Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies.

Autologous transplantation of CCR5 null hematopoietic stem and progenitor cells (HSPCs) is the only known cure for HIV-1 infection. However, this treatment is limited because of the rarity of CCR5 -null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to CCR5 knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineered ex vivo to produce both CCR5 KO cells and long-term secretion of potent HIV-1 inhibiting antibodies from B cell progeny. CRISPR-Cas9-engineered HSPCs maintain engraftment capacity and multi-lineage potential in vivo and can be engineered to express multiple antibodies simultaneously. Human B cells engineered to express each antibody secrete neutralizing concentrations capable of inhibiting HIV-1 pseudovirus infection in vitro . This work lays the groundwork for a potential one-time functional cure for HIV-1 through combining the long-term delivery of therapeutic antibodies against HIV-1 and the known efficacy of CCR5 KO HSPC transplantation.

Biliary Drainage in Hilar and Perihilar Cholangiocarcinoma; 25-Year Experience at a Tertiary Cancer Center.

INTRODUCTION: This study analyzes the optimal biliary stenting strategy for palliation in cholangiocarcinoma (CCA). METHODS: This is a retrospective study of patients with CCA who underwent biliary drainage from 1997-2023. A per-patient analysis of percutaneous biliary drainage (PTBD) rates, the median number of ERCPs, overall survival (OS), and a per-procedure analysis of clinical success (CS), stent-specific Adverse Events (AEs), and mean time to reintervention by stent type and laterality (unilateral(u) & bilateral(b)) is presented. RESULTS: A total of 333 patients underwent 1,050 ERCPs; 85% with plastic stents (PS). PTBD was eventually done in 23% of PS patients, 35% of whom had PS removed prior to PTBD. ERCPs with SEMS/uniSEMS use had higher CS (89%/91%) vs PS/uPS (85% both) and PS within SEMS (PS-SEMS)/uPS-SEMS (71%/74%;p=0.013/p=0.054). Compared to PS, SEMS and PS-SEMS were associated with higher stent-specific AEs (OR SEMS 4.85; 3.23-7.27; PS-SEMS 9.99; 5.33-18.71;p<0.001). Straight PS were associated with more stent-specific AEs compared to double-pigtail stents (OR 6.74; 3.95-11.45;p<0.001). More 7 Fr stents were used in cases with balloon dilation (BD, 109 vs. 88 with no BD; p<0.001). BD had 79% CS rate vs 87% without BD (p<0.001). Cases with pus on ERCP and those with BD had a shorter mean time to reintervention. On regression analyses, higher Bismuth class, PS use, and PS-SEMS use were associated with a shorter mean time to repeat ERCP. 52% of patients in the bSEMS arm died from cholangitis (p=0.005). CONCLUSION: The relatively higher clinical success of SEMS is countered by the higher stent-specific complication rate. PS can be removed and may better facilitate PTBD. Within PS types, DPTs may have fewer stent-specific AEs. Cases requiring balloon dilation and with endoscopic evidence of pus may benefit from earlier reintervention.

Leveraging Community Context, Data, and Resources to Inform Suicide Prevention Strategies.

Colorado has consistently had one of the highest rates of suicide in the United States, and El Paso County has the highest number of suicide and firearm-related suicide deaths within the state. Community-based solutions like those of the Suicide Prevention Collaborative of El Paso County may be more effective in preventing suicide as they are specific to local issues, sensitive to local culture, and informed by local data, community members, and stakeholders.

Evolutionary genetic algorithm identifies IL2RB as a potential predictive biomarker for immune-checkpoint therapy in colorectal cancer.

