E-cigarettes in college: Associations between mental health and e-cigarette use with other substances.

INTRODUCTION: College students are a priority population for substance use prevention, and other studies have reported associations between mental health and e-cigarette use. This study described the association of mental health to e-cigarette and other substance use (ECIG+ use) among US college students. METHODS: We used Fall 2018 and Spring 2019 National College Health Assessment data among undergraduate students aged 18-24 years (n=55654) at 138 institutions. We characterized substance use patterns and used multinomial regression to model adjusted odds of past 30-day ECIG use type [no substance use (reference); sole e-cigarette use; e-cigarette use and other substance use (ECIG+ use); no e-cigarette use but other substance use] by mental health characteristics, past 12-month diagnosis/treatment and psychological distress, individual characteristics, and college characteristics. RESULTS: Alcohol was the most prevalent substance (58%) used, followed by cannabis (23%) and e-cigarettes (15%). Nearly all (95%) students who used e-cigarettes reported using another substance. Adjusted odds of ECIG+ use (vs no substance use) were higher among students with past 12-month mental health diagnosis/treatment (AOR=1.5; 95% CI: 1.4-1.6) and higher psychological distress (AOR=1.1; 95% CI: 1.1-1.2). Other characteristics significantly associated with ECIG+ use included gender identity, sexual orientation, race and ethnicity, self-rated health, year in school, cumulative grade average, fraternity/sorority membership, and current residence. CONCLUSIONS: Most students who used e-cigarettes also reported other substance use, and this pattern of use was associated with poorer mental health outcomes than no substance use. Clarifying the relationship between mental health and ECIG+ use may enhance health interventions for college students.

Closer to Home: A Quality Improvement Initiative to Optimize Satellite Site Bed Capacity.

BACKGROUND: The coronavirus disease 2019 pandemic resulted in the underutilization of inpatient beds at our satellite location. A lack of clarity and standardized admission criteria for the satellite led to frequent transfers to the main campus, resulting in patients traveling larger distances to receive inpatient care. We sought to optimize inpatient resource use at the satellite campus and keep patients "closer to home" by admitting eligible patients to that inpatient unit (LA4). Our aim was to increase bed capacity use at the satellite from 45% to 70% within 10 months. Our process measure was to increase the proportion of patients needing hospitalization who presented to the satellite emergency department (ED) and were then admitted to LA4 from 76% to 85%. METHODS: A multidisciplinary team used quality improvement methods to optimize bed capacity use. Interventions included (1) the revision and dissemination of satellite admission guidelines, (2) steps to create shared understanding of appropriate satellite admissions between ED and inpatient providers, (3) directed provider feedback on preventable main campus admissions, and (4) consistent patient and family messaging about the potential for transfer. Data were collected via chart review. Annotated run charts were used to assess the impact of interventions over time. RESULTS: Average LA4 bed capacity use increased from 45% to 69%, which was sustained for 1 year. The average percentage of patients admitted from the satellite ED to LA4 increased from 76% to 84%. CONCLUSIONS: We improved bed capacity use at our satellite campus through transparent admission criteria and shared mental models of patient care needs between ED and inpatient providers.

Testing the Shamiri Intervention and Its Components With Kenyan Adolescents During the COVID-19 Pandemic: Outcomes of a Universal, Five-Arm Randomized Controlled Trial.

