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Quasar-driven galactic outflows are a major driver of the evolution of massive galaxies. We report observations of a powerful galactic-scale outflow in a z = 3 extremely red and intrinsically luminous ( L _bol ≃ 5 × 10 ^47 erg s ^−1 ) quasar SDSSJ1652 + 1728 with the Near-infrared Spectrograph on board JWST. We analyze the kinematics of rest-frame optical emission lines and identify the quasar-driven outflow extending out to ∼10 kpc from the quasar with a velocity offset of ( v _r = ± 500 km s ^−1 ) and high velocity dispersion (FWHM = 700–2400 km s ^−1 ). Due to JWST’s unprecedented surface brightness sensitivity in the near-infrared, we unambiguously show that the powerful high velocity outflow in an extremely red quasar encompasses a large swath of the host galaxy’s interstellar medium. Using the kinematics and dynamics of optical emission lines, we estimate the mass outflow rate—in the warm ionized phase alone—to be at least 2300 ± 1400 M _⊙ yr ^−1 . We measure a momentum flux ratio between the outflow and the quasar accretion disk of ∼1 on a kpc scale, indicating that the outflow was likely driven in a relatively high (>10 ^23 cm ^−2 ) column density environment through radiation pressure on dust grains. We find a coupling efficiency between the bolometric luminosity of the quasar and the outflow of 0.1%, matching the theoretical prediction of the minimum coupling efficiency necessary for negative quasar feedback. The outflow has sufficient energetics to drive the observed turbulence seen in shocked regions of the quasar host galaxy, which are likely directly responsible for prolonging the time that it takes for gas to cool efficiently.

Abstract Background Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such estimates. We explored effects of 24‐h height‐indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFRCr), muscle mass‐independent cystatin C (eGFRCys), and the combination of creatinine and cystatin C (eGFRCr‐Cys) and predicted probabilities of discordant classification given age, sex, and CER index. Methods We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFRCr

Significance: People with HIV (PWH) who smoke cigarettes have lower cessation rates than the general population. This study investigated whether changes in cannabis use frequency impedes cigarette cessation among PWH who are motivated to quit. Methods: Between 2016-2020, PWH who smoked cigarettes were enrolled in a randomized controlled trial for cigarette cessation. Analyses were limited to PWH who reported on their past 30-day (P30D) cannabis use during four study visits (baseline, 1-month, 3-month, and 6-month) (N=374). Descriptive statistics and multivariable logistic regression were used to evaluate changes in cannabis use frequency from baseline to 6 months and associations with cigarette abstinence at 6 months among PWH who reported no use during all four visits (n=176), as well as those who reported use during at least one visit and who increased (n=39), decreased (n=78), or had no change (n=81) in use frequency. Results: Among those who reported cannabis use during at least one visit (n=198), at baseline, 18.2% reported no use. At 6 months, 34.3% reported no use. Controlling for covariates, increased cannabis use frequency from baseline was associated with reduced odds of cigarette abstinence at 6 months versus decreased use frequency (aOR=0.22, 95% CI=0.03, 0.90) or no use at either time-point (aOR=0.25, 95% CI=0.04, 0.93). Conclusions: Increased cannabis use over 6 months was associated with reduced odds of cigarette smoking abstinence among PWH who were motivated to quit. Additional factors that influence cannabis use and cigarette cessation simultaneously are in need of further study.

Significance: Determining if tobacco-related biomarkers of exposure (BOE) are associated with respiratory symptoms is an important public health tool that can be used to evaluate the potential harm of different tobacco products. Methods: Adult data from people who exclusively smoked cigarettes (N = 2,438) in Waves 1–4 (2013–2017) of the Population Assessment of Tobacco and Health Study were stacked to examine associations between baseline and follow-up within wave pairs (W1-W2, W2-W3, W3-W4). Weighted generalized estimating equation models were used to evaluate associations between biomarkers of nicotine, tobacco-specific nitrosamines, acrolein, acrylonitrile, cadmium, and lead at baseline/follow-up and respiratory symptom(s) (wheezing/whistling in the chest, wheezing during exercise, and/or dry cough in the past 12 months) at follow-up. Results: Higher acrolein metabolite (CEMA) levels at follow-up were associated with increased odds of respiratory symptoms at follow-up for people who exclusively smoked cigarettes (aOR = 1.34; 95% CI = 1.06, 1.70), including when limited to those without a diagnosed respiratory disease (aOR = 1.46; 95% CI = 1.12, 1.90) and those who smoked daily (aOR = 1.40; 95% CI = 1.06, 1.84). Higher cadmium levels at baseline (while controlling for follow-up levels) were associated with reduced odds of respiratory symptoms at follow-up (aOR = 0.80; 95% CI = 0.65, 0.98) among people who exclusively smoked cigarettes without a respiratory disease. There were no significant associations between baseline/follow-up BOE and follow-up respiratory symptoms for people who smoked cigarettes non-daily. Conclusions: This research supports measuring biomarkers of acrolein, such as CEMA, as a potential intermediate measurement for increased respiratory symptom development. Measuring these biomarkers could help alleviate the clinical burden of respiratory disease.