Identifying robust predictive biomarkers to stratify colorectal cancer (CRC) patients based on their response to immune-checkpoint therapy is an area of unmet clinical need. Our evolutionary algorithm Atlas Correlation Explorer (ACE) represents a novel approach for mining The Cancer Genome Atlas (TCGA) data for clinically relevant associations. We deployed ACE to identify candidate predictive biomarkers of response to immune-checkpoint therapy in CRC. We interrogated the colon adenocarcinoma (COAD) gene expression data across nine immune-checkpoints (PDL1, PDCD1, CTLA4, LAG3, TIM3, TIGIT, ICOS, IDO1 and BTLA). IL2RB was identified as the most common gene associated with immune-checkpoint genes in CRC. Using human/murine single-cell RNA-seq data, we demonstrated that IL2RB was expressed predominantly in a subset of T-cells associated with increased immune-checkpoint expression (P < 0.0001). Confirmatory IL2RB immunohistochemistry (IHC) analysis in a large MSI-H colon cancer tissue microarray (TMA; n = 115) revealed sensitive, specific staining of a subset of lymphocytes and a strong association with FOXP3+ lymphocytes (P < 0.0001). IL2RB mRNA positively correlated with three previously-published gene signatures of response to immune-checkpoint therapy (P < 0.0001). Our evolutionary algorithm has identified IL2RB to be extensively linked to immune-checkpoints in CRC; its expression should be investigated for clinical utility as a potential predictive biomarker for CRC patients receiving immune-checkpoint blockade.

Effects of future climate on coral-coral competition.

As carbon dioxide (CO2) levels increase, coral reefs and other marine systems will be affected by the joint stressors of ocean acidification (OA) and warming. The effects of these two stressors on coral physiology are relatively well studied, but their impact on biotic interactions between corals are poorly understood. While coral-coral interactions are less common on modern reefs, it is important to document the nature of these interactions to better inform restoration strategies in the face of climate change. Using a mesocosm study, we evaluated whether the combined effects of ocean acidification and warming alter the competitive interactions between the common coral Porites astreoides and two other mounding corals (Montastraea cavernosa or Orbicella faveolata) common in the Caribbean. After 7 days of direct contact, P. astreoides suppressed the photosynthetic potential of M. cavernosa by 100% in areas of contact under both present (~28.5°C and ~400 µatm pCO2) and predicted future (~30.0°C and ~1000 µatm pCO2) conditions. In contrast, under present conditions M. cavernosa reduced the photosynthetic potential of P. astreoides by only 38% in areas of contact, while under future conditions reduction was 100%. A similar pattern occurred between P. astreoides and O. faveolata at day 7 post contact, but by day 14, each coral had reduced the photosynthetic potential of the other by 100% at the point of contact, and O. faveolata was generating larger lesions on P. astreoides than the reverse. In the absence of competition, OA and warming did not affect the photosynthetic potential of any coral. These results suggest that OA and warming can alter the severity of initial coral-coral interactions, with potential cascading effects due to corals serving as foundation species on coral reefs.

Investigating Visual-Spatial Abilities in Students and Expert Physical Therapists.

Purpose: Visual-spatial abilities (VSAs) - the aptitude for mentally processing, retaining, and manipulating visual input - are used by physical therapists in movement analysis. Superior VSAs have been demonstrated in experts compared with novices in other fields, including surgery, anatomy, and aviation, but no literature has investigated VSAs in physical therapy. The purpose of this study was to quantify VSAs in expert and student physical therapists and investigate the differences between the two groups. Our results could assist future researchers in identifying areas for skill development and improved clinical competency in students and novice therapists. Method: Expert physical therapists and first-year PT students completed four computerized VSA tests in the Psychology Experiment Building Language programme: Four-Choice Response, Sequential Pattern Comparison, Mental Rotation, and Situation Awareness. Results: A total of 16 participants were recruited for each group. Expert physical therapists responded more accurately to the Four-Choice Response test, but not significantly so (p = 0.06), and with a significantly slower response time than student physical therapists (p = 0.03). No other differences were found. Conclusions: These findings suggest that expert physical therapists use selective attention more effectively and may value accuracy over speed. No differences were found in other measures of VSAs. Further studies are required to confirm and expand our findings.

