Monitoring Small-Scale Bioreactor Studies for media Development using polarized Total Synchronous Fluorescence Spectroscopy (pTSFS) and Synchronous Light Scattering (SyLS).

Biopharmaceutical process development often involves the use of small-scale bioreactors (SSBR) for optimizing media formulations and process conditions during scale up to commercial scale production. Two key process parameters (CPP) used in SSBR studies are protein titre and viable cell density (VCD). Here, we explore the efficacy of parallel polarized total synchronous fluorescence spectroscopy (TSFS||) and Synchronous Light Scattering (SyLS||) to qualitatively monitor these CPPs and quantitatively predict titre and VCD for a large-scale cell culture media optimization SSBR study. The study involved 71 different media formulations (50+ components each), and the bioprocess was run for 13 days or more. Samples were extracted at set times (Day 0, 3, 9, and 13) and clarified by centrifugation. TSFS|| spectra showed significant emission changes along with increased light scatter over course of the bioprocess. SyLS|| measurements strongly correlated with particle size data obtained from Dynamic Light Scattering but did not correlate well with VCD probably because of the centrifugation-based sample preparation. Statistical and principal component analysis (PCA) of the pTSFS data showed that spectral variation was greater between media formulations than due to the evolving bioprocess. This prevented the development of accurate global prediction models for media performance (e.g., predicting product titre at day 9 from media spectra measured at day 0). However, classification methods were successfully used to select media subsets with better quantitative prediction accuracy based on spectral similarities. A practical binary (high/low performance) classification model based on Support Vector Machines was generated for media formulation screening. Combining emission and scatter measurements with multivariate data analysis provides a more holistic, multi-attribute bioprocess monitoring method that minimizes the need to use different offline analytical methods. This methodology can be used to monitor process trajectories and deviations, and ultimately be used to predict bioprocess CPPs when implemented on production scale processes where there is much less compositional variation in the media. We believe this SSBR-pTSFS/SyLS approach will provide a valuable resource to develop the design/parameter space for in process monitoring at production scale from early-stage process/media development studies.

Cytomegalovirus chronic retinal necrosis with ganciclovir resistance: a case report.

BACKGROUND: Cytomegalovirus (CMV) chronic retinal necrosis (CRN) is a rare viral retinal infection that occurs in mildly immunocompromised people. It shares some features with both acute retinal necrosis and CMV retinitis. It is typically treated with combination intravitreal and systemic ganciclovir. We discuss the management of a case of CMV CRN with ganciclovir resistance. CASE PRESENTATION: An 80-year-old female presented with one month of blurry vision in the left eye. She was being treated with abatacept, methotrexate, and prednisone for rheumatoid arthritis. Examination revealed anterior chamber and vitreous cell along with peripheral retinal whitening. Fluorescein angiogram showed diffuse retinal non-perfusion. Aqueous fluid PCR testing returned positive for CMV. The retinitis was initially controlled with oral and intravitreal ganciclovir, but then recurred and progressed despite these therapies. Ganciclovir resistance was suspected and the patient was switched to intravitreal foscarnet injections, along with oral letermovir and leflunomide, which lead to resolution of the retinitis. The patient has now continued with letermovir and leflunomide for approximately 2.5 years without reactivation of the retinitis or need for further intravitreal anti-viral injections and with adequate control of her rheumatoid arthritis. CONCLUSION: The incidence of CMV CRN may increase in the future as the use of non-cytotoxic immunosuppressive therapies that result in relatively mild immunosuppression also increases. Treatment with ganciclovir is effective but frequently leads to resistance, as in our case. In this situation, combination therapy with letermovir and leflunomide, particularly in the setting of rheumatoid arthritis where leflunomide can also have an anti-inflammatory effect, can be considered.

Treatment of Ocular Surface Disease in Ocular Cicatricial Pemphigoid.