OBJECTIVE: Mental health problems are prevalent among African adolescents, but professional treatment capacity is limited. Shamiri, an efficient lay-provider-delivered intervention, has significantly reduced depression and anxiety symptoms in previous RCTs. We investigated effects of the full Shamiri intervention and its components (growth-only, gratitude-only, and values-only), against a study-skills control. METHOD: In a five-group RCT with adolescents from Kenyan high-schools, anxiety, depression, and wellbeing were self-reported through eight-month follow-up. The RCT occurred immediately after an unanticipated government-mandated COVID shutdown forced three years of schoolwork into two, escalating academic pressures. RESULTS: Participants (N=1,252; 48.72% female) were allocated to: growth (n=249), gratitude (n=237), values (n=265), Shamiri (n=250), and study-skills (n=251). Longitudinal multilevel models showed that, across all conditions, anxiety scores significantly improved at midpoint (B=-0.847), endpoint (B=-2.948), one-month (B=-1.587), three-month (B=-2.374), and eight-month (B=-1.917) follow-ups. Depression scores also improved significantly at midpoint (B=-0.796), endpoint (B=-3.126), one-month (B=-2.382), three-month (B=-2.521), and eight-month (B=-2.237) follow-ups. Wellbeing scores improved significantly at midpoint (B=1.73), endpoint (B=3.44), one-month (B=2.21), three-month (B=1.78), and eight-month (B=1.59) follow-ups. Symptom-reduction with Shamiri matched that of pre-COVID trials, but symptom-reduction with study-skills far outpaced that of trials before the COVID-related school shutdown (31% greater anxiety reduction and 60% greater depression reduction). Thus, in contrast to previous RCTs, this COVID-era trial showed no significant differences between outcomes in any intervention and active control groups. CONCLUSION: Our RCT conducted during a post-COVID period of heightened academic pressure produced unexpected results. Improvements in youth-reported anxiety and depression were consistent with previous trials for Shamiri, but markedly larger than in previous trials for study-skills. "Control interventions" teaching life-skills may produce mental health benefits when they convey skills of particular contextual relevance.

Burden and trajectory of social needs after breast cancer diagnosis at a safety-net hospital.

PURPOSE: Unmet social needs pose barriers to cancer care, contributing to adverse outcomes and health inequities. A better understanding of how social needs change after cancer diagnosis can inform more effective, equity-focused interventions. METHODS: In this study, we examined self-reported social needs at 0, 3, and 6 months after a breast cancer diagnosis in a racially diverse, multilingual sample (n = 222) enrolled in patient navigation intervention at an urban safety-net hospital. At each timepoint, respondents completed surveys about social needs related to employment, disability benefits, housing and utilities, and personal and family stability. RESULTS: Over three-quarters (78%, n = 175) reported ≥ 1 social need, and 46% (n = 102) reported ≥ 3 social needs. The most frequently reported need was housing and utilities (64%, n = 142), followed by employment (40%, n = 90). Individuals from minoritized groups more frequently reported an increased number of social needs over time, compared with their White counterparts (p = 0.02). CONCLUSION: Our findings suggest that despite navigation, many cancer patients from historically underrepresented populations continue to experience social concerns over the first 6 months of treatment. Further research, conducted with historically underrepresented populations in research, is needed to better understand the social needs of breast cancer patients to inform effective and equitable interventions.

Do veterans with risky substance use (RSU) use distinct pain treatment modalities?

BACKGROUND AND OBJECTIVES: Risky substance use (RSU) is common among people with chronic pain and is associated with worse pain treatment outcomes. Nonopioid treatment is recommended, but it is unknown whether people with RSU use different or fewer pain treatment modalities. This study describes use of different pain treatments by veterans with and without RSU and those receiving versus not receiving opioid medication. METHODS: Veterans (N = 924) who filed service-connected disability claims related to musculoskeletal conditions and rated their pain four or higher on the Numeric Rating Scale, reported on 25 different pain services in the preceding 90 days. Recent RSU was identified via Alcohol, Smoking, and Substance Involvement Test (ASSIST) cutoffs and/or nail sample toxicology. RESULTS: Overall, RSU was not associated with number of provider-delivered or self-delivered pain modalities. Over-the-counter medications (71%), self-structured exercise (69%), and nonopioid prescription medications (38%) were the most used modalities. Veterans receiving prescribed opioids (8.4%) were more likely to see primary care, receive injections, and attend exercise and/or meditation classes, compared to those without opioid prescriptions. DISCUSSION AND CONCLUSIONS: Opioid and nonopioid pain treatment utilization did not differ based on RSU, and those prescribed opioids were more likely to engage in other nonopioid pain treatments. Regardless of RSU, veterans appear willing to try provider-delivered (58%) and self-delivered (79%) pain treatment. SCIENTIFIC SIGNIFICANCE: In this first-ever evaluation of 25 different pain treatment modalities among veterans with and without RSU, people with RSU did not use less treatment modalities.

Access to New Clinic Appointments for Patients With Cancer.