Diabetes results in an increased risk of atherosclerotic cardiovascular disease. This minireview will discuss whether monocyte and macrophage lipid loading contribute to this increased risk, as monocytes and macrophages are critically involved in the progression of atherosclerosis. Both uptake and efflux pathways have been described as being altered by diabetes or conditions associated with diabetes, which may contribute to the increased accumulation of lipids seen in macrophages in diabetes. More recently, monocytes have also been described as lipid-laden in response to elevated lipids, including triglyceride-rich lipoproteins, the class of lipids often elevated in the setting of diabetes.

We describe serial implantation of atrial flow regulator (AFR) devices in the Fontan fenestration of a 4-year-old patient. Initially, the fenestration size was decreased using a 6/5 AFR, resulting in improved saturations and hemodynamics. One year later, further improvement was achieved by placing a 4/10 AFR inside the original device. (Level of Difficulty: Advanced.)

Shin et al. report the molecular mechanics of membrane budding: actin and dynamin pull membrane inward to form a Λ-shape profile; dynamin helices convert Λ- to Ω-shape by constricting Λ’s base, and then constrict Ω-profile’s pore to form a vesicle.

Abstract The effects of adjuvants for increasing the immunogenicity of influenza vaccines are well known. However, the effect of adjuvants on increasing the breadth of cross-reactivity is less well understood. In this study we have performed a systematic screen of different toll-like receptor (TLR) agonists, with and without a squalene-in-water emulsion on the immunogenicity of a recombinant trimerized hemagglutinin (HA) vaccine in mice after single-dose administration. Antibody (Ab) cross-reactivity for other variants within and outside the immunizing subtype (homosubtypic and heterosubtypic cross-reactivity, respectively) was assessed using a protein microarray approach. Most adjuvants induced broad IgG profiles, although the response to a combination of CpG, MPLA and AddaVax (termed ‘IVAX-1’) appeared more quickly and reached a greater magnitude than the other formulations tested. Antigen-specific plasma cell labeling experiments show the components of IVAX-1 are synergistic. This adjuvant preferentially stimulates CD4 T cells to produce Th1>Th2 type (IgG2c>IgG1) antibodies and cytokine responses. Moreover, IVAX-1 induces identical homo- and heterosubtypic IgG and IgA cross-reactivity profiles when administered intranasally. Consistent with these observations, a single-cell transcriptomics analysis demonstrated significant increases in expression of IgG1, IgG2b and IgG2c genes of B cells in H5/IVAX-1 immunized mice relative to naïve mice, as well as significant increases in expression of the IFNγ gene of both CD4 and CD8 T cells. These data support the use of adjuvants for enhancing the breath and durability of antibody responses of influenza virus vaccines.

Abstract Background Expanding access to the opioid antagonist naloxone to reduce overdose mortality is a public health priority in the United States. Naloxone standing orders (NSOs) have been established in many states to increase naloxone dispensing at pharmacies, but increased pharmacy access does not ensure optimal uptake among those likely to witness an overdose. In a prior statewide purchase trial, we documented high levels of naloxone access at Massachusetts pharmacies under a statewide NSO. In this study, we characterize barriers to pharmacy-based naloxone uptake among potential opioid overdose “bystanders” (friends or family of people who use opioids) that may be amenable to intervention. Methods Eligible bystanders were Massachusetts residents ≥ 18 years of age, did not use illicit opioids in the past 30 days, and knew someone who currently uses illicit opioids. We used a sequential mixed methods approach, in which a series of semi-structured qualitative interviews (N = 22) were conducted April-July 2018, to inform the development of a subsequent quantitative survey (N = 260), conducted February-July 2020. Results Most survey participants (77%) reported ever obtaining naloxone but few (21%) attempted to purchase it at a pharmacy. Qualitative participants revealed that barriers to utilizing the NSO included low perceived risk of overdose, which was rooted in misconceptions regarding the risks of prescription opioid misuse, denial about their loved one’s drug use, and drug use stereotypes; inaccurate beliefs about the impact of naloxone on riskier opioid use; and concerns regarding anticipated stigma and confidentiality. Many participants had engaged in mutual support groups, which served as a source of free naloxone for half (50%) of those who had ever obtained naloxone. Conclusions Despite high levels of pharmacy naloxone access in Massachusetts, few bystanders in our study had attempted to obtain naloxone under the NSO. Low perceived risk of overdose, misinformation, stigma, and confidentiality were important barriers to pharmacy naloxone uptake, all of which are amenable to intervention. Support groups provided a setting for addressing stigma and misinformation and provided a discreet and comfortable setting for naloxone access. Where these groups do not exist and for bystanders who do not participate in such groups, pharmacies are well-positioned to fill gaps in naloxone availability.

