Phenome-wide association study identifies new clinical phenotypes associated with Staphylococcus aureus infections.

BACKGROUND: Phenome-Wide Association study (PheWAS) is a powerful tool designed to systematically screen clinical observations derived from medical records (phenotypes) for association with a variable of interest. Despite their usefulness, no systematic screening of phenotypes associated with Staphylococcus aureus infections (SAIs) has been done leaving potential novel risk factors or complications undiscovered. METHOD AND COHORTS: We tailored the PheWAS approach into a two-stage screening procedure to identify novel phenotypes correlating with SAIs. The first stage screened for co-occurrence of SAIs with other phenotypes within medical records. In the second stage, significant findings were examined for the correlations between their age of onset with that of SAIs. The PheWAS was implemented using the medical records of 754,401 patients from the Marshfield Clinic Health System. Any novel associations discovered were subsequently validated using datasets from TriNetX and All of Us, encompassing 109,884,571 and 118,538 patients respectively. RESULTS: Forty-one phenotypes met the significance criteria of a p-value < 3.64e-5 and odds ratios of > 5. Out of these, we classified 23 associations either as risk factors or as complications of SAIs. Three novel associations were discovered and classified either as a risk (long-term use of aspirin) or complications (iron deficiency anemia and anemia of chronic disease). All novel associations were replicated in the TriNetX cohort. In the All of Us cohort, anemia of chronic disease was replicated according to our significance criteria. CONCLUSIONS: The PheWAS of SAIs expands our understanding of SAIs interacting phenotypes. Additionally, the novel two-stage PheWAS approach developed in this study can be applied to examine other disease-disease interactions of interest. Due to the possibility of bias inherent in observational data, the findings of this study require further investigation.

Self-Reported Hypersensitivity to Smells: Objective Evidence for Hyposmia, not Hyperosmia.

OBJECTIVE: To compare, using state-of-the-art psychophysical tests, the olfactory function of patients complaining and not complaining of olfactory hypersensitivity. STUDY DESIGN: Retrospective cross-sectional. SETTING: The Smell and Taste Center at the University of Pennsylvania. METHODS: University of Pennsylvania Smell Identification Test (UPSIT) scores were obtained from 148 patients complaining of hyperosmia and 494 patients with no such complaints; detection threshold test scores were obtained from 77 and 483 patients of these respective groups. The effects of subject group, age, and sex on the test scores were assessed using analyses of variance. Categorical variables were evaluated by χ2. Responses to items within a detailed intake questionnaire, for example, the Beck Depression Inventory (BDI-II), were also evaluated. RESULTS: Unexpectedly, those complaining of hyperosmia had lower olfactory test scores than those with no such complaints (respective UPSIT means [95% confidence interval [CIs]] = 27.86 (26.85, 28.87) and 32.19 (31.67, 32.71); P < .001; respective threshold means (log vol/vol) = -4.49 (-4.89, -4.09) and -5.22 (-5.36, -5.06); P < .001). Remarkably, 70.95% of the self-identified hyperosmics exhibited mild to severe microsmia. The hyposmia complainers also exhibited elevated BDI scores (11.02 [9.53, 12.51] vs 7.58 [6.80, 8.34]). CONCLUSION: When objectively tested, many patients who complain of hypersensitivity to odors are actually less sensitive to them. The basis of this phenomenon is unclear. It could reflect the presence of emotionally disturbing altered smell sensations, or one or more comorbidities, such as hypochondria or osmophobia. These findings point to the importance of objective testing of persons with complaints of chemosensory dysfunction and reiterate the inaccuracy of self-reports.

A morphoscopic exploration of cranial sexual dimorphism among modern South Africans using computed tomography scans.

Continual re-evaluation of standards for forensic anthropological analyses are necessary, particularly as new methods are explored or as populations change. Indian South Africans are not a new addition to the South African population; however, a paucity of skeletal material is available for analysis from medical school collections, which has resulted in a lack of information on the sexual dimorphism in the crania. For comparable data, computed tomography scans of modern Black, Coloured and White South Africans were included in addition to Indian South Africans. Four cranial morphoscopic traits, were assessed on 408 modern South Africans (equal sex and population distribution). Frequencies, Chi-squared tests, binary logistic regression and random forest modelling were used to assess the data. Males were more robust than females for all populations, while White South African males were the most robust, and Black South African females were the most gracile. Population differences were noted among most groups for at least two variables, necessitating the creation of populations-specific binary logistic regression equations. Only White and Coloured South Africans were not significantly different. Indian South Africans obtained the highest correct classifications for binary logistic regression (94.1%) and random forest modelling (95.7%) and Coloured South Africans had the lowest correct classifications (88.8% and 88.0%, respectively). This study provides a description of the patterns of sexual dimorphism in four cranial morphoscopic traits in the current South African population, as well as binary logistic regression functions for sex estimation of Black, Coloured, Indian and White South Africans.