Objectif : les physiothérapeutes font appel à leurs aptitudes visuospatiales (AVS), c'est-à-dire les aptitudes mentales à traiter, à retenir et à manipuler les données visuelles, lors de l'analyse des mouvements. Dans d'autres domaines, les spécialistes ont des AVS supérieures à celles des novices, y compris en chirurgie, en anatomie et en aviation, mais aucune publication ne traite des AVS en physiothérapie. La présente étude visait à quantifier les AVS des physiothérapeutes spécialisés et des étudiants en physiothérapie et à explorer les différences entre les deux groupes. Les résultats pourraient aider les futurs chercheurs à déterminer les secteurs où il est nécessaire d'acquérir des aptitudes et d'améliorer les compétences cliniques chez les étudiants en physiothérapie et les thérapeutes novices. Méthodologie : des physiothérapeutes spécialisés et des étudiants en première année de physiothérapie ont effectué quatre tests d'AVS informatisés du programme d'acquisition du langage de psychologie expérimentale : quatre choix de réponses, comparaison de configurations séquentielles, rotation mentale et conscience situationnelle. Résultats : au total, les chercheurs ont recruté 16 participants dans chaque groupe. Les physiothérapeutes spécialisés ont répondu avec plus de précision au test des quatre choix de réponses, mais pas de manière significative (p = 0,06), et leur temps de réponse était significativement plus long que celui des étudiants en physiothérapie (p = 0,03). Aucune autre différence n'a été observée. Conclusions : selon ces résultats, les physiothérapeutes spécialisés utilisent l'attention sélective avec plus d'efficacité et privilégieraient la précision plutôt que la vitesse. Les chercheurs n'ont pas remarqué de différences dans les autres mesures d'AVS. D'autres mesures s'imposent pour confirmer et élargir les observations.

Prehabilitation: The Right Medicine for Older Frail Adults Anticipating Transcatheter Aortic Valve Replacement, Coronary Artery Bypass Graft, and Other Cardiovascular Care.

The wait before elective cardiac intervention or surgery presents an opportunity to prevent further physiologic decline preoperatively in older patients. Implementation of prehabilitation programs decreases length of hospital stay postoperatively, decreases time spent in the intensive care unit, decreases postoperative complications, and improves self-reported quality of life postsurgery. Prehabilitation programs should adopt multimodal approaches including nutrition, exercise, and worry reduction to improve patient resilience in the preoperative period. High-quality research in larger cohorts is needed, and interventions focusing on underrepresented frailer populations and women. Creative ways to improve accessibility, adherence, and benefits received from prehabilitation should be explored.

Impacts of Ocean Acidification on Sensory Function in Marine Organisms.

SYNOPSIS: Ocean acidification has been identified as a major contributor to ocean ecosystem decline, impacting the calcification, survival, and behavior of marine organisms. Numerous studies have observed altered sensory perception of chemical, auditory, and visual cues after exposure to elevated CO2. Sensory systems enable the observation of the external environment and therefore play a critical role in survival, communication, and behavior of marine organisms. This review seeks to (1) summarize the current knowledge of sensory impairment caused by ocean acidification, (2) discuss potential mechanisms behind this disruption, and (3) analyze the expected taxa differences in sensitivities to elevated CO2 conditions. Although a lack of standardized methodology makes cross-study comparisons challenging, trends and biases arise from this synthesis including a substantial focus on vertebrates, larvae or juveniles, the reef ecosystem, and chemosensory perception. Future studies must broaden the scope of the field by diversifying the taxa and ecosystems studied, incorporating ontogenetic comparisons, and focusing on cryptic sensory systems such as electroreception, magnetic sense, and the lateral line system. A discussion of possible mechanisms reveals GABAA receptor reversal as the conspicuous physiological mechanism. However, the potential remains for alternative disruption through structure or cue changes. Finally, a taxonomic comparison of physiological complexity reveals few trends in sensory sensitivities to lowered pH, but we hypothesize potential correlations relating to habitat, life history or relative use of sensory systems. Elevated CO2, in concordance with other global and local stressors, has the potential to drastically shift community composition and structure. Therefore research addressing the extent of sensory impairment, the underlying mechanisms, and the differences between taxa is vital for improved predictions of organismal response to ocean acidification.

Efficacy and Safety of a Hyaluronic Acid Filler to Correct Aesthetically Detracting or Deficient Features of the Asian Nose: A Prospective, Open-Label, Long-Term Study.