Abstract Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may increase total daily energy expenditure by 20%. Humans normally have more beige and potentially beige-able fat than brown fat. Strategies to increase beige fat differentiation and activation may be useful for the treatment of obesity and diabetes. Mice were fed chow or high-fat diet (HFD) with or without the iron chelator deferasirox. Animals fed HFD + deferasirox were markedly lighter than their HFD controls with increased energy expenditure (12% increase over 24 h, p

Abstract There is conflicting evidence regarding the effect of coronavirus disease (COVID-19) in pregnancy. Risk factors for COVID-19 overlap with risk factors for pregnancy complications. We aimed to assess the effects of the COVID-19 pandemic and confirmed SARS-CoV-2 infection on pregnancy outcomes. A retrospective interrupted time-series and matched cohort analysis was performed. Singleton pregnancies completed between 1st January 2016 and 31st January 2021 were included. Trends in outcomes were analysed over time. Modelled COVID-19 transmission data were applied to deliveries since 1st January 2020 to assign a risk of COVID-19 to each pregnancy, and incorporated into a regression model of birthweight. Confirmed COVID-19 cases were matched to controls delivered in the pre-pandemic period, and maternal and neonatal outcomes compared. 43,802 pregnancies were included, with 8343 in the model of birthweight. There was no increase in the risk of stillbirth (p = 0.26) or neonatal death (p = 0.64) during the pandemic. There was no association between modelled COVID-19 attack rate (%) in any trimester and birthweight (first trimester p = 0.50, second p = 0.15, third p = 0.16). 214 COVID-positive women were matched to controls. Preterm birth was more common in symptomatic cases (14/62, 22.6%) compared to asymptomatic cases (9/109, 8.3%, p = 0.008) and controls (5/62, 8.1%, p = 0.025). Iatrogenic preterm birth was more common in cases (21/214, 9.8%) than controls (9/214, 4.2%, p = 0.02). All other examined outcomes were similar between groups. There was no significant impact of COVID-19 on the examined birth outcomes available. Symptomatic COVID-19 should be considered a risk factor for preterm birth, possibly due to an increase in iatrogenic deliveries for maternal indications.

Observations of high-redshift galaxies provide a critical direct test to the theories of early galaxy formation, yet to date, only three have been spectroscopically confirmed at z > 12. Due to strong gravitational lensing over a wide area, the galaxy cluster field A2744 is ideal for searching for the earliest galaxies. Here we present JWST/NIRSpec observations of two galaxies: a robust detection at ${z}_{\mathrm{spec}}={12.393}_{-0.001}^{+0.004}$ , and a plausible candidate at ${z}_{\mathrm{spec}}={13.079}_{-0.001}^{+0.013}$ . The galaxies are discovered in JWST/NIRCam imaging and their distances are inferred with JWST/NIRSpec spectroscopy, all from the JWST Cycle 1 UNCOVER Treasury survey. Detailed stellar population modeling using JWST NIRCam and NIRSpec data corroborates the primeval characteristics of these galaxies: low mass (∼10 ^8 M _⊙ ), young, rapidly assembling, metal-poor, and star-forming. Interestingly, both galaxies are spatially resolved, having lensing-corrected rest-UV effective radii on the order of 300–400 pc, which are notably larger than other spectroscopically confirmed systems at similar redshifts. The observed dynamic range of z ≳ 10 sizes spans over 1 order of magnitude, implying a significant scatter in the size–mass relation at early times. Deep into the epoch of reionization, these discoveries elucidate the emergence of the first galaxies.