PURPOSE: While substantial research has focused on systemic immunomodulatory therapy for ocular cicatricial pemphigoid (OCP), limited data exist on managing associated ocular surface disease (OSD). This study evaluates treatments for OCP-related OSD at our institution. METHODS: We conducted a retrospective analysis of patients diagnosed with cicatrizing conjunctivitis at the University of Colorado Hospital from January 1, 2013, to October 31, 2023. Patients with cicatrizing conjunctivitis due to non-OCP conditions were excluded, and disease severity was classified using the Foster Staging System. RESULTS: Our review included 30 patients with OCP, all with at least six months of follow-up. The mean age of symptom onset (n = 19) was 62.2 years (SD = 16.4), while the mean age at diagnosis (n = 28) was 65.1 years (SD = 12.7). The most common OSD treatments at the last visit were preservative-free artificial tears (87%), topical corticosteroids (43%), autologous serum eye drops (40%), topical antibiotics (30%), and topical immunomodulators (23%). All patients used at least one treatment, with 83.3% on prescription therapies. Patients averaged 3.33 (SD: 1.4) treatments, with 1.7 (SD: 1.2) being prescriptions. Topical immunomodulators had the highest discontinuation rate at 73.1% (n = 19/26). Autologous serum eye drops and topical corticosteroids were the least discontinued treatments. Number of total treatments, prescriptions, and procedures sharply increased at stage three OCP. CONCLUSIONS: The number of treatments and procedures increased with OCP severity, indicating that advanced OCP often necessitated more intensive OSD management.

An engineered model of metastatic colonization of human bone marrow reveals breast cancer cell remodeling of the hematopoietic niche.

Incomplete understanding of metastatic disease mechanisms continues to hinder effective treatment of cancer. Despite remarkable advancements toward the identification of druggable targets, treatment options for patients in remission following primary tumor resection remain limited. Bioengineered human tissue models of metastatic sites capable of recreating the physiologically relevant milieu of metastatic colonization may strengthen our grasp of cancer progression and contribute to the development of effective therapeutic strategies. We report the use of an engineered tissue model of human bone marrow (eBM) to identify microenvironmental cues regulating cancer cell proliferation and to investigate how triple-negative breast cancer (TNBC) cell lines influence hematopoiesis. Notably, individual stromal components of the bone marrow niche (osteoblasts, endothelial cells, and mesenchymal stem/stromal cells) were each critical for regulating tumor cell quiescence and proliferation in the three-dimensional eBM niche. We found that hematopoietic stem and progenitor cells (HSPCs) impacted TNBC cell growth and responded to cancer cell presence with a shift of HSPCs (CD34+CD38-) to downstream myeloid lineages (CD11b+CD14+). To account for tumor heterogeneity and show proof-of-concept ability for patient-specific studies, we demonstrate that patient-derived tumor organoids survive and proliferate in the eBM, resulting in distinct shifts in myelopoiesis that are similar to those observed for aggressively metastatic cell lines. We envision that this human tissue model will facilitate studies of niche-specific metastatic progression and individualized responses to treatment.

Strong Surface-Enhanced Coherent Phonon Generation in van der Waals Materials.

Terahertz (THz) coherent phonons have emerged as promising candidates for the next generation of high-speed, low-energy information carriers in atomically thin phononic or phonon-integrated on-chip devices. However, effectively manipulating THz coherent phonons remains a significant challenge. In this study, we investigated THz coherent phonon generation in exfoliated van der Waals (vdW) flakes of Fe3GeTe2, Fe5GeTe2, and FePS3. We successfully generated the THz A1g coherent phonon mode in these vdW flakes. An innovative approach involved partially exfoliating vdW flakes on a gold substrate and partially on a silicon (Si) substrate to compare the THz coherent phonon generation between both sides. Interestingly, we observed a significantly enhanced THz coherent phonon in the vdW/gold area compared with that in the vdW/Si area. Frequency-domain Raman mapping across the vdW flakes corroborated these findings. Numerical simulations further indicated a stronger enhanced surface field in vdW/gold structures than in vdW/Si structures. Consequently, we attribute the observed enhancement in THz coherent phonon generation to the increased surface field on the gold substrate. This enhancement was consistent across the three different vdW materials studied, suggesting the universality of this strategy. Our results hold promise for advancing the design of THz phononic and phonon-integrated devices.

Standardized assessment of evidence supporting the adoption of mobile health solutions: A Clinical Consensus Statement of the ESC Regulatory Affairs Committee: Developed in collaboration with the European Heart Rhythm Association (EHRA), the Association of Cardiovascular Nursing & Allied Professions (ACNAP) of the ESC, the Heart Failure Association (HFA) of the ESC, the ESC Young Community, the ESC Working Group on e-Cardiology, the ESC Council for Cardiology Practice, the ESC Council of Cardio-Oncology, the ESC Council on Hypertension, the ESC Patient Forum, the ESC Digital Health Committee, and the European Association of Preventive Cardiology (EAPC).

