribution of 3000–4000 J kg−1 compared to 6000–8000 J kg−1 over the United States), thunderstorms over Europe have a higher probability for convective initiation given a favorable environment. Conversely, the lowest probability for initiation is observed over the Great Plains, but, once a thunderstorm develops, the probability that it will become severe is much higher compared to Europe. Prime conditions for severe thunderstorms over the United States are between April and June, typically from 1200 to 2200 central standard time (CST), while across Europe favorable environments are observed from June to August, usually between 1400 and 2100 UTC.
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