Deep observations with the James Webb Space Telescope (JWST) have revealed an emerging population of red pointlike sources that could provide a link between the postulated supermassive black hole seeds and observed quasars. In this work, we present a JWST/NIRSpec spectrum from the JWST Cycle 1 UNCOVER Treasury survey of a massive accreting black hole at z = 8.50 displaying a clear broad-line component as inferred from the H β line with FWHM = 3439 ± 413 km s ^−1 , typical of the broad-line region of an active galactic nucleus (AGN). The AGN nature of this object is further supported by high ionization, as inferred from emission lines, and a point-source morphology. We compute a black hole mass of ${\mathrm{log}}_{10}({M}_{\mathrm{BH}}/{M}_{\odot })=8.17\pm 0.42$ and a bolometric luminosity of L _bol ∼ 6.6 × 10 ^45 erg s ^−1 . These values imply that our object is accreting at ∼40% of the Eddington limit. Detailed modeling of the spectral energy distribution in the optical and near-infrared, together with constraints from ALMA, indicate an upper limit on the stellar mass of ${\mathrm{log}}_{10}({M}_{* }/{M}_{\odot })\lt 8.7$ , which would lead to an unprecedented ratio of black hole to host mass of at least ∼30%. This is orders of magnitude higher compared to the local QSOs but consistent with recent AGN studies at high redshift with JWST. This finding suggests that a nonnegligible fraction of supermassive black holes either started out from massive seeds and/or grew at a super-Eddington rate at high redshift. Given the predicted number densities of high- z faint AGN, future NIRSpec observations of larger samples will allow us to further investigate galaxy–black hole coevolution in the early Universe.

The James Webb Space Telescope is now detecting early black holes (BHs) as they transition from “seeds” to supermassive BHs. Recently, Bogdan et al. reported the detection of an X-ray luminous supermassive BH, UHZ-1, with a photometric redshift at z > 10. Such an extreme source at this very high redshift provides new insights on seeding and growth models for BHs given the short time available for formation and growth. Harnessing the exquisite sensitivity of JWST/NIRSpec, here we report the spectroscopic confirmation of UHZ-1 at z = 10.073 ± 0.002. We find that the NIRSpec/Prism spectrum is typical of recently discovered z ≈ 10 galaxies, characterized primarily by star formation features. We see no clear evidence of the powerful X-ray source in the rest-frame UV/optical spectrum, which may suggest heavy obscuration of the central BH, in line with the Compton-thick column density measured in the X-rays. We perform a stellar population fit simultaneously to the new NIRSpec spectroscopy and previously available photometry. The fit yields a stellar-mass estimate for the host galaxy that is significantly better constrained than prior photometric estimates ( ${M}_{\star }\sim {1.4}_{-0.4}^{+0.3}\times {10}^{8}$ M _⊙ ). Given the predicted BH mass ( M _BH ∼ 10 ^7 –10 ^8 M _⊙ ), the resulting ratio of M _BH / M _⋆ remains 2 to 3 orders of magnitude higher than local values, thus lending support to the heavy seeding channel for the formation of supermassive BHs within the first billion years of cosmic evolution.

This paper reports the first measurement of the relationship between turbulent velocity and cloud size in the diffuse circumgalactic medium (CGM) in typical galaxy halos at redshift z ≈ 0.4–1. Through spectrally resolved absorption profiles of a suite of ionic transitions paired with careful ionization analyses of individual components, cool clumps of size as small as l _cl ∼ 1 pc and density lower than n _H = 10 ^−3 cm ^−3 are identified in galaxy halos. In addition, comparing the line widths between different elements for kinematically matched components provides robust empirical constraints on the thermal temperature T and the nonthermal motions b _NT , independent of the ionization models. On average, b _NT is found to increase with l _cl following ${b}_{\mathrm{NT}}\propto {l}_{\mathrm{cl}}^{0.3}$ over three decades in spatial scale from l _cl ≈ 1 pc to l _cl ≈ 1 kpc. Attributing the observed b _NT to turbulent motions internal to the clumps, the best-fit b _NT – l _cl relation shows that the turbulence is consistent with Kolmogorov at

The [O iii ] 5007 Å emission line is the most common tracer of warm, ionized outflows in active galactic nuclei across cosmic time. JWST newly allows us to use mid-IR spectral features at both high spatial and spectral resolution to probe these same winds. Here we present a comparison of ground-based, seeing-limited [O iii ] and space-based, diffraction-limited [S iv ] 10.51 μ m maps of the powerful, kiloparsec-scale outflow in the Type 1 red quasar SDSS J110648.32+480712.3. The JWST data are from the Mid-InfraRed Instrument. There is a close match in resolution between the data sets (∼0.″6), in ionization potential of the O ^+2 and S ^+3 ions (35 eV) and in line sensitivity (1–2 × 10 ^−17 erg s ^−1 cm ^−2 arcsec ^−2 ). The [O iii ] and [S iv ] line shapes match in velocity and line width over much of the 20 kpc outflowing nebula, and [S iv ] is the brightest line in the rest-frame 3.5–19.5 μ m range, demonstrating its usefulness as a mid-IR probe of quasar outflows. [O iii ] is nevertheless intrinsically brighter and provides better contrast with the point-source continuum, which is strong in the mid-IR. There is a strong anticorrelation of [O iii ]/[S iv ] with average velocity, which is consistent with a scenario of differential obscuration between the approaching (blueshifted) and receding (redshifted) sides of the flow. The dust in the wind may also obscure the central quasar, consistent with models that attribute red quasar extinction to dusty winds.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.