Mobile health (mHealth) solutions have the potential to improve self-management and clinical care. For successful integration into routine clinical practice, healthcare professionals (HCPs) need accepted criteria helping the mHealth solutions' selection, while patients require transparency to trust their use. Information about their evidence, safety and security may be hard to obtain and consensus is lacking on the level of required evidence. The new Medical Device Regulation is more stringent than its predecessor, yet its scope does not span all intended uses and several difficulties remain. The European Society of Cardiology Regulatory Affairs Committee set up a Task Force to explore existing assessment frameworks and clinical and cost-effectiveness evidence. This knowledge was used to propose criteria with which HCPs could evaluate mHealth solutions spanning diagnostic support, therapeutics, remote follow-up and education, specifically for cardiac rhythm management, heart failure and preventive cardiology. While curated national libraries of health apps may be helpful, their requirements and rigour in initial and follow-up assessments may vary significantly. The recently developed CEN-ISO/TS 82304-2 health app quality assessment framework has the potential to address this issue and to become a widely used and efficient tool to help drive decision-making internationally. The Task Force would like to stress the importance of co-development of solutions with relevant stakeholders, and maintenance of health information in apps to ensure these remain evidence-based and consistent with best practice. Several general and domain-specific criteria are advised to assist HCPs in their assessment of clinical evidence to provide informed advice to patients about mHealth utilization.

A Multi-Specialty Delphi Consensus on Assessing and Managing Cardiopulmonary Risk in Patients with COPD.

Background: In Canada, COPD represents a significant burden to the patient and health system, as it is often under or misdiagnosed and sub-optimally treated. Cardiovascular disease (CVD) is a common co-morbidity in COPD and there is significant interplay between these two chronic conditions. Across all stages of COPD disease severity, deaths can be attributed not only to respiratory causes but also to cardiovascular-related factors. The established links between COPD and CVD suggest the need for a greater degree of collaboration between respirologists and cardiologists. This modified Delphi consensus was initiated to consider how optimal COPD care can be delivered within Canada, with specific consideration of reducing cardiopulmonary risk and outcomes in COPD patients. Methods: A steering group with interest in the management of COPD and CVD from primary care, cardiology, and respirology identified 40 statements formed from four key themes. A 4-point Likert scale questionnaire was sent to healthcare professionals working in COPD across Canada by an independent third party to assess agreement (consensus) with these statements. Consensus was defined as high if ≥75% and very high if ≥90% of respondents agreed with a statement. Results: A total of 100 responses were received from respirologists (n=30), cardiologists (n=30), and primary care physicians (n=40). Consensus was very strong (≥90%) in 28 (70%) statements, strong (≥75 and <90%) in 7 (17.5%) statements and was not achieved (<75%) in 5 (12.5%) of statements. Conclusion: Based on the consensus scores, 9 key recommendations were proposed by the steering group. These focus on the need to comprehensively risk stratify and manage COPD patients to help prevent exacerbations. Consensus within this study provides a call to action for the expeditious implementation of the latest COPD guidelines from the Canadian Thoracic Society.

Computational modeling of social decision-making.

Social decision-making is guided by a complex set of social norms. Computational modeling can play a significant role in enriching our understanding of these norms and how precisely they direct social choices. Here, we highlight three major advantages to using computational modeling, particularly models derived from Utility Theory, in the study of social norms. We illustrate how such models can help generate detailed processes of decision-making, enforce theoretical precision by delineating abstract concepts, and unpack when, and why, people adhere to specific social norms. For each benefit, we discuss a recent study which has employed modeling in the service of assessing the role of norms in decision-making, collectively revealing how computational modeling enables better prediction, description, and explanation of important social choices.

Virtual Reality as an Adjunct to Traditional Patient Counseling in Patients With Newly Diagnosed Localized Prostate Cancer.

