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Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface.

Maternal COVID-19 vaccination could protect infants who are ineligible for vaccine through antibody transfer during pregnancy and lactation. We measured the quantity and durability of SARS-CoV-2 antibodies in human milk and infant blood before and after maternal booster vaccination. Prospective cohort of lactating women immunized with primary and booster COVID-19 vaccines during pregnancy or lactation and their infants. Milk and blood samples from October 2021 to April 2022 were included. Anti-nucleoprotein (NP) and anti-receptor binding domain (RBD) IgG and IgA in maternal milk and maternal and infant blood were measured and compared longitudinally after maternal booster vaccine. Forty-five lactating women and their infants provided samples. 58% of women were anti-NP negative and 42% were positive on their first blood sample prior to booster vaccine. Anti-RBD IgG and IgA in milk remained significantly increased through 120–170 days after booster vaccine and did not differ by maternal NP status. Anti-RBD IgG and IgA did not increase in infant blood after maternal booster. Of infants born to women vaccinated in pregnancy, 74% still had positive serum anti-RBD IgG measured on average 5 months after delivery. Infant to maternal IgG ratio was highest for infants exposed to maternal primary vaccine during the second trimester compared to third trimester (0.85 versus 0.29; p<0.001). Maternal COVID-19 primary and booster vaccine resulted in robust and long-lasting transplacental and milk antibodies. These antibodies may provide important protection against SARS-CoV-2 during the first six months of life.

GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation. GPR61 is an orphan GPCR of interest for treatment of appetite disorders, such as obesity and cachexia. Here, the authors report structures of GPR61 in its active and inactive states, including with a G protein-competitive small molecule inverse agonist.

Introduction The desire to reduce patient morbidity has led to de-escalation of axillary surgery after neoadjuvant chemotherapy (NAC) for breast cancer; however, the impact of such de-escalation on oncologic outcomes is unknown. Methods We evaluated the relationship between axillary surgery type (sentinel lymph node [SLN] only vs. axillary lymph node dissection [ALND]) and 5-year outcomes in I-SPY2 trial patients from 2011 to 2022 who completed NAC and surgery. Rates of axillary recurrence (AxR), locoregional recurrence (LRR), distant recurrence-free survival (DRFS), and event-free survival (EFS) were compared. Results Of 1515 patients, SLN-only was performed in 804/1014 (79.3%) ypN0 patients and 127/501 (25.3%) ypN+ patients. Median follow-up time was 3.5 years. Most patients received adjuvant radiation (73.8% of ypN0 patients and 90.8% of ypN+ patients). In ypN0 cases, there was no difference between the SLN-only and ALND groups in 5-year estimated AxR (2.0% vs. 0.8%, p  = 0.57), LRR (4.6% vs. 4.4%, p  = 0.72), or EFS (88.3% vs. 86.4%, p  = 0.09). On multivariable analysis, SLN-only was associated with better DRFS (90.8% vs. 87.9%; hazard ratio [HR] 0.54, p  = 0.04). In ypN+ cases, there was no difference between the SLN-only and ALND groups in 5-year estimated AxR (5.2% vs. 3.6%, p  = 0.81), LRR (7.7% vs. 14%, p  = 0.13), DRFS (70.0% vs. 66.7%, p  = 0.09), or EFS (70.4% vs. 63.2%, p  = 0.07). Conclusions With short-term follow-up, omission of ALND in selected patients was not associated with worse AxR, LRR, DRFS, or EFS in patients with ypN0 or ypN+ disease. While prospective trial results are awaited, these data suggest that ALND may not be necessary for all patients with residual nodal disease after NAC.

ObjectiveTo test whether azithromycin eradicates Ureaplasma from the respiratory tract in preterm infants.DesignProspective, phase IIb randomised, double-blind, placebo-controlled trial.SettingSeven level III–IV US, academic, neonatal intensive care units (NICUs).PatientsInfants 240–286 weeks’ gestation (stratified 240–266; 270–286 weeks) randomly assigned within 4 days following birth from July 2013 to August 2016.InterventionsIntravenous azithromycin 20 mg/kg or an equal volume of D5W (placebo) every 24 hours for 3 days.Main outcome measuresThe primary efficacy outcome was Ureaplasma-free survival. Secondary outcomes were all-cause mortality, Ureaplasma clearance, physiological bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age, comorbidities of prematurity and duration of respiratory support.ResultsOne hundred and twenty-one randomised participants (azithromycin: n=60; placebo: n=61) were included in the intent-to-treat analysis (mean gestational age 26.2±1.4 weeks). Forty-four of 121 participants (36%) were Ureaplasma positive (azithromycin: n=19; placebo: n=25). Ureaplasma-free survival was 55/60 (92% (95% CI 82% to 97%)) for azithromycin compared with 37/61 (61% (95% CI 48% to 73%)) for placebo. Mortality was similar comparing the two treatment groups (5/60 (8%) vs 6/61 (10%)). Azithromycin effectively eradicated Ureaplasma in all azithromycin-assigned colonised infants, but 21/25 (84%) Ureaplasma-colonised participants receiving placebo were culture positive at one or more follow-up timepoints. Most of the neonatal mortality and morbidity was concentrated in 21 infants with lower respiratory tract Ureaplasma colonisation. In a subgroup analysis, physiological BPD-free survival was 5/10 (50%) (95% CI 19% to 81%) among azithromycin-assigned infants with lower respiratory tract Ureaplasma colonisation versus 2/11 (18%) (95% CI 2% to 52%) in placebo-treated infants.ConclusionA 3-day azithromycin regimen effectively eradicated respiratory tract Ureaplasma colonisation in this study.Trial registration number NCT01778634.

