Dysphoric milk ejection reflex: A case report

Dysphoric Milk Ejection Reflex (D-MER) is an abrupt emotional "drop" that occurs in some women just before milk release and continues for not more than a few minutes. The brief negative feelings range in severity from wistfulness to self-loathing, and appear to have a physiological cause. The authors suggest that an abrupt drop in dopamine may occur when milk release is triggered, resulting in a real or relative brief dopamine deficit for affected women. Clinicians can support women with D-MER in several ways; often, simply knowing that it is a recognized phenomenon makes the condition tolerable. Further study is needed

Why Are Clinicians Not Embracing the Results from Pivotal Clinical Trials in Severe Sepsis? A Bayesian Analysis

BACKGROUND: Five pivotal clinical trials (Intensive Insulin Therapy; Recombinant Human Activated Protein C [rhAPC]; Low-Tidal Volume; Low-Dose Steroid; Early Goal-Directed Therapy [EGDT]) demonstrated mortality reduction in patients with severe sepsis and expert guidelines have recommended them to clinical practice. Yet, the adoption of these therapies remains low among clinicians. OBJECTIVES: We selected these five trials and asked: Question 1--What is the current probability that the new therapy is not better than the standard of care in my patient with severe sepsis? Question 2--What is the current probability of reducing the relative risk of death (RRR) of my patient with severe sepsis by meaningful clinical thresholds (RRR >15%; >20%; >25%)? METHODS: Bayesian methodologies were applied to this study. Odds ratio (OR) was considered for Question 1, and RRR was used for Question 2. We constructed prior distributions (enthusiastic; mild, moderate, and severe skeptic) based on various effective sample sizes of other relevant clinical trials (unfavorable evidence). Posterior distributions were calculated by combining the prior distributions and the data from pivotal trials (favorable evidence). MAIN FINDINGS: Answer 1--The analysis based on mild skeptic prior shows beneficial results with the Intensive Insulin, rhAPC, and Low-Tidal Volume trials, but not with the Low-Dose Steroid and EGDT trials. All trials' results become unacceptable by the analyses using moderate or severe skeptic priors. Answer 2--If we aim for a RRR>15%, the mild skeptic analysis shows that the current probability of reducing death by this clinical threshold is 88% for the Intensive Insulin, 62-65% for the Low-Tidal Volume, rhAPC, EGDT trials, and 17% for the Low-Dose Steroid trial. The moderate and severe skeptic analyses show no clinically meaningful reduction in the risk of death for all trials. If we aim for a RRR >20% or >25%, all probabilities of benefits become lower independent of the degree of skepticism. CONCLUSIONS: Our clinical threshold analysis offers a new bedside tool to be directly applied to the care of patients with severe sepsis. Our results demonstrate that the strength of evidence (statistical and clinical) is weak for all trials, particularly for the Low-Dose Steroid and EGDT trials. It is essential to replicate the results of each of these five clinical trials in confirmatory studies if we want to provide patient care based on scientifically sound evidence

Euclid preparation: XVII. Cosmic Dawn Survey: Spitzer Space Telescope observations of the Euclid deep fields and calibration fields

We present a new infrared survey covering the three Euclid deep fields and four other Euclid calibration fields using Spitzer Space Telescope's Infrared Array Camera (IRAC). We combined these new observations with all relevant IRAC archival data of these fields in order to produce the deepest possible mosaics of these regions. In total, these observations represent nearly 11 % of the total Spitzer Space Telescope mission time. The resulting mosaics cover a total of approximately 71.5 deg^{2} in the 3.6 and 4.5 μm bands, and approximately 21.8 deg^{2} in the 5.8 and 8 μm bands. They reach at least 24 AB magnitude (measured to 5σ, in a 2″​​.5 aperture) in the 3.6 μm band and up to ∼5 mag deeper in the deepest regions. The astrometry is tied to the Gaia astrometric reference system, and the typical astrometric uncertainty for sources with 16 "< "[3.6]< 19 is ≲ 0″​​.15. The photometric calibration is in excellent agreement with previous WISE measurements. We extracted source number counts from the 3.6 μm band mosaics, and they are in excellent agreement with previous measurements. Given that the Spitzer Space Telescope has now been decommissioned, these mosaics are likely to be the definitive reduction of these IRAC data. This survey therefore represents an essential first step in assembling multi-wavelength data on the Euclid deep fields, which are set to become some of the premier fields for extragalactic astronomy in the 2020s