A 53-day-old girl with absent right atrioventricular (AV) connection, malposed great vessels, and pulmonary atresia underwent placement of a central shunt on the sixth day of her life. Her postoperative course was complicated by progressive desaturation, and computed tomographic angiography (CTA) demonstrated near-complete occlusion of her left pulmonary artery (LPA). Angiography demonstrated a nonocclusive thrombus in the distal central shunt and a thrombus with complete occlusion of the LPA. The Indigo aspiration system (Penumbra) was used to remove the thrombus from the central shunt and LPA, allowing placement of a stent in the narrowed LPA. Subsequent angiography showed a wide patient central shunt and LPA. The Indigo aspiration system (Penumbra) provides a viable option for removing thrombus in a patients refractory to other methods.

Sphingolipids like sphingosine-1-phosphate (S1P) have been implicated in the pathophysiology of pre-eclampsia. We hypothesized that plasma S1P would be increased in women at high risk of developing pre-eclampsia who subsequently develop the disease. Low circulating placental growth factor (PlGF) is known to be associated with development of pre-eclampsia; so further, we hypothesized that increased S1P would be associated with concurrently low PlGF. This was a case-control study using stored maternal blood samples from 14 to 24 weeks of pregnancy, collected from 95 women at increased risk of pre-eclampsia. Pregnancy outcome was classified as uncomplicated, preterm pre-eclampsia (

Abstract Carbonate rocks undergo low-temperature, post-depositional changes, including mineral precipitation, dissolution, or recrystallisation (diagenesis). Unravelling the sequence of these events is time-consuming, expensive, and relies on destructive analytical techniques, yet such characterization is essential to understand their post-depositional history for mineral and energy exploitation and carbon storage. Conversely, hyperspectral imaging offers a rapid, non-destructive method to determine mineralogy, while also providing compositional and textural information. It is commonly employed to differentiate lithology, but it has never been used to discern complex diagenetic phases in a largely monomineralic succession. Using spatial-spectral endmember extraction, we explore the efficacy and limitations of hyperspectral imaging to elucidate multi-phase dolomitization and cementation in the Cathedral Formation (Western Canadian Sedimentary Basin). Spectral endmembers include limestone, two replacement dolomite phases, and three saddle dolomite phases. Endmember distributions were mapped using Spectral Angle Mapper, then sampled and analyzed to investigate the controls on their spectral signatures. The absorption-band position of each phase reveals changes in %Ca (molar Ca/(Ca + Mg)) and trace element substitution, whereas the spectral contrast correlates with texture. The ensuing mineral distribution maps provide meter-scale spatial information on the diagenetic history of the succession that can be used independently and to design a rigorous sampling protocol.

El propósito de la investigación fue integrar las buenas prácticas y normas internacionales relacionadas con las tecnologías de información para definir un marco de gestión y adoptar el modelo de computación en la nube en universidades peruanas con la finalidad de garantizar eficientemente la continuidad, disponibilidad y capacidad de los servicios de tecnologías de información bajo el esquema pago por uso. La investigación estuvo enmarcada en el aspecto tecnológico, en virtud de la propuesta realizada para solucionar un problema real presentado en el sistema universitario; por cuanto se logró definir el marco de gestión para la adopción del modelo de computación en la nube, la misma que contempla cinco dimensiones: negocio, personas, tecnología, información y seguridad, contemplado en cinco categorías: planificación, implementación, monitoreo, soporte y evaluación, los cuales están definidos en 24 procesos, roles y productos de trabajo.; el que será implementado mediante el ciclo de desarrollo. Se concluye que el modelo de computación en la nube, permitirá a las instituciones involucradas ventajas competitivas y generación de valor.