Importance: Racial and ethnic disparities have been observed in the outpatient visit rates for specialist care, including cancer care; however, little is known about patients' experience at the critical step of attempting to access new clinic appointments for cancer care. Objective: To determine simulated English-speaking, Spanish-speaking, and Mandarin-speaking patient callers' ability to access new clinic appointments for 3 cancer types (colon, lung, and thyroid cancer) that disproportionately impact Hispanic and Asian populations. Design, Setting, and Participants: This cross-sectional audit study was conducted between November 2021 and March 2023 using 479 clinic telephone numbers that were provided by the hospital general information personnel at 143 hospitals located across 12 US states. Using standardized scripts, trained research personnel assigned to the roles of English-speaking, Spanish-speaking, and Mandarin-speaking patients called the telephone number for a clinic that treats colon, lung, or thyroid cancer to inquire about a new clinic appointment. Data analysis was conducted from June to September 2023. Main Outcomes and Measures: The primary outcome was whether the simulated patient caller was able to access cancer care (binary variable, yes or no), which was defined to include being provided with a clinic appointment date or scheduling information. Multivariable logistic regression analysis was performed to determine factors independently associated with simulated patient callers being able to access cancer care. Results: Of 985 total calls (399 English calls; 302 Spanish calls; 284 Mandarin calls), simulated patient callers accessed cancer care in 409 calls (41.5%). Differences were observed based on language type, with simulated English-speaking patient callers significantly more likely to access cancer care compared with simulated Spanish-speaking and Mandarin-speaking patient callers (English, 245 calls [61.4%]; Spanish, 110 calls [36.4%]; Mandarin, 54 calls [19.0%]; P < .001). A substantial number of calls ended due to linguistic barriers (291 of 586 Spanish or Mandarin calls [49.7%]) and workflow barriers (239 of 985 calls [24.3%]). Compared with English-speaking simulated patient callers, the odds of accessing cancer care were lower for Spanish-speaking simulated patient callers (adjusted odds ratio [aOR], 0.34; 95% CI, 0.25-0.46) and Mandarin-speaking simulated patient callers (aOR, 0.13; 95% CI, 0.09-0.19). Compared with contacting clinics affiliated with teaching hospitals, callers had lower odds of accessing cancer care when contacting clinics that were affiliated with nonteaching hospitals (aOR, 0.53; 95% CI, 0.40-0.70). Conclusions and Relevance: In this cross-sectional audit study, simulated patient callers encountered substantial barriers when attempting to access clinic appointments for cancer care. These findings suggest that interventions focused on mitigating these barriers are necessary to increase access to cancer care for all patients.

Brief communication: Carrier rate, antimicrobial resistance and molecular typing of Staphylococcus aureus and Staphylococcus pseudintermedius in healthy dogs from Morogoro, Tanzania.

BACKGROUND: Staphylococcus pseudintermedius and S. aureus are important pathogens in dogs. This study established carrier rates, strain diversity and antimicrobial resistance of these bacteria among healthy dogs in Tanzania. RESULTS: Based on cultures of mouth and perineal swabs, 11.3% and 50.3% of 151 healthy dogs were carriers of S. aureus and S. pseudintermedius, respectively. Only four dogs (3%) carried meticillin-resistant S. aureus (MRSA), while none of the S. pseudintermedius strains were meticillin-resistant. 12 of 19 S. aureus strains tested were resistant to penicillin G, and resistance to enrofloxacin and tetracycline was also commonly detected. The most common resistances in 103 S. pseudintermedius strains tested were to penicillin G (28.2%) and tetracycline (22.3%). S. pseudintermedius strains showed 65 different random amplified polymorphic DNA (RAPD) fingerprints, and S. aureus strains belonged to eight different spa types, including two novel types (t18988 and t18989). MRSA strains carried SCCmec type V. CONCLUSIONS AND CLINICAL RELEVANCE: Healthy dogs in Tanzania were carriers of MRSA at low frequency, and half of the dogs carried S. pseudintermedius with high strain diversity.

Synthesis and antibacterial action of 3',6'-disubstituted spectinomycins.

