Recent theoretical studies have shown that conditioning on an instrumental variable (IV), a variable that is associated with exposure but not associated with outcome except through exposure, can ...increase both bias and variance of exposure effect estimates. Although these findings have obvious implications in cases of known IVs, their meaning remains unclear in the more common scenario where investigators are uncertain whether a measured covariate meets the criteria for an IV or rather a confounder. The authors present results from two simulation studies designed to provide insight into the problem of conditioning on potential IVs in routine epidemiologic practice. The simulations explored the effects of conditioning on IVs, near-IVs (predictors of exposure that are weakly associated with outcome), and confounders on the bias and variance of a binary exposure effect estimate. The results indicate that effect estimates which are conditional on a perfect IV or near-IV may have larger bias and variance than the unconditional estimate. However, in most scenarios considered, the increases in error due to conditioning were small compared with the total estimation error. In these cases, minimizing unmeasured confounding should be the priority when selecting variables for adjustment, even at the risk of conditioning on IVs.
During austral summer 2015–2016, prolonged extreme ocean warming events, known as marine heatwaves (MHWs), occurred in the waters around tropical Australia. MHWs arose first in the southeast tropical ...Indian Ocean in November 2015, emerging progressively east until March 2016, when all waters from the North West Shelf to the Coral Sea were affected. The MHW maximum intensity tended to occur in March, coinciding with the timing of the maximum sea surface temperature (SST). Large areas were in a MHW state for 3–4 months continuously with maximum intensities over 2°C. In 2016, the Indonesian‐Australian Basin and areas including the Timor Sea and Kimberley shelf experienced the longest and most intense MHW from remotely sensed SST dating back to 1982. In situ temperature data from temperature loggers at coastal sites revealed a consistent picture, with MHWs appearing from west to east and peaking in March 2016. Temperature data from moorings, an Argo float, and Slocum gliders showed the extent of warming with depth. The events occurred during a strong El Niño and weakened monsoon activity, enhanced by the extended suppressed phase of the Madden‐Julian Oscillation. Reduced cloud cover in January and February 2016 led to positive air‐sea heat flux anomalies into the ocean, predominantly due to the shortwave radiation contribution with a smaller additional contribution from the latent heat flux anomalies. A data‐assimilating ocean model showed regional changes in the upper ocean circulation and a change in summer surface mixed layer depths and barrier layer thicknesses consistent with past El Niño events.
Plain Language Summary
From the southeast tropical Indian Ocean to the Coral Sea, waters across tropical Australia experienced extreme warming during austral summer 2015–2016. This widespread warming was mainly caused by changes in the atmospheric conditions related to the strong El Niño. These regions had reduced cloud cover and weakened winds, leading to enhanced oceanic heating by the atmosphere. In the Indonesian‐Australian Basin and surroundings areas, the shallower mixed layer depth further intensified the near‐surface warming. We used satellite sea surface temperature and a range of instruments to document the warming events near the coast and in the deeper ocean. The warmer than average conditions persisted through austral winter and weakened in spring.
Key Points
During 2016, the southeast tropical Indian Ocean experienced the longest and most intense marine heatwave on record from 1982
Around tropical Australia, coastal warming was caused by shortwave radiation and latent heat flux anomalies in January and February 2016
The 2015–2016 air‐sea heat flux anomalies, weakened monsoon winds and mixed layer depth anomalies were consistent with past El Niños
Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein-protein interaction (PPI) networks within human cells. ...Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery.
Abstract Marine Heatwaves (MHWs) can directly influence survival of marine fishes, particularly for early life stages, including age-0 juveniles during their residence in coastal nursery habitats. ...However, the ability of nurseries to support high fish densities, optimize foraging and growth, and protect against predators may be altered during MHWs. Gulf of Alaska Pacific cod ( Gadus macrocephalus ) larval, juvenile, and adult abundances declined dramatically following MHW events in 2014–2016 and 2019. To evaluate coastal nursery function during MHWs, we compared diet composition, recent growth, size, condition, and abundance of age-0 juveniles throughout their first summer before, during, and between MHWs. Diet shifted to larger prey during MHWs, particularly mysids, but diet did not appear to influence growth. We observed faster growth rates during MHWs, yet even when accounting for growth, we could not explain the higher body sizes observed in August during MHWs. Together with lower abundance and the near absence of small fish in the nursery by August during MHWs, these patterns highlight potential for size-selection and a reduced ability of nursery habitats to buffer against environmental variability during MHWs, with only a small number of large “super survivors” persisting through the summer.
Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple ...preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.
Carbon dioxide (CO2) lasers are used for a variety of soft tissue procedures. This report describes their use in dermatitis associated with feline herpesvirus‐1 (FHV) in two cheetahs. To the best of ...the authors' knowledge, this is the first report describing CO2 laser use to adjunctively treat FHV‐associated skin lesions.
Résumé
Les lasers au dioxyde de carbone (CO2) sont utilisés pour une variété de procédures sur les tissus mous. Ce rapport décrit leur utilisation dans la dermatite associée à l'herpèsvirus félin‐1 (FHV) chez deux guépards. À la connaissance des auteurs, il s'agit du premier article décrivant l'utilisation du laser CO2 pour traiter de manière complémentaire les lésions cutanées associées au FHV.
Resumen
Los láseres de dióxido de carbono (CO2) se utilizan para una variedad de procedimientos de tejidos blandos. Este informe describe su uso en la dermatitis asociada con el herpesvirus felino‐1 (FHV) en dos guepardos. A entender de los autores, este es el primer informe que describe el uso del láser de CO2 para tratar de forma complementaria las lesiones cutáneas asociadas con infección con FHV.
Zusammenfassung
Kohlendioxid (CO2) Laser werden für eine ganze Reihe von Weichteileingriffen angewendet. Dieser Bericht beschreibt seinen Einsatz bei einer Dermatitis im Zusammenhang mit felinem Herpesvirus‐1 (FHV) bei zwei Geparden. Nach bestem Wissen der Autoren handelt es sich hierbei um den ersten Fallbericht, welcher die Verwendung von CO2 Laser als Zusatzbehandlung bei FHV‐induzierten Hautläsionen beschreibt.
要約
炭酸ガス (CO2) レーザーは、様々な軟部組織の処置に使用されている。本報告では、2頭のチーターにおけるネコヘルペスウィルス‐1(FHV) に関連した皮膚炎への使用について記述する。筆者らの知る限り、これはFHVに関連した皮膚病変を補助的に治療するためのCO2レーザーの使用を記述した最初の報告である。
摘要
二氧化碳(CO2)激光器可用于各种软组织手术。本报告描述了将其使用在两只猎豹的猫疱疹病毒‐1(FHV)皮炎上。据作者所知, 这是第一份描述CO2激光用于辅助治疗FHV‐皮肤病变的报告。
Resumo
Lasers de dióxido de carbono (CO2) são utilizados em uma grande variedade de procedimentos de tecidos moles. Este relato descreve a sua utilização na dermatite associada ao herpesvírus felino (HVF)‐1 em duas chitas. De acordo com o conhecimento dos autores, este é o primeiro relato descrevendo a utilização do laser de CO2 no tratamento adjunto de lesões cutâneas associadas o HVF.
Carbon dioxide (CO2) lasers are used for a variety of soft tissue procedures. This report describes their use in dermatitis associated with feline herpesvirus‐1 (FHV) in two cheetahs. To the best of the authors' knowledge, this is the first report describing CO2 laser use to adjunctively treat FHV‐associated skin lesions.
•mRNA SARS-CoV-2 vaccine induced higher surrogate neutralizing antibody titres and a more potent, RBD-targeted B cell response than adenoviral vaccine.•Although adenoviral vaccine boosted antibodies ...against human Adenovirus, those titres did not correlate with anti-spike titres.•Further work is needed to improve the immunogenicity of viral vector vaccines as they remain an important option for pandemic and outbreak responses.
Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. The aim of this study was to validate whether immunogenicity differs for adenoviral vectored (AdV) versus mRNA vaccines against SARS-CoV-2, and to investigate how anti-vector immunity and B cell dynamics modulate immunogenicity. We enrolled SARS-CoV-2 infection-naïve health care workers who had received two doses of either AdV AZD1222 (n = 184) or mRNA BNT162b2 vaccine (n = 274) between April and October 2021. Blood was collected at least once, 10–48 days after vaccine dose 2 for antibody and B cell analyses. Median ages were 42 and 39 years, for AdV and mRNA vaccinees, respectively. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p < 0.001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine, which reflected greater B cell expansion and targeting of the RBD rather than an attenuating effect of anti-vector antibodies.
ClinicalTrials.gov Identifier: NCT05110911.