Abstract Plasmodium knowlesi, a simian malaria parasite responsible for all recent indigenous cases of malaria in Malaysia, infects humans throughout Southeast Asia. There are two genetically distinct subpopulations of Plasmodium knowlesi in Malaysian Borneo, one associated with long-tailed macaques (termed cluster 1) and the other with pig-tailed macaques (cluster 2). A prospective study was conducted to determine whether there were any between-subpopulation differences in clinical and laboratory features, as well as in epidemiological characteristics. Over 2 years, 420 adults admitted to Kapit Hospital, Malaysian Borneo with knowlesi malaria were studied. Infections with each subpopulation resulted in mostly uncomplicated malaria. Severe disease was observed in 35/298 (11.7%) of single cluster 1 and 8/115 (7.0%) of single cluster 2 infections (p = 0.208). There was no clinically significant difference in outcome between the two subpopulations. Cluster 1 infections were more likely to be associated with peri-domestic activities while cluster 2 were associated with interior forest activities consistent with the preferred habitats of the respective macaque hosts. Infections with both P. knowlesi subpopulations cause a wide spectrum of disease including potentially life-threatening complications, with no implications for differential patient management.

Background: Previous reports have revealed inadequate resident education and textbook representation of dermatological conditions in patients with skin of color (SoC). This suggests that the literature and continuing medical education are important alternative dermatology educational resources to aid in diagnosing and treating patients of color. Objective: This study develops criteria to assess and examine the prevalence of SoC-related publications among top dermatology journals. Methods: We developed the first-ever prespecified criteria that allow for the assessment of diversity in the dermatologic literature. The archives of 52 dermatology journals from January 2018 to October 2020, selected based on Scopus ranking, were analyzed for journal characteristics and content regarding skin and hair of color, diversity and inclusion, and socioeconomic/health care disparities that affect underrepresented populations with SoC. Results: Our study reveals that the average percentage of overall publications relevant to SoC is quite low. The percent of SoC articles ranged from 2.04% to 16.8% with a mean of 16.3%. The top-performing dermatology journals in SoC were, not surprisingly, from countries with populations with SoC; however, the Journal of Cosmetic and Laser Therapy, Australasian Journal of Dermatology, and Journal of the American Academy of Dermatol Case Reports were among the top 10. Research and higher-impact journals were among the lowest in SoC rankings, including the Journal of Investigative Dermatology, Experimental Dermatology, and Journal of the American Academy of Dermatology, and had

Background: Mentorship can have a profound impact on the success and happiness of a mentee while also providing a sense of fulfillment and enrichment for the mentor. Both officially designated and spontaneously chosen mentors can be useful for protégés as they navigate through their training and professional work environment while striving to obtain the optimal work–life balance. Different genders can have variable experiences, in both their personal lives managing family obligations and their professional lives as dermatologists, which may affect the advice and guidance offered. Objective: We studied the impact of gender on the mentor–mentee relationship for both official and spontaneous mentorships through a voluntary survey with a focus on reported outcomes from the perspective of the mentee. Methods: Participants were selected through e-mail invitation via the Women's Dermatologic Society and program directors of the Association of Professors of Dermatology membership lists and given a link to the anonymous survey tool. The survey included 13 questions looking at official and spontaneous mentorships, the role of gender, and success in the dermatology field. Results: Of the 288 respondents, 202 (69.9%) were women, 86 (29.8%) were men, and one identified as other. Of the survey participants, 81% had official mentors and 91% had spontaneous mentors, with the overlap indicating that there may have been a history of multiple mentors per individual. Mentoring had an overall significant positive impact, and 98.5% of those in the spontaneous-mentor group rated the mentor as helpful compared with 87.6% in the official-mentor cohort. For official mentorships, 60.1% involved gender-similar mentors, and of those who had officially designated mentors of any type, 55% indicated a preference for mentors of the same gender. When specifically looking at respondents who participated in same-gender official mentorships, 65.5% preferred this type; of those who had a gender-dissimilar equivalent, only 36.7% indicated a preference for gender similarity in a mentor. Comparably, 59% of protégés with spontaneous mentors had a gender-similar one, and of those who had spontaneous mentors of any type, 59.2% preferred gender similarity. When considering only those in gender-similar spontaneous mentorships, 74.5% favored a same-gender pairing compared with 32.9% of those in the gender-dissimilar group. For female–female official mentorships, 75% preferred a female mentor, similar to 80.5% of the spontaneous-mentor cohort. Conclusion: Spontaneous mentors may provide a greater benefit than officially designated ones. For the majority of the categories, there was no statistical difference between female same-gender mentorships and gender-dissimilar relationships, which is in contrast with previously published literature. Overall, based on the feedback provided, the respondents believed that the quality of the relationship was the most important defining factor, but some noted that same-gender mentorships can provide additional benefit geared toward similar interests and experiences in life.