Spectinomycin is an aminocyclitol antibiotic with a unique ribosomal binding site. Prior synthetic modifications of spectinomycin have enhanced potency and antibacterial spectrum through addition at the 6'-position to produce trospectomycin and to the 3'-position to produce spectinamides and aminomethyl spectinomycins. This study focused on the design, synthesis, and evaluation of three 3',6'-disubstituted spectinomycin analogs: trospectinamide, N-benzyl linked aminomethyl, and N-ethylene linked aminomethyl trospectomycins. Computational experiments predicted that these disubstituted analogs would be capable of binding within the SPC ribosomal binding site. The new analogs were synthesized from trospectomycin, adapting the previously established routes for the spectinamide and aminomethyl spectinomycin series. In a cell-free translation assay, the disubstituted analogs showed ribosomal inhibition similar to spectinomycin or trospectomycin. These disubstituted analogs demonstrated inhibitory MIC activity against various bacterial species with the 3'-modification dictating spectrum of activity, leading to improved activity against mycobacterium species. Notably, N-ethylene linked aminomethyl trospectomycins exhibited increased potency against Mycobacterium abscessus and trospectinamide displayed robust activity against M. tuberculosis, aligning with the selective efficacy of spectinamides. The study also found that trospectomycin is susceptible to efflux in M. tuberculosis and M. abscessus. These findings contribute to the understanding of the structure-activity relationship of spectinomycin analogs and can guide the design and synthesis of more effective spectinomycin compounds.

Follow-Up of Secundum ASD, Muscular VSD, or PDA Diagnosed During Neonatal Hospitalization.

The ideal follow-up of neonates who have a secundum atrial septal defect (ASD), muscular ventricular septal defect (VSD), or patent ductus arteriosus (PDA) remains uncertain. Newborns with findings limited to a secundum ASD, muscular VSD, and/or PDA on their neonatal hospitalization discharge echocardiogram and at least one outpatient follow-up echocardiogram performed between 9-1-17 and 9-1-21 were evaluated and patient follow-up assessed through 9-1-23. 95 infants met inclusion criteria. 43 infants had a secundum ASD, 41 had a muscular VSD, and 54 had a PDA at newborn hospital discharge. 39/95 had more than one intracardiac shunt. 56 were discharged from care, 26 were still in follow-up and 13 were lost to recommended follow-up. No patients received intervention during the follow-up period of 2 to 6 years. Of the 43 infants with a secundum ASD, 16 (37.2%) had demonstrated closure of the ASD, and 13 (30.2%) were discharged from care with an ASD < 3.5 mm in diameter. 3/43 infants with secundum ASD had a defect with a diameter of more than 5 mm at their last echocardiogram. No infant discharged from their neonatal hospitalization with a secundum ASD, muscular VSD, or PDA needed any intervention from 2 to 6 years of follow-up. Ongoing follow-up with echocardiography of those infants with a secundum ASD is of greater value than of those with muscular VSD or PDA.

Self-reported decreases in the purchases of selected unhealthy foods resulting from the implementation of warning labels in Mexican youth and adult population.

BACKGROUND: Front-of-package nutritional warning labels (WLs) are designed to facilitate identification and selection of healthier food choices. We assessed self-reported changes in purchasing different types of unhealthy foods due to WLs in Mexico and the association between the self-reported reductions in purchases of sugary beverages and intake of water and sugar-sweetened beverages. METHODS: Data came from 14 to 17 year old youth (n = 1,696) and adults ≥ 18 (n = 7,775) who participated in the Mexican arm of the 2020-2021 International Food Policy Study, an annual repeat cross-sectional online survey. Participants self-reported whether the WLs had influenced them to purchase less of each of nine unhealthy food categories due to WLs. Among adults, a 23-item Beverage Frequency Questionnaire was used derive past 7-day intake of water and sugary beverages analyzed to determine the relationship between self-reported reductions in purchasing sugary drinks due to the WLs. Multilevel mixed-effects logistic regression models were fitted to estimate the percentage of participants who self-reported reducing purchases within each food group, and overall. Sociodemographic characteristics associated with this reduction were investigated as well. RESULTS: Overall, 44.8% of adults and 38.7% of youth reported buying less of unhealthy food categories due to the implementation of WL, with the largest proportion reporting decreased purchases of cola, regular and diet soda. A greater impact of WLs on the reported purchase of unhealthy foods was observed among the following socio-demographic characteristics: females, individuals who self-identified as indigenous, those who were overweight, individuals with lower educational levels, those with higher nutrition knowledge, households with children, and those with a significant role in household food purchases. In addition, adults who reported higher water intake and lower consumption of sugary beverages were more likely to report reduced purchases of sugary drinks due to the WLs. Adults who reported greater water intake and lower sugary beverages intake were significantly more likely to report buying fewer sugary drinks due to the WLs. CONCLUSION: Our findings suggest that implementation of WLs has reduced perceived purchases of unhealthy foods in Mexico. These results underscore the potential positive impact of the labeling policy particularly in subpopulations with lower levels of education and among indigenous adults.

Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology.

Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.

Adeno-associated viral delivery of Env-specific antibodies prevents SIV rebound after discontinuing antiretroviral therapy.

An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here we show that adeno-associated virus (AAV)-delivery of two rhesus macaque antibodies to the SIV envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIVmac239M after discontinuing suppressive ART. Following AAV administration, sustained antibody expression with minimal anti-drug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within two weeks in all of the control animals but remained below the threshold of detection in plasma (<15 copies/mL) for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals with delayed rebound exhibited restricted barcode diversity and antibody escape. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.

Sarcoma_CellminerCDB: A tool to interrogate the genomic and functional characteristics of a comprehensive collection of sarcoma cell lines.

Sarcomas are a diverse group of rare malignancies composed of multiple different clinical and molecular subtypes. Due to their rarity and heterogeneity, basic, translational, and clinical research in sarcoma has trailed behind that of other cancers. Outcomes for patients remain generally poor due to an incomplete understanding of disease biology and a lack of novel therapies. To address some of the limitations impeding preclinical sarcoma research, we have developed Sarcoma_CellMinerCDB, a publicly available interactive tool that merges publicly available sarcoma cell line data and newly generated omics data to create a comprehensive database of genomic, transcriptomic, methylomic, proteomic, metabolic, and pharmacologic data on 133 annotated sarcoma cell lines. The reproducibility, functionality, biological relevance, and therapeutic applications of Sarcoma_CellMinerCDB described herein are powerful tools to address and generate biological questions and test hypotheses for translational research. Sarcoma_CellMinerCDB (https://discover.nci.nih.gov/SarcomaCellMinerCDB) aims to contribute to advancing the preclinical study of sarcoma.

Contributions of site- and sex-specific LTPs to everyday memory.

Commentaries about long-term potentiation (LTP) generally proceed with an implicit assumption that largely the same physiological effect is sampled across different experiments. However, this is clearly not the case. We illustrate the point by comparing LTP in the CA3 projections to CA1 with the different forms of potentiation in the dentate gyrus. These studies lead to the hypothesis that specialized properties of CA1-LTP are adaptations for encoding unsupervised learning and episodic memory, whereas the dentate gyrus variants subserve learning that requires multiple trials and separation of overlapping bodies of information. Recent work has added sex as a second and somewhat surprising dimension along which LTP is also differentiated. Triggering events for CA1-LTP differ between the sexes and the adult induction threshold is significantly higher in females; these findings help explain why males have an advantage in spatial learning. Remarkably, the converse is true before puberty: Females have the lower LTP threshold and are better at spatial memory problems. A mechanism has been identified for the loss-of-function in females but not for the gain-of-function in males. We propose that the many and disparate demands of natural environments, with different processing requirements across ages and between sexes, led to the emergence of multiple LTPs. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Skin sympathetic nerve activity in symptomatic and asymptomatic paroxysmal atrial fibrillation.

BACKGROUND: It remains unclear what causes symptoms in patients with paroxysmal atrial fibrillation (AF). OBJECTIVE: This study aimed to correlate the magnitudes of the skin sympathetic nerve activity (SKNA) with symptoms in patients with AF. METHODS: We prospectively enrolled patients with symptomatic paroxysmal AF for ambulatory electrocardiogram and SKNA recording. Heart rhythms at time of symptoms were categorized as AF or normal sinus rhythm (NSR). Maximal and average SKNA (aSKNA) and heart rate (HR) were compared between symptomatic and asymptomatic AF and NSR episodes using mixed effects models to account for within-patient correlations. RESULTS: Among the 31 enrolled patients, 16 (52%) had at least one episode of AF, and 24 (77%) endorsed symptoms during the monitoring period. Compared with asymptomatic AF episodes, symptomatic AF episodes had higher maximal aSKNA (1.260 [IQR 1.114-1.723] µV vs. 1.108 [IQR 0.974-1.312] µV, p<0.001) and higher maximal HR (152±24 bpm vs. 132±19 bpm, p<0.001). Symptomatic NSR episodes were associated with higher maximal aSKNA (1.612 [IQR 1.287-2.027] µV vs. 1.332 [IQR 1.033-1.668] µV, p=0.001) and higher maximal HR (152±24 bpm vs. 105±16 bpm, p<0.001) than asymptomatic NSR episodes. Of the symptomatic episodes, 66 (73%) occurred during NSR and 24 (27%) during AF. All p-values were obtained from mixed effects models. CONCLUSION: Symptomatic episodes in patients with paroxysmal AF were more frequently associated with NSR than AF. Symptomatic AF and NSR episodes were associated with higher aSKNA than asymptomatic episodes. In patients with paroxysmal AF, symptoms correlate better with SKNA than heart rhythm.

