After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor (SSRI), it is not known whether switching to one antidepressant is more effective than switching to another.
...We randomly assigned 727 adult outpatients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks: sustained-release bupropion (239 patients) at a maximal daily dose of 400 mg, sertraline (238 patients) at a maximal daily dose of 200 mg, or extended-release venlafaxine (250 patients) at a maximal daily dose of 375 mg. The study was conducted in 18 primary and 23 psychiatric care settings. The primary outcome was symptom remission, defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of the study. Scores on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16), obtained at treatment visits, determined secondary outcomes, including remission (a score of 5 or less at exit) and response (a reduction of 50 percent or more on baseline scores).
Remission rates as assessed by the HRSD-17 and the QIDS-SR-16, respectively, were 21.3 percent and 25.5 percent for sustained-release bupropion, 17.6 percent and 26.6 percent for sertraline, and 24.8 percent and 25.0 percent for extended-release venlafaxine. QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion, 26.7 percent for sertraline, and 28.2 percent for extended-release venlafaxine. These treatments did not differ significantly with respect to outcomes, tolerability, or adverse events.
After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression. (ClinicalTrials.gov number, NCT00021528.).
COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like ...advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.
To investigate the effects of repeated work bouts in the heat on peak body core temperature and to explore sex-based differences in body core temperature responses.
Fourteen males and fifteen females ...performed four work bouts (two heavy and two moderate, alternating) in 32.5 °C Wet Bulb Globe Temperature (WBGT), each separated by 30-min seated rest in 28.0 °C WBGT. Participants wore a military combat uniform with body armour and helmet (10 kg load) during the work bouts, removing the vest and helmet during recovery periods.
Body core temperature elevation over time was faster in the first compared with subsequent work bouts of each intensity. Body core temperature elevation was similar between males and females during the first heavy work bout, then remained significantly lower in females for the reminder of the trial.
Contrary to the assumed progressive elevation in strain, but in agreement with recent literature, a gradual reduction in heat storage in subsequent exercise bouts prevented a cumulative increase in heat strain in the conditions tested.
•This study examined the physiological strain of repeated work bouts in the heat.•Military work tables are appropriate for both sexes when working in the heat.•The number of work bouts could be increased without excessive elevation in strain.•Sex differences in core temperature were likely due to morphology and work rate.
This audit examined UK vulvar cancer practice from March 2018 to January 2019 and compared it to standards from national and international recommendations. Follow-up data collection in 2020 examined ...patient outcomes and toxicity.
Audit standards were based on Royal College of Radiologists (RCR) guidance and published literature. A web-based questionnaire was sent to the audit leads at all cancer centres in the UK. Prospective data collection included patient demographics, tumour characteristics, radiotherapy indications, dosimetry, timelines, and follow-up data. The audit targets were 95% compliance with the RCR dose/fractionation schemes in definitive and adjuvant patients, 40% use of intensity modulated radiotherapy (IMRT), 100% of radical patients treated as category 1, and 95% use of gap compensation for category 1 patients.
34/54 UK radiotherapy centres (63%) completed data entry for 152 patients. 23 out of 34 (68%) centres submitted follow-up data for 94 patients. One indicator exceeded the audit target: 98% of radical patients received IMRT. The indicators of RCR dose/fractionation compliance for adjuvant/definitive radiotherapy were achieved by 80%/43% for the primary, 80%/86% for elective lymph nodes, and 21%/21% for pathological lymph nodes. The use of concomitant chemotherapy with radical radiotherapy in suitable patients was achieved by 71%. Other indicators demonstrated that 78% were treated as category 1 and 27% used gap compensation. Acute toxicity was mostly related to skin, gastrointestinal, and genitourinary sites. Grade 3 and Grade 4 toxicities were seen at acceptable rates within the radical and adjuvant groups. Late toxicity was mostly grade 0.
This audit provides a comprehensive picture of UK practice. IMRT is widely used in the UK, and treatment-related toxicity is moderate. The dose fractionation was very heterogeneous. The designation of vulvar cancer as category 1 was not regularly followed for radical/adjuvant patients, and there was minimal gap compensation during treatment.
•There is widespread use of IMRT as an RT technique for vulvar cancer in the UK with acceptable reported toxicity.•There is a considerable range of dose and fractionation used for vulvar cancer and there is no consensus regarding the minimum dose to maximize local control.•Compliance to RCR guidelines on designation of category 1 and compensation of gaps in radical treatment is below acceptable variance and should be improved.
Although toxicants may initiate cell damage or stress, the cellular proteins that are involved in control of cell cycle and apoptosis are the final arbiters of cell fate. The biochemical pathways ...that restrain cell cycle transition and/or induce cell death after stress are known as cell cycle checkpoints. These checkpoints maintain the fidelity of DNA replication, repair, and division. Herein, select cell cycle checkpoint signaling pathways will be discussed and how different components of these pathways are regulated by exogenous and endogenous agents, with focus on the p53 tumor suppressor signaling. The p53 protein is known to play a key role in growth arrest and apoptosis after cell stress, primarily through its ability to regulate the transcription of select downstream target genes in the cell. Further elucidation of the signaling pathways that control growth arrest and apoptosis will continue to provide insights to the complex cellular responses to environmental toxicants.