OBJECTIVE: To determine the utility of a virtual reality (VR) model constructed using patient-derived clinical imaging to improve patient understanding of localized prostate cancer (PCa) diagnosis and surgical plan. METHODS: Patients undergoing robotic radical prostatectomy were selected and demographic data recorded. Patients completed a questionnaire to assess baseline knowledge of their diagnosis after consultation and shared-decision making with their surgeon. A trained non-clinical staff member then guided the patient through a VR experience to view patient-specific anatomy in a 3-dimensional space. Patients then completed the same questionnaire, followed by an additional post-VR questionnaire evaluating patient satisfaction. Questions 1-7 (patient understanding of prostate cancer and treatment plan) and 11-17 (patient opinion of VR) used a standard Likert scale and Questions 8-10 were multiple choice with 1 correct answer. RESULTS: In total, 15 patients were included with an average age of 64.1 years. 6 of 7 questions showed an improvement after VR (P <.001). The percentage of correct responses on Questions 8-10 was higher after VR but not statistically significant (P >.13). Mean responses range from 4.3 to 4.8 (Likert scale, 1 through 5) for the post-VR questionnaire, with a mean total of 31.9 out of 35. CONCLUSION: This small preliminary investigation of a novel technology to improve the patient experience showed potential as an adjunct to traditional patient counseling. However, due the small sample size and study design, further research is needed to determine the value VR adds to prostate cancer surgical counseling.

Engagement and factors associated with annual anal human papillomavirus screening among sexual and gender minority individuals.

BACKGROUND: While self-sampling could help address anal cancer screening barriers, no studies have investigated annual engagement with this method or compared it to annual screening with a provider. Building on our baseline paper,(7) we compared annual anal screening engagement between home-based self-sampling and clinic-based clinician sampling. METHODS: The Prevent Anal Cancer Self-Swab Study recruited and randomized sexual and gender minority individuals 25 years and over who have sex with men to a home or clinic arm. Home-based participants were mailed an anal human papillomavirus self-sampling kit at baseline and 12 months, while clinic-based participants were asked to schedule and attend one of five participating clinics at baseline and 12 months. Using Poisson regression, we conducted an intention-to-treat analysis of 240 randomized participants who were invited to screen at both timepoints. RESULTS: 58.8% of participants completed annual (median = 370 days) anal screening. In the home arm, 65.0% of participants engaged in annual screening compared to 52.5% of clinic-based participants (p = 0.049). When stratified by HIV status, persons living with HIV had a higher proportion of home (71.1%) versus clinic (22.2%) annual screening (p < 0.001). Non-Hispanic Black participants participated more in home-based annual anal screening(73.1%) than annual clinic screening(31.6%) (p = 0.01). Overall, annual screening engagement was significantly higher among participants who had heard of anal cancer from an LGBTQ organization, reported "some" prior anal cancer knowledge, preferred an insertive anal sex position, and reported any prior cancer diagnosis. CONCLUSIONS: Annual screening engagement among those at disproportionate anal cancer risk was higher in the home arm.

Preclinical and clinical evidence for using perinatal tissue allografts in nerve sparing robot assisted radical prostatectomy to hasten recovery of functional outcomes: a literature review.

INTRODUCTION: Localized prostate cancer (PCa) is one of the most common malignancies in the United States. Despite continued refinement of robot assisted radical prostatectomy (RARP) surgical methods, post-surgical erectile dysfunction and urinary incontinence remain significant challenges due to iatrogenic injury of local nervous tissue. Thus, the development of therapeutic strategies, including the use of biologic adjuncts to protect and/or enhance recovery and function of nerves following RARP is of growing interest. Perinatal tissue allografts have been investigated as one such biologic adjunct to nerve sparing RARP. However, knowledge regarding their clinical efficacy in hastening return of potency and continence as well as the potential underpinning biological mechanisms involved remains understudied. Thus, the objective of this literature review was to summarize published basic science and clinical studies supporting and evaluating the use of perinatal allografts for nerve repair and their clinical efficacy as adjuncts to RARP, respectively. METHODS: The literature as of May 2024 was reviewed non-systematically using PubMed, EMBASE, Scopus, and Web of Science databases. The search terms utilized were "robotic prostatectomy", "prostate cancer", "nerve sparing", "perinatal tissue", "allograft", "potency", and "continence" alone or in combination. All articles were reviewed and judged for scientific merit by authors RP and JM, only peer-reviewed studies were considered. RESULTS: Eight studies of perinatal tissue allograph use in RARP were deemed worthy of inclusion in this nonsystematic review. CONCLUSIONS: Incontinence and impotence remain significant comorbidities despite continued advancement in surgical technique. However, basic science research has demonstrated potential neurotrophic, anti-fibrotic, and anti-inflammatory properties of perinatal tissue allografts, and clinical studies have shown that patients who receive an intra-operative prostatic perinatal membrane wrap have faster return to potency and continence.