Cutaneous T-cell lymphoma (CTCL) encompasses a group of low-grade, non-Hodgkin lymphoma, including mycosis fungoides and Sézary syndrome. Diagnosis of CTCL can be challenging given the prolonged, gradual onset and shared characteristics with many benign inflammatory skin diseases. In this case series, we describe four unique cases of patients with chronic, recalcitrant eczematous dermatitis who presented for a patch-test consultation and were ultimately diagnosed with CTCL. In particular, we highlight clinical pearls to aid in distinguishing CTCL from inflammatory dermatoses and describe the diagnostic strategy to help dermatologists arrive at the diagnosis of CTCL at earlier stages of the disease.

Invariant natural killer T (iNKT) cells are innate T cells that are recognized for their potent immune modulatory functions. Over the last three decades, research in murine models and human observational studies have revealed that iNKT cells can act to limit inflammatory pathology in a variety of settings. Since iNKT cells are multi-functional and can promote inflammation in some contexts, understanding the mechanistic basis for their anti-inflammatory effects is critical for effectively harnessing them for clinical use. Two contrasting mechanisms have emerged to explain the anti-inflammatory activity of iNKT cells: that they drive suppressive pathways mediated by other regulatory cells, and that they may cytolytically eliminate antigen presenting cells that promote excessive inflammatory responses. How these activities are controlled and separated from their pro-inflammatory functions remains a central question. Murine iNKT cells can be divided into four functional lineages that have either pro-inflammatory (NKT1, NKT17) or anti-inflammatory (NKT2, NKT10) cytokine profiles. However, in humans these subsets are not clearly evident, and instead most iNKT cells that are CD4+ appear oriented towards polyfunctional (TH0) cytokine production, while CD4- iNKT cells appear more predisposed towards cytolytic activity. Additionally, structurally distinct antigens have been shown to induce TH1- or TH2-biased responses by iNKT cells in murine models, but human iNKT cells may respond to differing levels of TCR stimulation in a way that does not neatly separate TH1 and TH2 cytokine production. We discuss the implications of these differences for translational efforts focused on the anti-inflammatory activity of iNKT cells.

Transforming growth factor β (TGFβ) is an important differentiation factor for cytotoxic T lymphocytes (CTLs) and alters the expression levels of several of homing receptors during infection. SMAD4 is part of the canonical signaling network used by members of the transforming growth factor family. For this study, genetically modified mice were used to determine how SMAD4 and TGFβ receptor II (TGFβRII) participate in transcriptional programming of pathogen-specific CTLs. We show that these molecules are essential components of opposing signaling mechanisms, and cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissues. TGFβ uses a canonical SMAD-dependent signaling pathway to downregulate Eomesodermin (EOMES), KLRG1, and CD62L, while CD103 is induced. Conversely, in vivo and in vitro data show that EOMES, KLRG1, CX3CR1, and CD62L are positively regulated via SMAD4, while CD103 and Hobit are downregulated. Intravascular staining also shows that signaling via SMAD4 promotes formation of long-lived terminally differentiated CTLs that localize in the vasculature. Our data show that inflammatory molecules play a key role in lineage determination of pathogen-specific CTLs, and use SMAD-dependent signaling to alter the expression levels of multiple homing receptors and transcription factors with known functions during memory formation.

Background: Positive interactions that build good relationships between patients and providers demonstrate improved health outcomes for patients. Yet, racial minority patients may not be on an equal footing in having positive interactions. Stereotype threat and implicit bias in clinical medicine negatively affect the quality of care that racial minorities receive. Dermatology, one of the least racially diverse specialties in medicine, further falls short in providing patients with options for race-concordant visits, which are noted to afford improved experiences and outcomes. Objective: This study aimed to analyze implicit bias and stereotype threat in a dermatology clinical scenario with the goal of identifying actions that providers, particularly those that are not racial minorities, can take to improve the quality of the clinical interactions between the minority patient and provider. Methods: We illustrate a hypothetical patient visit and identify elements that are susceptible to both stereotype threat and implicit bias. We then develop an action plan that dermatologists can use to combat stereotype threat and implicit bias in the clinical setting. Results: The details of an action plan to combat the effect of stereotype threat and implicit bias are as follows: 1) Invite practices that increase representation within all aspects of the patient visit (from wall art to mission statements to creating a culture that embraces difference and not just diversity); 2) employ communication techniques targeted to invite and understand the patient perspective; and 3) practice making empathic statements to normalize anxiety and foster connection during the visit. Conclusion: Knowledge of stereotype threat and implicit bias and their sequelae, as well as an understanding of steps that can be taken preemptively to counteract these factors, create opportunities to improve clinical care and patient outcomes in racial minority patients.

Infections with bacteria of the genus Sarcina are associated with gastric diseases of unclear etiology. Here, Owens et al. show that infection with a distinct Sarcina species is strongly associated with a lethal disease that affects sanctuary chimpanzees in Sierra Leone.