In NASA's first technology demonstration of CubeSats in deep space, MarCO-A and MarCO-B were launched with the Mars InSight mission. These CubeSats successfully transmitted the InSight lander's ...entry, descent, and landing telemetry back to Earth in near-real time, which was not possible with existing Mars orbital data relay systems. In addition to solar arrays, each MarCO CubeSat was powered by a 3S4P battery comprising 18650-size lithium-ion cells. These commercial lithium-ion cells (Panasonic NCR18650B) were screened and matched using a cell selection process that was simplified relative to larger missions, to ensure safe and reliable battery behavior at an acceptable cost. This paper describes the design of the MarCO power system and battery, the lithium-ion battery cell testing and screening processes and results, and initial performance data from MarCO flight telemetry.
•Li-ion batteries with commercial 18650 cells supported MarCO CubeSats successfully.•Panasonic NCRB 18650 cells showed high specific energy and radiation tolerance.•Space-quality batteries are possible with COTS cells with suitable cell selection.•MarCO CubeSats were used to follow Entry Descent and Landing of Mars Insight Lander.
To investigate the influence of acute normobaric hypoxia on standing balance under single and dual-task conditions, both with and without visual input.
20 participants (7 female, 20-31 years old) ...stood on a force plate for 16, 90-s trials across four balance conditions: single-task (quiet stance) or dual-task (auditory Stroop test), with eyes open or closed. Trials were divided into four oxygen conditions where the fraction of inspired oxygen (F
O
) was manipulated (normoxia: 0.21 and normobaric hypoxia: 0.16, 0.145 and 0.13 F
O
) to simulate altitudes of 1100, 3,400, 4300, and 5200 m. Participants breathed each F
O
for ~ 3 min before testing, which lasted an additional 7-8 min per oxygen condition. Cardiorespiratory measures included heart rate, peripheral blood oxygen saturation, and pressure of end tidal (P
) CO
and O
. Center of pressure measures included total path length, 95% ellipse area, and anteroposterior and mediolateral velocity. Auditory Stroop test performance was measured as response accuracy and latency.
Significant decreases in oxygen saturation and P
O
, and increased heart rate were observed between normoxia and normobaric hypoxia (P < 0.0001). Total path length was higher at 0.13 compared to 0.21 F
O
for the eyes closed no Stoop test condition (P = 0.0197). No other significant differences were observed.
These findings suggest that acute normobaric hypoxia has a minimal impact on standing balance and does not influence auditory Stroop test or dual-task performance. Further investigation with longer exposure is required to understand the impact and time course of normobaric hypoxia on standing balance.
Anaplastic thyroid cancer is a rare but devastating malignancy. Anaplastic thyroid cancer cells exhibit the Warburg effect by preferentially undergoing glycolysis even in aerobic conditions, leading ...to high glucose use. Here we assess if targeted inhibition of glycolysis can diminish anaplastic thyroid cancer growth and improve outcomes.
Human anaplastic thyroid cancer cell line 8505C was grown in medium containing high (25 mmol/L) or low (3 mmol/L) glucose concentration and hexokinase II inhibitor 3-bromopyruvate (200 μM). Cellular proliferation, migration, and invasion were measured. An orthotopic xenograft model of anaplastic thyroid cancer was generated in nude mice using 8505C cells. Animals were provided standard chow or a ketogenic diet and treated with 3-bromopyruvate (1.8 mg/kg). Overall survival time was monitored. Necropsies were performed to harvest tumors for analysis.
Growth of 8505C in low-glucose medium with 3-bromopyruvate decreased cell proliferation by 89%, migration by 44%, and invasion by 73% (P < .001 for all) compared with high glucose. Animals concomitantly receiving a ketogenic diet and 3-bromopyruvate exhibited smaller tumor volumes (P = .03), slower tumor growth rates (P = .01), and improved overall survival (P = .006) compared with standard-diet control subjects. Monotherapy with a ketogenic diet or 3-bromopyruvate alone did not reduce tumor size or increase survival over the standard-diet control group.
Glycolytic inhibition with 3-bromopyruvate inhibits tumor growth and extends survival in a murine model of anaplastic thyroid cancer when combined with the ketogenic diet. Thus, targeted glycolytic inhibition of anaplastic thyroid cancer exhibits context-specific utility and may only be effective during ketosis induced by dietary restriction of glycolytic inputs.
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