Central Hearing Loss in a Pediatric Patient.

Sensorineural hearing loss is typically caused by dysfunction of the inner ear or auditory nerve. In pediatric patients diagnosed with sensorineural hearing loss, work-up often includes genetic testing and imaging studies of the auditory pathway. Here, we report a case of a pediatric patient with a history of sensorineural hearing loss following cisplatin and radiation therapy for brainstem medulloblastoma, developing symptoms and signs of central hearing loss based on audiometric and MRI/diffusion tensor imaging studies. Though rare, central hearing loss should be considered among the causes of sensorineural hearing loss in children. Laryngoscope, 2024.

Pathogenic diversification of the gut commensal Providencia alcalifaciens via acquisition of a second type III secretion system.

Providencia alcalifaciens is a Gram-negative bacterium found in various water and land environments and organisms, including insects and mammals. Some P. alcalifaciens strains encode gene homologs of virulence factors found in pathogenic Enterobacterales members, such as Salmonella enterica serovar Typhimurium and Shigella flexneri. Whether these genes are pathogenic determinants in P. alcalifaciens is not known. In this study, we investigated P. alcalifaciens-host interactions at the cellular level, focusing on the role of two type III secretion systems (T3SS) belonging to the Inv-Mxi/Spa family. T3SS1b is widespread in Providencia spp. and encoded on the chromosome. A large plasmid that is present in a subset of P. alcalifaciens strains, primarily isolated from diarrheal patients, encodes for T3SS1a. We show that P. alcalifaciens 205/92 is internalized into eukaryotic cells, lyses its internalization vacuole, and proliferates in the cytosol. This triggers caspase-4-dependent inflammasome responses in gut epithelial cells. The requirement for the T3SS1a in entry, vacuole lysis, and cytosolic proliferation is host cell type-specific, playing a more prominent role in intestinal epithelial cells than in macrophages or insect cells. In a bovine ligated intestinal loop model, P. alcalifaciens colonizes the intestinal mucosa and induces mild epithelial damage with negligible fluid accumulation in a T3SS1a- and T3SS1b-independent manner. However, T3SS1b was required for the rapid killing of Drosophila melanogaster. We propose that the acquisition of two T3SS has allowed P. alcalifaciens to diversify its host range, from a highly virulent pathogen of insects to an opportunistic gastrointestinal pathogen of animals.

Association Between Systemic Levels of Vascular Endothelial Growth Factor and Optical Coherence Tomography Biomarkers in a Non-Neovascular Age-Related Macular Degeneration Cohort.

BACKGROUND AND OBJECTIVE: Investigate associations between systemic vascular endothelial growth factor (VEGF) and optical coherence tomography (OCT) biomarkers in eyes with complete retinal pigment epithelium and outer retina atrophy (cRORA) secondary to non-neovascular age-related macular degeneration. PATIENTS AND METHODS: Cross-sectional study of patients with cRORA. OCT images and blood samples were collected at study enrollment. OCT images were evaluated for biomarkers. Systemic VEGF levels were measured using a standard multiplex assay. RESULTS: Study included 187 eyes from 96 patients. Lower levels of systemic VEGF were significantly associated with retinal pseudocysts (RPs) and subretinal hyper-reflective material (SHRM), a median of 7.7 pg/mL and 6.1 pg/mL for patients with the imaging biomarkers compared to those without (10.3 pg/mL [P = 0.004] and 9.3 pg/mL [P = 0.02], respectively). CONCLUSION: This novel study shows that lower systemic VEGF levels were associated with SHRM and RP, which was shown to correspond to an intermediate stage of the atrophic process in age-related macular degeneration. Systemic VEGF could be a useful biomarker and therapeutic target for eyes with cRORA. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Differential effects of 40S ribosome recycling factors on reinitiation at regulatory uORFs in GCN4 mRNA are not dictated by their roles in bulk 40S recycling.