Escape from parasites in their native range is one of many mechanisms that can contribute to the success of an invasive species. Gnathiid isopods are blood-feeding ectoparasites that infest a wide range of fish hosts, mostly in coral reef habitats. They are ecologically similar to terrestrial ticks, with the ability to transmit blood-borne parasites and cause damage or even death to heavily infected hosts. Therefore, being highly resistant or highly susceptible to gnathiids can have significant fitness consequences for reef-associated fishes. Indo-Pacific red lionfish (Pterois volitans) have invaded coastal habitats of the western tropical and subtropical Atlantic and Caribbean regions. We assessed the susceptibility of red lionfish to parasitic gnathiid isopods in both their native Pacific and introduced Atlantic ranges via experimental field studies during which lionfish and other, ecologically-similar reef fishes were caged and exposed to gnathiid infestation on shallow coral reefs. Lionfish in both ranges had very few gnathiids when compared with other species, suggesting that lionfish are not highly susceptible to infestation by generalist ectoparasitic gnathiids. While this pattern implies that release from gnathiid infestation is unlikely to contribute to the success of lionfish as invaders, it does suggest that in environments with high gnathiid densities, lionfish may have an advantage over species that are more susceptible to gnathiids. Also, because lionfish are not completely resistant to gnathiids, our results suggest that lionfish could possibly have transported blood parasites between their native Pacific and invaded Atlantic ranges.

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

Climate change will affect most populations in the next decades and put the health of billions of people at risk. Health care facilities represent a significant source of pollution around the world and contribute to environmental changes. To address this topic, we performed a review of the available literature on tactics to reduce operating room (OR) waste and the potential of these strategies to impact the environment. A literature search was performed querying PubMed, Web of Science, and Science Direct. No comparative data were found; most were opinion papers, white papers, and case studies. For this reason, we proceeded with a narrative review, which provides an overview of the evidence on this topic and identifies areas for future research. This systematic review summarizes the available literature on the 5 “Rs” of waste management: reduction, reusing, recycling, rethinking, and renewable energies. Surgery has a unique opportunity to transition to more environmentally-friendly operating room strategies, which may help decrease waste and lessen the impact of climate change. •Surgical waste is contributing to landfill mass and climate change.•Strategies such as repurposing and anesthetic gas reclaiming are potential strategies to address surgical waste.•Donation of unused or repurposed surgical supplies may help global surgery efforts while decreasing surgical waste.

Background For patients with clinically node-positive (cN+) breast cancer undergoing neoadjuvant chemotherapy (NAC), retrieving previously clipped, biopsy-proven positive lymph nodes during sentinel lymph node biopsy [i.e., targeted axillary dissection (TAD)] may reduce false negative rates. However, the overall utilization and impact of clipping positive nodes remains uncertain. Patients and Methods We retrospectively analyzed cN+ ISPY-2 patients (2011–2022) undergoing axillary surgery after NAC. We evaluated trends in node clipping and associations with type of axillary surgery [sentinel lymph node (SLN) only, SLN and axillary lymph node dissection (ALND), or ALND only] and event-free survival (EFS) in patients that were cN+ on a NAC trial. Results Among 801 cN+ patients, 161 (20.1%) had pre-NAC clip placement in the positive node. The proportion of patients that were cN+ undergoing clip placement increased from 2.4 to 36.2% between 2011 and 2021. Multivariable logistic regression showed nodal clipping was independently associated with higher odds of SLN-only surgery [odds ratio (OR) 4.3, 95% confidence interval (CI) 2.8–6.8, p < 0.001]. This was also true among patients with residual pathologically node-positive (pN+) disease. Completion ALND rate did not differ based on clip retrieval success. No significant differences in EFS were observed in those with or without clip placement, both with or without successful clip retrieval [hazard ratio (HR) 0.85, 95% CI 0.4–1.7, p = 0.7; HR 1.8, 95% CI 0.5–6.0, p = 0.3, respectively]. Conclusion Clip placement in the positive lymph node before NAC is increasingly common. The significant association between clip placement and omission of axillary dissection, even among patients with pN+ disease, suggests a paradigm shift toward TAD as a definitive surgical management strategy in patients with pN+ disease after NAC.