What Encourages Patients to Recommend Their Doctor After an Online Medical Consultation? The Influence of Patient-Centered Communication, Trust, and Negative Health Information Seeking Experiences.

The doctor-patient relationship in China has become increasingly tense, with patients lacking trust in doctors. Meanwhile, online healthcare flourished, accelerated by the COVID-19 pandemic. This study utilized the direct and indirect pathway model of clinician-patient communication to health outcomes and online trust theory to examine the associations between online patient-centered communication (OPCC), benevolence and ability trust in doctors, negative online health information seeking experiences, and willingness to recommend doctors. The findings revealed that benevolence and ability trust mediated the relationship between OPCC and willingness to recommend doctors. Additionally, when participants had a high level of negative online health information seeking experiences, OPCC had a stronger effect on ability trust; meanwhile, the mediation effect of ability trust between the relationship of OPCC and willingness to recommend was stronger. This study also discussed theoretical and practical implications.

Glucose-based biofuel cells and their applications in medical implants: A review.

In glucose biofuel cells (G-BFCs), glucose oxidation at the anode and oxygen reduction at the cathode yield electrons, which generate electric energy that can power a wide range of electronic devices. Research associated with the development of G-BFCs has increased in popularity among researchers because of the eco-friendly nature of G-BFCs (as related to their construction) and their evolution from inexpensive bio-based materials. In addition, their excellent specificity towards glucose as an energy source, and other properties, such as small size and weight, make them attractive within various demanding applied environments. For example, G-BFCs have received much attention as implanted devices, especially for uses related to cardiac activities. Envisioned pacemakers and defibrillators powered by G-BFCs would not be required to have conventional lithium batteries exchanged every 5-10 years. However, future research is needed to develop G-BFCs demonstrating more stable power consistency and improved lifespan, as well as solving the challenges in converting laboratory-made implantable G-BFCs into implanted devices in the human body. The categorization of G-BFCs as a subcategory of different biofuel cells and their performance is reviewed in this article.

Association of hepatitis B virus treatment with all-cause and liver-related mortality among individuals with HBV and cirrhosis: a population-based cohort study.

Background: We evaluated the association of hepatitis B virus (HBV) treatment with all-cause, and liver-related mortality among individuals with HBV and cirrhosis in British Columbia (BC), Canada. Methods: This analysis included people diagnosed with HBV and had cirrhosis in the BC Hepatitis Testers Cohort, including data on all individuals diagnosed with HBV from 1990 to 2015 in BC and integrated with healthcare administrative data. We followed people with cirrhosis from the first cirrhosis diagnosis date until death or December 31, 2020. We compared all-cause and liver related mortality between those who received treatment and those who did not. HBV treatment was considered a time-varying variable. We performed multivariable Cox proportional hazards model and competing risk regression models to assess the association of HBV treatment with all causes, and liver-related mortality respectively using inverse probability of treatment weighted population. Findings: Among 4962 individuals with HBV and cirrhosis, 48.1% received HBV treatment. Treated individuals had a median follow-up of 2.97 years, compared to 2.87 years for untreated individuals. The treated group was older (median age 57 vs 54 years), had higher proportion of treated of males [1802 (75.50%) vs 1766 (68.8%)], from urban area [2318 (97.2%) vs 2355 (91.8%)], and from East and South Asian ethnicity [1506 (63.1%) vs 709 (27.5%)] compared to untreated group. Untreated people experienced higher all-cause mortality (115.47 vs. 35.72 per 1000 person-years) and liver-related mortality (49.86 vs. 11.39 per 1000 person-years). Multivariable models showed that HBV treatment significantly lowered the risk of all-cause mortality (adjusted hazard ratio (aHR) 0.74; 95% CI: 0.65, 0.84) and liver-related mortality (adjusted subdistribution hazard ratio (asHR) 0.72; 95% CI: 0.58, 0.89) compared to untreated individuals. Among untreated individuals with HBV, those with HCV coinfection had a higher risk of both all-cause and liver-related mortality (aHR 1.57; 95% CI: 1.22, 2.04, and asHR 1.60; 95% CI: 1.25, 2.05, respectively). Interpretation: HBV treatment was associated with a significant reduction in all-cause and liver-related mortality among individuals with cirrhosis. The findings highlight the need for treatment among individuals with HBV related cirrhosis especially those with coinfection with hepatitis C virus. Funding: This work was supported by the BC Centre for Disease Control and the Canadian Institutes of Health Research (CIHR) [Grant # NHC-142832, PJT-156066, and SC1 -178736]. JDM has received doctoral fellowship from the Canadian Network on Hepatitis C (CanHepC). DJ has received Doctoral Research Award (#201910DF1-435705-64343) from the Canadian Institutes of Health Research (CIHR) and doctoral fellowship from the CanHepC. CanHepC is funded by a joint initiative of the Canadian Institutes of Health Research (CIHR) (NHC-142832) and the Public Health Agency of Canada (PHAC).