Ocean acidification (OA) threatens the growth and function of coral reef ecosystems. A key component to coral health is the microbiome, but little is known about the impact of OA on coral ...microbiomes. A submarine CO
vent at Maug Island in the Northern Mariana Islands provides a natural pH gradient to investigate coral responses to long-term OA conditions. Three coral species (
,
, and
) were sampled from three sites where the mean seawater pH is 8.04, 7.98, and 7.94. We characterized coral bacterial communities (using 16S rRNA gene sequencing) and determined pH of the extracellular calcifying fluid (ECF) (using skeletal boron isotopes) across the seawater pH gradient. Bacterial communities of both
species stabilized (decreases in community dispersion) with decreased seawater pH, coupled with large increases in the abundance of
, an endosymbiont.
experienced a significant decrease in ECF pH near the vent, whereas
experienced a trending decrease in ECF pH near the vent. In contrast,
exhibited bacterial community destabilization (increases in community dispersion), with significant decreases in
abundance, while its ECF pH remained unchanged across the pH gradient. Our study shows that OA has multiple consequences on
abundance and suggests that
abundance may be an indicator of coral response to OA. We reveal an interesting dichotomy between two facets of coral physiology (regulation of bacterial communities and regulation of calcification), highlighting the importance of multidisciplinary approaches to understanding coral health and function in a changing ocean.
Ocean acidification (OA) is a consequence of anthropogenic CO
emissions that is negatively impacting marine ecosystems such as coral reefs. OA affects many aspects of coral physiology, including growth (i.e., calcification) and disrupting associated bacterial communities. Coral-associated bacteria are important for host health, but it remains unclear how coral-associated bacterial communities will respond to future OA conditions. We document changes in coral-associated bacterial communities and changes to calcification physiology with long-term exposure to decreases in seawater pH that are environmentally relevant under midrange IPCC emission scenarios (0.1 pH units). We also find species-specific responses that may reflect different responses to long-term OA. In
, calcification physiology was highly regulated despite changing seawater conditions. In
spp., changes in bacterial communities do not reflect a breakdown of coral-bacterial symbiosis. Insights into calcification and host-microbe interactions are critical to predicting the health and function of different coral taxa to future OA conditions.
The complex and varied motion of the cervix–uterus target during external beam radiotherapy (EBRT) underscores the clinical benefits afforded by adaptive radiotherapy (ART) techniques. These gains ...have already been realised in the implementation of image-guided adaptive brachytherapy, where adapting to anatomy at each fraction has seen improvements in clinical outcomes and a reduction in treatment toxicity. With regards to EBRT, multiple adaptive strategies have been implemented, including a personalised internal target volume, offline replanning and a plan of the day approach. With technological advances, there is now the ability for real-time online ART using both magnetic resonance imaging and computed tomography-guided imaging. However, multiple challenges remain in the widespread dissemination of ART. This review investigates the ART strategies and their clinical implementation in EBRT delivery for cervical cancer.
In this work, a computational spectroscopy approach was used to provide a complete assignment of the inelastic neutron scattering spectra of three title alkoxysilane ...derivatives-3-aminopropyltrimethoxysilane (APTS), N-methyl-3-aminopropyltrimethoxysilane (MAPTS), and 3-aminopropyltriethoxysilane (APTES). The simulated spectra obtained from density functional theory (DFT) calculations exhibit a remarkable match with the experimental spectra. The description of the experimental band profiles improves as the number of molecules considered in the theoretical model increases, from monomers to trimers. This highlights the significance of incorporating non-covalent interactions, encompassing classical NH···N, N-H···O, as well as C-H···N and C-H···O hydrogen bond contacts, to achieve a comprehensive understanding of the system. A distinct scenario emerges when considering optical vibrational techniques, infrared and Raman spectroscopy. In these instances, the monomer model provides a reasonable description of the experimental spectra, and no substantial alterations are observed in the simulated spectra when employing dimer and trimer models. This observation underscores the distinctive ability of neutron spectroscopy in combination with DFT calculations in assessing the structure and dynamics of molecular materials.
More than half the world's rainforest has been lost to agriculture since the Industrial Revolution. Among the most widespread tropical crops is oil palm (Elaeis guineensis): global production now ...exceeds 35 million tonnes per year. In Malaysia, for example, 13% of land area is now oil palm plantation, compared with 1% in 1974. There are enormous pressures to increase palm oil production for food, domestic products, and, especially, biofuels. Greater use of palm oil for biofuel production is predicated on the assumption that palm oil is an "environmentally friendly" fuel feedstock. Here we show, using measurements and models, that oil palm plantations in Malaysia directly emit more oxides of nitrogen and volatile organic compounds than rainforest. These compounds lead to the production of ground-level ozone (O₃), an air pollutant that damages human health, plants, and materials, reduces crop productivity, and has effects on the Earth's climate. Our measurements show that, at present, O₃ concentrations do not differ significantly over rainforest and adjacent oil palm plantation landscapes. However, our model calculations predict that if concentrations of oxides of nitrogen in Borneo are allowed to reach those currently seen over rural North America and Europe, ground-level O₃ concentrations will reach 100 parts per billion (10⁹) volume (ppbv) and exceed levels known to be harmful to human health. Our study provides an early warning of the urgent need to develop policies that manage nitrogen emissions if the detrimental effects of palm oil production on air quality and climate are to be avoided.
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