Recycling of 40S ribosomal subunits following translation termination, entailing release of deacylated tRNA and dissociation of the empty 40S from mRNA, involves yeast Tma20/Tma22 heterodimer and Tma64, counterparts of mammalian MCTS1/DENR and eIF2D. MCTS1/DENR enhance reinitiation (REI) at short upstream open reading frames (uORFs) harboring penultimate codons that confer heightened dependence on these factors in bulk 40S recycling. Tma factors, by contrast, inhibited REI at particular uORFs in extracts; however, their roles at regulatory uORFs in vivo were unknown. We examined effects of eliminating Tma proteins on REI at regulatory uORFs mediating translational control of GCN4 optimized for either promoting (uORF1) or preventing (uORF4) REI. We found that the Tma proteins generally impede REI at native uORF4 and its variants equipped with various penultimate codons regardless of their Tma-dependence in bulk recycling. The Tma factors have no effect on REI at native uORF1 and equipping it with Tma-hyperdependent penultimate codons generally did not confer Tma-dependent REI; nor did converting the uORFs to AUG-stop elements. Thus, effects of the Tma proteins vary depending on the REI potential of the uORF and penultimate codon, but unlike in mammals, are not principally dictated by the Tma-dependence of the codon in bulk 40S recycling.

INTRAVITREAL 0.18-mg FLUOCINOLONE ACETONIDE IMPLANT FOR PEDIATRIC UVEITIS.

PURPOSE: This study reports the outcomes of the 0.18-mg intravitreal fluocinolone acetonide implant in the treatment of pediatric noninfectious uveitis. METHODS: A retrospective cohort study was performed on patients under 18 years old who received fluocinolone acetonide implant between June 1, 2020 and March 1, 2023. Data collected included demographics, uveitis diagnosis, use of anti-inflammatory therapy, visual acuity, intraocular pressure, and grading of uveitis activity. Uveitis recurrence was defined as increased inflammation that required additional anti-inflammatory therapy. RESULTS: Eleven eyes from seven patients were included in this study. One patient (one eye) had a diagnosis of immune recovery uveitis and the remaining six patients (10 eyes) had pars planitis. The rate of remaining recurrence-free was 82% at 6 months, 60% at 12 months, and 60% at 24 months. Two of the six phakic eyes at baseline required cataract extraction during follow-up. Two of the four eyes that did not have intraocular pressure-lowering surgery before implantation required surgery in follow-up. CONCLUSION: The 0.18-mg fluocinolone acetonide implant has a similar efficacy for the treatment of pediatric uveitis, particularly pars planitis, as in the adult population, although with higher rates of ocular hypertension requiring intervention.

Orphan and paediatric medical devices in Europe: recommendations to support their availability for on-label and off-label clinical indications.

INTRODUCTION: The Medical Device Regulation (EU)745/2017, increased the regulatory requirements and thus the time and the cost associated with marketing medical devices. For a majority of medical device manufacturers, this has lead to reconsiderations of their product portfolio. The risk of important or essential devices being withdrawn is particularly relevant for pediatric patients and other rare disease patients where limited numbers of devices can be sold and hence the investment needed may not be recovered. This generates critical challenges and opportunities from a regulatory and public health perspective. AREAS COVERED: This paper is based upon the experience of the authors who contributed to working groups, guidance development and research related to orphan and pediatric devices. We examine the use of medical devices in orphan and pediatric conditions, the relevant aspects of regulations and associated guidance, and we suggest possible policy and practice interventions to ensure the continued availability of essential devices for children and people with rare diseases. EXPERT OPINION: We recommend a more proactive approach to identifying devices at risk and essential devices, increasing the use of exceptional market approvals, expanding the role of expert panels, engaging with the rare disease communities and supporting registries and standards.

Decapping activators Edc3 and Scd6 act redundantly with Dhh1 in post-transcriptional repression of starvation-induced pathways.