Positionally distinct interferon stimulated dermal immune acting fibroblasts promote neutrophil recruitment in Sweet's syndrome.

Sweet's syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet's syndrome revealed a prominent interferon signature in Sweet's syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet's syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet's syndrome through recognition of type I interferons.

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. METHODS: Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. RESULTS: PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). CONCLUSIONS: The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.

Who are the people with chronic severe back pain not receiving pain treatment?

There are substantial access to care barriers for persons with chronic pain. Little is known about persons who do not receive treatment for chronic severe back pain as most studies rely on clinical samples. We sought to explore demographic, socioeconomic and clinical characteristics of U.S. adults with chronic severe back pain who had not received pain care in the preceding 3 months. In this cross-sectional study, we used data from the 2019 National Health Interview Survey and identified persons who did/did not receive treatment (including self-management strategies) in the last three months for their chronic severe back pain. We used bivariate and multivariable analyses to explore factors associated with not receiving pain treatment. Almost 21% of persons with chronic severe back pain did not receive treatment in the past three months. The following were independently associated with not having treatment in the preceding 3 months: male sex (OR = 1.40; 95% CI 1.11-1.76), living near or below the poverty level (OR 1.92; 95% CI 1.33-2.77), having less than a high-school education (OR, 2.37; 95% CI 1.52-3.68), not having insurance coverage (OR 1.77; 95% CI 1.21-2.59), living in the South (OR 2.05; 95% CI 1.40-3.00), having heart disease (OR 1.47; 95% CI 1.11-1.93). Being a single parent, having depression and multiple comorbid painful health conditions were associated with having treatment. Our conclusions are that one-fifth of persons with chronic severe back pain did not receive treatment for at least three months and socioeconomic factors were highly associated with not receiving treatment. PERSPECTIVE: In a nationally representative sample of persons with chronic severe back pain, one-fifth did not receive treatment for at least three months. Socioeconomic factors were highly associated with not receiving treatment. There is a need to implement solutions to reduce barriers to care.

Structural color in the bacterial domain: The ecogenomics of a 2-dimensional optical phenotype.

Structural color is an optical phenomenon resulting from light interacting with nanostructured materials. Although structural color (SC) is widespread in the tree of life, the underlying genetics and genomics are not well understood. Here, we collected and sequenced a set of 87 structurally colored bacterial isolates and 30 related strains lacking SC. Optical analysis of colonies indicated that diverse bacteria from at least two different phyla (Bacteroidetes and Proteobacteria) can create two-dimensional packing of cells capable of producing SC. A pan-genome-wide association approach was used to identify genes associated with SC. The biosynthesis of uroporphyrin and pterins, as well as carbohydrate utilization and metabolism, was found to be involved. Using this information, we constructed a classifier to predict SC directly from bacterial genome sequences and validated it by cultivating and scoring 100 strains that were not part of the training set. We predicted that SCr is widely distributed within gram-negative bacteria. Analysis of over 13,000 assembled metagenomes suggested that SC is nearly absent from most habitats associated with multicellular organisms except macroalgae and is abundant in marine waters and surface/air interfaces. This work provides a large-scale ecogenomics view of SC in bacteria and identifies microbial pathways and evolutionary relationships that underlie this optical phenomenon.

Physician and Practice Characteristics Influencing Telemedicine Uptake Among Frontline Clinicians in the Early COVID-19 Pandemic Response: National Survey Study.