Sustained signaling through the B cell antigen receptor (BCR) is thought to occur only when antigen(s) crosslink or disperse multiple BCR units, such as by multimeric antigens found on the surfaces of viruses or bacteria. B cell-intrinsic Toll-like receptor (TLR) signaling synergizes with the BCR to induce and shape antibody production, hallmarked by immunoglobulin (Ig) class switch recombination (CSR) of constant heavy chains from IgM/IgD to IgG, IgA or IgE isotypes, and somatic hypermutation (SHM) of variable heavy and light chains. Full B cell differentiation is essential for protective immunity, where class switched high affinity antibodies neutralize present pathogens, memory B cells are held in reserve for future encounters, and activated B cells also serve as semi-professional APCs for T cells. But the rules that fine-tune B cell differentiation remain partially understood, despite their being essential for naturally acquired immunity and for guiding vaccine development. To address this in part, we have developed a cell culture system using splenic B cells from naive mice stimulated with several biotinylated ligands and antibodies crosslinked by streptavidin reagents. In particular, biotinylated lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, and biotinylated anti-IgM were pre-assembled (multimerized) using streptavidin, or immobilized on nanoparticles coated with streptavidin, and used to active B cells in this precisely controlled, high throughput assay. Using B cell proliferation and Ig class switching as metrics for successful B cell activation, we show that the stimuli are both synergistic and dose-dependent. Crucially, the multimerized immunoconjugates are most active over a narrow concentration range. These data suggest that multimericity is an essential requirement for B cell BCR/TLRs ligands, and clarify basic rules for B cell activation. Such studies highlight the importance in determining the choice of single vs multimeric formats of antigen and PAMP agonists during vaccine design and development.

Humans are infected with two types of EBV (Type 1 (T1) and Type 2 (T2)) that differ substantially in their EBNA2 and EBNA 3A/B/C latency proteins and have different phenotypes in B cells. T1 EBV transforms B cells more efficiently than T2 EBV in vitro, and T2 EBV-infected B cells are more lytic. We previously showed that both increased NFATc1/c2 activity, and an NFAT-binding motif within the BZLF1 immediate-early promoter variant (Zp-V3) contained in all T2 strains, contribute to lytic infection in T2 EBV-infected B cells. Here we compare cellular and viral gene expression in early-passage lymphoblastoid cell lines (LCLs) infected with either T1 or T2 EBV strains. Using bulk RNA-seq, we show that T2 LCLs are readily distinguishable from T1 LCLs, with approximately 600 differentially expressed cellular genes. Gene Set Enrichment Analysis (GSEA) suggests that T2 LCLs have increased B-cell receptor (BCR) signaling, NFAT activation, and enhanced expression of epithelial-mesenchymal-transition-associated genes. T2 LCLs also have decreased RNA and protein expression of a cellular gene required for survival of T1 LCLs, IRF4. In addition to its essential role in plasma cell differentiation, IRF4 decreases BCR signaling. Knock-down of IRF4 in a T1 LCL (infected with the Zp-V3-containing Akata strain) induced lytic reactivation whereas over-expression of IRF4 in Burkitt lymphoma cells inhibited both NFATc1 and NFATc2 expression and lytic EBV reactivation. Single-cell RNA-seq confirmed that T2 LCLs have many more lytic cells compared to T1 LCLs and showed that lytically infected cells have both increased NFATc1, and decreased IRF4, compared to latently infected cells. These studies reveal numerous differences in cellular gene expression in B cells infected with T1 versus T2 EBV and suggest that decreased IRF4 contributes to both the latent and lytic phenotypes in cells with T2 EBV. Author summary EBV is an important cause of human B-cell malignancies and transforms B cells in vitro. Although there are two different types of EBV (T1 and T2), most research has been performed using T1 strains and much less is known about how T2 EBV interacts with B cells. T2 EBV is most frequently found in regions of Africa where malaria is common, and we recently showed that B cells infected with T2 EBV have more lytic infection compared to B cells infected with T1 EBV. Here we used both bulk and single-cell RNA-seq analysis to globally define the differences in cellular gene expression in early passage EBV-transformed lymphoblastoid cell lines (LCLs) infected with T1 versus T2 EBV strains. These studies reveal that hundreds of cellular genes are differentially expressed in T1 versus T2 LCLs, and that most of these differences in gene expression occur in the latently infected cells. We also find that decreased expression of the cellular transcription factor, IRF4, contributes to the both the latent and lytic phenotypes of T2 EBV infected B cells. Together these results suggest that T1 and T2 EBV have distinctly different effects in infected B cells.