Global, regional, and national burden of meningitis and its aetiologies, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Although meningitis is largely preventable, it still causes hundreds of thousands of deaths globally each year. WHO set ambitious goals to reduce meningitis cases by 2030, and assessing trends in the global meningitis burden can help track progress and identify gaps in achieving these goals. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we aimed to assess incident cases and deaths due to acute infectious meningitis by aetiology and age from 1990 to 2019, for 204 countries and territories. Methods: We modelled meningitis mortality using vital registration, verbal autopsy, sample-based vital registration, and mortality surveillance data. Meningitis morbidity was modelled with a Bayesian compartmental model, using data from the published literature identified by a systematic review, as well as surveillance data, inpatient hospital admissions, health insurance claims, and cause-specific meningitis mortality estimates. For aetiology estimation, data from multiple causes of death, vital registration, hospital discharge, microbial laboratory, and literature studies were analysed by use of a network analysis model to estimate the proportion of meningitis deaths and cases attributable to the following aetiologies: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, group B Streptococcus, Escherichia coli, Klebsiella pneumoniae, Listeria monocytogenes, Staphylococcus aureus, viruses, and a residual other pathogen category. Findings: In 2019, there were an estimated 236 000 deaths (95% uncertainty interval [UI] 204 000–277 000) and 2·51 million (2·11–2·99) incident cases due to meningitis globally. The burden was greatest in children younger than 5 years, with 112 000 deaths (87 400–145 000) and 1·28 million incident cases (0·947–1·71) in 2019. Age-standardised mortality rates decreased from 7·5 (6·6–8·4) per 100 000 population in 1990 to 3·3 (2·8–3·9) per 100 000 population in 2019. The highest proportion of total all-age meningitis deaths in 2019 was attributable to S pneumoniae (18·1% [17·1–19·2]), followed by N meningitidis (13·6% [12·7–14·4]) and K pneumoniae (12·2% [10·2–14·3]). Between 1990 and 2019, H influenzae showed the largest reduction in the number of deaths among children younger than 5 years (76·5% [69·5–81·8]), followed by N meningitidis (72·3% [64·4–78·5]) and viruses (58·2% [47·1–67·3]). Interpretation: Substantial progress has been made in reducing meningitis mortality over the past three decades. However, more meningitis-related deaths might be prevented by quickly scaling up immunisation and expanding access to health services. Further reduction in the global meningitis burden should be possible through low-cost multivalent vaccines, increased access to accurate and rapid diagnostic assays, enhanced surveillance, and early treatment. Funding: Bill & Melinda Gates Foundation

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

BACKGROUND: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). INTERPRETATION: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids

Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer

Background: Cancer stem cells are suggested to contribute to the extremely poor prognosis of pancreatic ductal adenocarcinoma and dysregulation of symmetric and asymmetric stem cell division may be involved. Anticancer benefits of phytochemicals like the polyphenol quercetin, present in many fruits, nuts and vegetables, could be expedited by microRNAs, which orchestrate cell-fate decisions and tissue homeostasis. The mechanisms regulating the division mode of cancer stem cells in relation to phytochemical-induced microRNAs are poorly understood. Methods: Patient-derived pancreas tissue and 3 established pancreatic cancer cell lines were examined by immunofluorescence and time-lapse microscopy, microRNA microarray analysis, bioinformatics and computational analysis, qRT-PCR, Western blot analysis, self-renewal and differentiation assays. Results: We show that symmetric and asymmetric division occurred in patient tissues and in vitro, whereas symmetric divisions were more extensive. By microarray analysis, bioinformatics prediction and qRT-PCR, we identified and validated quercetin-induced microRNAs involved in Notch signaling/cell-fate determination. Further computational analysis distinguished miR-200b-3p as strong candidate for cell-fate determinant. Mechanistically, miR-200b-3p switched symmetric to asymmetric cell division by reversing the Notch/Numb ratio, inhibition of the self-renewal and activation of the potential to differentiate to adipocytes, osteocytes and chondrocytes. Low miR-200b-3p levels fostered Notch signaling and promoted daughter cells to become symmetric while high miR-200b-3p levels lessened Notch signaling and promoted daughter cells to become asymmetric. Conclusions: Our findings provide a better understanding of the cross talk between phytochemicals, microRNAs and Notch signaling in the regulation of self-renewing cancer stem cell divisions