BACKGROUND:  Telemedicine expanded rapidly during the COVID-19 pandemic, as key policy changes, financial support, and pandemic fears tipped the balance toward internet-based care. Despite this increased support and benefits to patients and clinicians, telemedicine uptake was variable across clinicians and practices. Little is known regarding physician and institutional characteristics underlying this variability. OBJECTIVE:  This study aimed to evaluate factors influencing telemedicine uptake among frontline physicians in the early pandemic response. METHODS:  We surveyed a national stratified sample of frontline clinicians drawn from the American Medical Association Physician Professional Data in June or July 2020. The survey inquired about the first month and most recent month (June 2020) of pandemic telemedicine use; sample data included clinician gender, specialty, census region, and years in practice. Local pandemic conditions were estimated from county-level data on COVID-19 rates at the time of survey response. Data were analyzed in a weighted logistic regression, controlling for county-specific pandemic data, and weighted to account for survey data stratification and nonresponse. RESULTS:  Over the first 3-4 months of the pandemic, the proportion of physicians reporting use of telemedicine in >30% of visits increased from 29.2% (70/239) to 35.7% (85/238). Relative to primary care, odds of substantial telemedicine use (>30%) both during the first month of the pandemic and in June 2020 were increased among infectious disease and critical care physicians and decreased among hospitalists and emergency medicine physicians. At least minimal prepandemic telemedicine use (odds ratio [OR] 11.41, 95% CI 1.34-97.04) and a high 2-week moving average of local COVID-19 cases (OR 10.16, 95% CI 2.07-49.97) were also associated with substantial telemedicine use in June 2020. There were no significant differences according to clinician gender, census region, or years in practice. CONCLUSIONS:  Prepandemic telemedicine use, high local COVID-19 case counts, and clinician specialty were associated with higher levels of substantial telemedicine use during the early pandemic response. These results suggest that telemedicine uptake in the face of the pandemic may have been heavily influenced by the level of perceived threat and the resources available for implementation. Such understanding has important implications for reducing burnout and preparation for future public health emergencies.

Discovery of GS-7682, a Novel 4'-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys.

Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and enterovirus (EC50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.

The Rebirth of Radioimmunotherapy of Non-Hodgkin Lymphoma: The Phoenix of Nuclear Medicine?

In Greek mythology, The Phoenix is an immortal bird that dies, but then achieves new life by rising from the ashes of its predecessor. Radioimmunotherapy (RIT) of B-cell Non-Hodgkin lymphoma (NHL) is a field which once began to fly high-with FDA approval of the anti-CD20 RITs Zevalin® and Bexxar® in 2002 and 2003 respectively, as safe and effective therapies of NHL. However, despite their therapeutic efficacy, Bexxar® was withdrawn from the market by the manufacturer in 2014 due to limited commercial demand and Zevalin® has had very limited to no availability of late. I-131 rituximab is used to a limited extent in Australia, India and other countries, as well. But has RIT of NHL been (perhaps prematurely) left for dead by many? Given the current great clinical and commercial interest in radiopharmaceutical therapies of cancer, notably PSMA and SSTR targeting agents in prostate and neuroendocrine cancers, can radioimmunotherapy of NHL-like the mythical Phoenix-now rise from its ashes in an even better form to fly higher, faster, farther and longer than before?

Slow dynamic elasticity at short times.

It has been reported that slow dynamic nonlinear elastic relaxations, widely thought to proceed universally in proportion to the logarithm of time after cessation of mechanical conditioning, actually recover with a smaller slope at early times, with a time of transition that varies with the grain size of the material. This would constitute a heretofore unreported failure of the claimed universality, while suggesting application to nondestructive evaluation and structural health monitoring. Here, we present further observations at short times, in the single bead system, in cement paste, mortar, concrete, sandstone, and granite. Within the limits imposed by finite-duration ring-down such that the effective instant of conditioning cessation is imprecise, and the corresponding ambiguity as to the time at which relaxation begins, we find no reliable sign of such a transition, even in samples of large grain-size mortar and concrete similar to those described elsewhere as having clear and late cutoffs.

Liver stiffness measurement by magnetic resonance elastography predicts cirrhosis and decompensation in alcohol-related liver disease.