BACKGROUND: There is increasing interest among patients and plastic surgeons for alternatives to rhinoplasty, a common surgical procedure performed in Asia. OBJECTIVES: To evaluate the safety, efficacy, and longevity of a hyaluronic acid filler in the correction of aesthetically detracting or deficient features of the Asian nose. METHODS: Twenty-nine carefully screened Asian patients had their noses corrected with the study filler (Juvéderm VOLUMA [Allergan plc, Dublin, Ireland] with lidocaine injectable gel), reflecting individualized treatment goals and utilizing a standardized injection procedure, and were followed for over 12 months. RESULTS: A clinically meaningful correction (≥1 grade improvement on the Assessment of Aesthetic Improvement Scale) was achieved in 27 (93.1%) patients at the first follow-up visit. This was maintained in 28 (96.6%) patients at the final visit, based on the independent assessments of a central non-injecting physician and the patients. At this final visit, 23 (79.3%) patients were satisfied or very satisfied with the study filler and 25 (86.2%) would recommend it to others. In this small series of patients, there were no serious adverse events (AEs), with all treatment-related AEs being mild to moderate, transient injection site reactions, unrelated to the study filler. CONCLUSIONS: Using specific eligibility criteria, individualized treatment goals, and a standardized injection procedure, the study filler corrected aesthetically detracting or deficient features of the Asian nose, with the therapeutic effects lasting for over 12 months, consistent with a high degree of patient satisfaction. This study supports the safety and efficacy of this HA filler for specific nose augmentation procedures in selected Asian patients. LEVEL OF EVIDENCE 3: Therapeutic.

Predator identity influences metacommunity assembly.

Predation is among the most important biotic factors influencing natural communities, yet we have a rather rudimentary understanding of its role in modulating metacommunity assembly. We experimentally examined the effects of two different predators (a generalist and a specialist) on metacommunity assembly, using protist microcosm metacommunities that varied in predator identity, dispersal among local communities and the history of species colonization into local communities. Generalist predation resulted in reduced α diversity and increased ß diversity irrespective of dispersal, likely due to predation-induced stochastic extinction of different prey species in different local communities. Dispersal, however, induced source-sink dynamics in the presence of specialist predators, resulting in higher α diversity and marginally lower ß diversity. These results demonstrate the distinct effects of different predators on prey metacommunity assembly, emphasizing the need to explore the role of predator diet breadth in structuring metacommunities.

Nurse practitioner work: A case study.

Abstract Within any professional practice, knowledge developments to support service delivery and to understand roles inherent within that practice context are critical. The purpose of this article is to present findings from case study research that used the AUSPRAC Research Toolkit Interview Schedule and to propose an additional theme to the Interview Schedule. Case Study method was used to explore the role of a nurse practitioner (NP) within a specific context of practice in an Australian Healthcare institution. Three semi-structured interviews with a NP using the AUSPRAC Research Toolkit Interview Schedule and one additional interview were employed. Data was analysed where initial free coding, then theme generation contributed to knowledge development. The AUSPRAC Research Toolkit Interview Schedule generated knowledge about the NP role. Themes identified for interviews in the Schedule were: the organisation of care, team functioning and patient service. Analysis of data from these themes identified that information related to ongoing development of professional practice was not forthcoming from the participant. The authors recommend adding a fourth theme to the Interview Schedule to enable exploration of the professional elements of the NP role.

The Nurse Practitioner Role: A pilot study based on the Interview Schedule from the AUSPRAC Research Toolkit.

Abstract Within any professional practice, knowledge developments to support service delivery and to understand roles inherent within that practice context are critical. The purpose of this article is to present findings from case study research that used the AUSPRAC Research Toolkit Interview Schedule and to propose an additional theme to the Interview Schedule. Case Study method was used to explore the role of a nurse practitioner within a specific context of practice in an Australian Healthcare institution. Three semi-structured interviews with a Nurse Practitioner using the AUSPRAC Research Toolkit Interview Schedule and one additional interview were employed. Data was analysed where initial free coding, then theme generation contributed to knowledge development. The AUSPRAC Research Toolkit Interview Schedule generated knowledge about the nurse practitioner role. Themes identified for interviews in the Schedule were; the organisation of care, team functioning and patient service. Analysis of data from these themes identified that information related to ongoing development of professional practice was not forthcoming from the participant. The authors recommend adding a fourth theme to the Interview Schedule to enable exploration of the professional elements of the Nurse Practitioner role.

Reversing the evolution of antibiotic resistance.

Inhibiting mutation pathways could represent a novel approach to combating the evolution of antibiotic resistance.

Sulforaphane halts breast cancer cell growth.

Sulforaphane is a chemical found in cruciferous vegetables such as broccoli, sprouts and kale. This compound is a potent inducer of protective enzymes that provide defense against cancer-causing chemicals. Researchers have discovered that sulforaphane can halt human breast cancer cells in their tracks and have identified a new mechanism of action for the compound.