Multi-center study on sellar reconstruction after endoscopic transsphenoidal pituitary surgery.

INTRODUCTION: Surgical techniques for sellar reconstruction include no reconstruction, use of synthetic materials, autologous grafts, and/or vascularized flaps. The aim of this study was to conduct a multi-center study comparing the efficacy and postoperative morbidity associated with different sellar reconstruction techniques. METHODS: A retrospective chart review of patients who underwent endoscopic transsphenoidal surgery for pituitary tumors from five participating sites between January 2021 and March 2023 was performed. The variables included demographics, tumor characteristics, reconstruction technique, postoperative cerebrospinal fluid leak (CSF) leak, and 22-item Sino-Nasal Outcome Test (SNOT-22) scores. Comparisons of postoperative complications, SNOT-22 scores, and duration of surgery by type of onlay reconstruction were evaluated using Fisher's exact test, analysis of variance, and Kruskal‒Wallis test. RESULTS: Five hundred and one patients were identified. The median tumor size was 2.1 cm, and 64% were non-functioning. Intraoperative CSF leak was identified in 38% of patients. A total of 89% of patients underwent onlay reconstruction: 49% were reconstructed with mucosal grafts, 35% with nasoseptal flaps, and 5% with other onlay techniques. Nasoseptal flaps were utilized more frequently in the setting of giant pituitary adenomas (>3 cm), medial cavernous sinus wall resection, and high-flow intraoperative CSF leaks. Cases who utilized mucosal grafts had an overall shorter operating time (median: 183 min vs. 240 min; p < 0.001). Five postoperative CSF leaks were identified, and therefore, statistical analysis could not be performed for this complication. CONCLUSION: The effectiveness and morbidity of different sellar reconstruction techniques are comparable. Vascularized flaps were utilized more frequently in the setting of larger tumors and high-flow intraoperative CSF leaks.

Immunotoxin-mediated depletion of Gag-specific CD8+ T cells undermines natural control of Simian immunodeficiency virus.

Antibody-mediated depletion studies have demonstrated that CD8+ T cells are required for effective immune control of SIV. However, this approach is confounded by several factors, including reactive CD4+ T cell proliferation, and further provides no specificity information. We circumvented these limitations by selectively depleting CD8+ T cells specific for the Gag epitope CTPYDINQM (CM9) via the administration of immunotoxin-conjugated tetrameric complexes of CM9/Mamu-A*01. Immunotoxin administration effectively depleted circulating but not tissuelocalized CM9-specific CD8+ T cells, akin to the bulk depletion pattern observed with antibodies directed against CD8. However, we found no evidence to indicate that circulating CM9-specific CD8+ T cells suppressed viral replication in Mamu-A*01+ rhesus macaques during acute or chronic progressive infection with a pathogenic strain of SIV. This observation extended to macaques with established infection during and after continuous antiretroviral therapy. In contrast, natural controller macaques experienced dramatic increases in plasma viremia after immunotoxin administration, highlighting the importance of CD8+ T cell-mediated immunity against CM9. Collectively, these data showed that CM9-specific CD8+ T cells were necessary but not sufficient for robust immune control of SIV in a nonhuman primate model and, more generally, validated an approach that could inform the design of next-generation vaccines against HIV-1.

Unlocking the Next Frontier in Precision Oncology: Addressing Drug-Tolerant Residual Disease.

SUMMARY: Drug-tolerant residual disease (DTRD) after the initial maximal response to a systemic therapy can serve as a tumor reservoir for the development of acquired drug resistance and represents a major clinical challenge across various cancers and types of therapies. To unlock the next frontier in precision oncology, we propose a fundamental paradigm shift in the treatment of metastatic cancers with a sharpened focus towards defining, monitoring, and therapeutically targeting the DTRD state.