PURPOSE: To evaluate magnetic resonance elastography (MRE)-based liver stiffness measurement as a biomarker to predict the onset of cirrhosis in early-stage alcohol-related liver disease (ALD) patients, and the transition from compensated to decompensated cirrhosis in ALD. METHODS: Patients with ALD and at least one MRE examination between 2007 and 2020 were included in this study. Patient demographics, liver chemistries, MELD score (within 30 days of the first MRE), and alcohol abstinence history were collected from the electronic medical records. Liver stiffness and fat fraction were measured. Disease progression was assessed in the records by noting cirrhosis onset in early-stage ALD patients and decompensation in those initially presenting with compensated cirrhosis. Nomograms and cut-off values of liver stiffness, derived from Cox proportional hazards models were created to predict the likelihood of advancing to cirrhosis or decompensation. RESULTS: A total of 182 patients (132 men, median age 57 years) were included in this study. Among 110 patients with early-stage ALD, 23 (20.9%) developed cirrhosis after a median follow-up of 6.2 years. Among 72 patients with compensated cirrhosis, 33 (45.8%) developed decompensation after a median follow-up of 4.2 years. MRE-based liver stiffness, whether considered independently or adjusted for age, alcohol abstinence, fat fraction, and sex, was a significant and independent predictor for both future cirrhosis (Hazard ratio [HR] = 2.0-2.2, p = 0.002-0.003) and hepatic decompensation (HR = 1.2-1.3, p = 0.0001-0.006). Simplified Cox models, thresholds, and corresponding nomograms were devised for practical use, excluding non-significant or biased variables. CONCLUSIONS: MRE-based liver stiffness assessment is a useful predictor for the development of cirrhosis or decompensation in patients with ALD.

In-Vitro Comparison of Titanium Disc Surface Roughness and Bacterial Colonization after Ultrasonic Instrumentation with Three Different Tips.

During implant maintenance, preserving a smooth surface on the machined trans-mucosa abutment is critical to reduce biofilm attachment and colonization. The present study compare the surface roughness and bacterial colonization of machined titanium surfaces after instrumentation with various materials. Forty-four machined Grade 23 titanium discs were instrumented with a round Polyether Ether Ketone (PEEK) tip, a plastic curette tip, or a pure titanium curette tip with piezoelectric devices. Before and after instrumentation, the surface roughness (Ra and Rz) values were analyzed with a profilometer and scanning electron microscopy (SEM). Streptococcus sanguinis was cultured and incubated for 24 hours on the instrumented discs, and colony-forming units (CFU)/mL were obtained for each group. Samples instrumented with the metal ultrasonic tip significantly increased surface roughness compared to the other groups. Thisresulted in greater colonization by S. sanguinis than surfaces instrumented with PEEK tips or the negative control. Samples instrumented with PEEK and plastic tips did not exhibit any statistically significant increase in surface roughness. SEM analysis revealed a significantly rougher surface of discs instrumented with metal compared to discs instrumented with plastic or PEEK tip, despite the possibility of debris from tip dissolution. Our results suggested that instrumentation with metal ultrasonic tips with piezoelectric devices significantly increase machined titanium's surface roughness and elicited higher biofilm formation in vitro. Meanwhile, instrumentation of machined titanium with PEEK or plastic ultrasonic tips did not affect the surface roughness or bacterial adhesion.

A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response.

The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell-intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.

Huntingtin is an RNA binding protein and participates in NEAT1-mediated paraspeckles.

Huntingtin protein, mutated in Huntington's disease, is implicated in nucleic acid-mediated processes, yet the evidence for direct huntingtin-nucleic acid interaction is limited. Here, we show wild-type and mutant huntingtin copurify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA-immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wild-type and mutant huntingtin revealed long noncoding RNA NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntington's disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin colocalized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a huntingtin interactor, demonstrating huntingtin's involvement in RNA-mediated functions and paraspeckle regulation.

The Effect of Retinoic Acid on Neutrophil Innate Immune Interactions With Cutaneous Bacterial Pathogens.

Vitamin A and its biologically active derivative, retinoic acid (RA), are important for many immune processes. RA, in particular, is essential for the development of immune cells, including neutrophils, which serve as a front-line defense against infection. While vitamin A deficiency has been linked to higher susceptibility to infections, the precise role of vitamin A/RA in host-pathogen interactions remains poorly understood. Here, we provided evidence that RA boosts neutrophil killing of methicillin-resistant Staphylococcus aureus (MRSA). RA treatment stimulated primary human neutrophils to produce reactive oxygen species, neutrophil extracellular traps, and the antimicrobial peptide cathelicidin (LL-37). Because RA treatment was insufficient to reduce MRSA burden in an in vivo murine model of skin infection, we expanded our analysis to other infectious agents. RA did not affect the growth of a number of common bacterial pathogens, including MRSA, Escherichia coli K1 and Pseudomonas aeruginosa; however, RA directly inhibited the growth of group A Streptococcus (GAS). This antimicrobial effect, likely in combination with RA-mediated neutrophil boosting, resulted in substantial GAS killing in neutrophil killing assays conducted in the presence of RA. Furthermore, in a murine model of GAS skin infection, topical RA treatment showed therapeutic potential by reducing both skin lesion size and bacterial burden. These findings suggest that RA may hold promise as a therapeutic agent against GAS and perhaps other clinically significant human pathogens.