Degradation of many yeast mRNAs involves decapping by the Dcp1:Dcp2 complex. Previous studies on decapping activators Edc3 and Scd6 suggested their limited roles in mRNA decay. RNA-seq analysis of mutants lacking one or both proteins revealed that Scd6 and Edc3 have largely redundant activities in targeting numerous mRNAs for degradation that are masked in the single mutants. These transcripts also are frequently targeted by decapping activators Dhh1 and Pat1, and the collective evidence suggests that Scd6/Edc3 act interchangeably to recruit Dhh1 to Dcp2. Ribosome profiling shows that redundancy between Scd6 and Edc3 and their functional interactions with Dhh1 and Pat1 extend to translational repression of particular transcripts, including a cohort of poorly translated mRNAs displaying interdependent regulation by all four factors. Scd6/Edc3 also participate with Dhh1/Pat1 in post-transcriptional repression of proteins required for respiration and catabolism of alternative carbon sources, which are normally expressed only in limiting glucose. Simultaneously eliminating Scd6/Edc3 increases mitochondrial membrane potential and elevates metabolites of the tricarboxylic acid and glyoxylate cycles typically observed only during growth in low glucose. Thus, Scd6/Edc3 act redundantly, in parallel with Dhh1 and in cooperation with Pat1, to adjust gene expression to nutrient availability by controlling mRNA decapping and decay.

Association between non-injection drug use and hepatitis C infection among HIV-negative men who have sex with men.

BACKGROUND: Prior research predominantly examined the association between HIV-positive men who have sex with men (MSM) or those using injection drugs and hepatitis C virus (HCV) infection. However, limited attention has been given to understanding the association among HIV-negative MSM who do not inject drugs. This gap leaves apportion of the population unexamined, potentially overlooking important factor that may contribute to the transmission and prevalence of HCV. This study aims to investigate the relationship between non-injection drug use and HCV infection in this population. METHODS: In this cross-sectional study, we analyzed data on 118 MSM who reported use of non-injection drugs. The participants were recruited from two inner-city communities in Houston, TX, between 2004 and 2007 and were negative for both HIV and hepatitis B virus infection. Latent class analysis (LCA) was used to identify drug use latent classes. Multinomial logistic regression analysis was used to evaluate the association between drug use latent class and HCV infection. RESULTS: Four distinct latent classes of drug use were identified: class 1, persons ≥ 42 years of age who used only crack cocaine; class 2, persons approximately 42 years of age who used > 2 drugs; class 3, persons < 42 years of age who used > 5 drugs; and class 4, persons ≥ 42 years of age who used > 6 drugs. Class 4 was significantly associated with HCV infection. The odds of HCV infection in members of class 4 was 17 times higher than in class 2 members (adjusted odds ratio [aOR] = 16.9, 95% confidence interval [CI]: 1.4-205.4) and almost 22 times higher than in class 3 members (aOR = 21.8, 95% CI: 1.5-322.8). CONCLUSIONS: Among MSM with non-injection drug use, the subgroup of individuals who were ≥ 42 years of age and used multiple drugs (including heroin, speedball, methamphetamine, crack cocaine, and marijuana) had a high probability of HCV infection. Public health and education programs, as well as drug treatment and rehabilitation programs, should be developed for this high-risk subgroup of individuals to prevent HCV acquisition and transmission.

Cytomegalovirus Retinitis in the Modern Era of Solid Organ Transplantation.

BACKGROUND: Cytomegalovirus retinitis (CMVR) is a well-described complication of CMV disease in immunocompromised hosts. While robust data exists for CMVR in patients with acquired immunodeficiency syndrome (AIDS), the incidence and risk factors for CMVR in solid organ transplant recipients (SOTR) with CMV viremia are less defined. METHODS: We performed a retrospective cohort study of SOTR who had CMV viremia and underwent routine ophthalmologic examination between 1/1/2018 and 3/16/2022. Univariate statistics were performed to evaluate risk factors for development of CMVR. RESULTS: Overall, 38 patients were included, primarily kidney (78.9%), heart (7.9%), and liver (7.9%) transplant recipients. Five patients (13.2%) developed CMVR during the study period. CMVR was diagnosed an average 281 days after index transplantation, 84 days from the most recent rejection episode, and 69 days from onset of viremia. Only 1 patient (20%) had symptoms at the time of CMVR diagnosis. CMVR was associated with preceding allograft rejection as well as transplanted organ type. CONCLUSION: While CMV tissue disease more commonly manifests in other organs, CMVR occurred relatively frequently in this group of high-risk SOTR with CMV viremia. As most of the patients in our study did not have ocular symptoms at the time of diagnosis, routine ophthalmologic screening should be considered in SOTR with CMV viremia.