Disease Tolerance as an Inherent Component of Immunity.

Pathogenic organisms exert a negative impact on host health, revealed by the clinical signs of infectious diseases. Immunity limits the severity of infectious diseases through resistance mechanisms that sense and target pathogens for containment, killing, or expulsion. These resistance mechanisms are viewed as the prevailing function of immunity. Under pathophysiologic conditions, however, immunity arises in response to infections that carry health and fitness costs to the host. Therefore, additional defense mechanisms are required to limit these costs, before immunity becomes operational as well as thereafter to avoid immunopathology. These are tissue damage control mechanisms that adjust the metabolic output of host tissues to different forms of stress and damage associated with infection. Disease tolerance is the term used to define this defense strategy, which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection. Under this argument, we propose that disease tolerance is an inherent component of immunity.

Reconstructing Prehistoric African Population Structure.

We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers ∼8,100-2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers ∼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a ∼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a ∼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PAPERCLIP.

Ferritin heavy chain supports stability and function of the regulatory T cell lineage.

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

Ancient DNA and deep population structure in sub-Saharan African foragers.

Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa1-4. Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations3,5. Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch.

A framework and process for community-engaged, mixed-methods cancer needs assessments.

PURPOSE: Community health needs assessments are required for most state and local public health agencies and non-profit hospitals. Typically based on community health improvement planning models, these assessments encompass overall community health and multiple diseases to inform program planning. National Cancer Institute (NCI)-designated Cancer Centers and community-based cancer-focused programs share the goal of reducing cancer burden in the catchment areas they serve. However, to date, no published models exist to guide cancer-specific needs assessments for a determined geographic area that can inform both public health and research initiatives. The purpose of this article is to outline a cancer needs assessment (CNA) framework and community-engaged, mixed-methods process, along with a case study of how we applied it in Kentucky. METHODS: We convened a steering committee of key organizational partners to provide input throughout the process. We developed a conceptual framework of multi-level determinants affecting cancer-related outcomes. We incorporated both quantitative and qualitative data gathered through a variety of means, including a novel application of group concept mapping to guide definition of priorities. RESULTS: The resulting CNA has helped guide strategic planning and priorities for Kentucky's Cancer Action Plan, Markey Cancer Center, state agencies, and community-based organizations. CONCLUSION: This framework and process can be used collaboratively by cancer center Community Outreach and Engagement offices, public health agencies, oncology programs, and community partners to plan impactful cancer control programs and research in their catchment areas. Universities can also use them to inform the planning of community engagement and health equity research efforts.

Proximity-induced superconductivity in epitaxial topological insulator/graphene/gallium heterostructures.

The introduction of superconductivity to the Dirac surface states of a topological insulator leads to a topological superconductor, which may support topological quantum computing through Majorana zero modes1,2. The development of a scalable material platform is key to the realization of topological quantum computing3,4. Here we report on the growth and properties of high-quality (Bi,Sb)2Te3/graphene/gallium heterostructures. Our synthetic approach enables atomically sharp layers at both hetero-interfaces, which in turn promotes proximity-induced superconductivity that originates in the gallium film. A lithography-free, van der Waals tunnel junction is developed to perform transport tunnelling spectroscopy. We find a robust, proximity-induced superconducting gap formed in the Dirac surface states in 5-10 quintuple-layer (Bi,Sb)2Te3/graphene/gallium heterostructures. The presence of a single Abrikosov vortex, where the Majorana zero modes are expected to reside, manifests in discrete conductance changes. The present material platform opens up opportunities for understanding and harnessing the application potential of topological superconductivity.

Routine Clinical Breast Examination Is a Low-Yield Practice Among Women at High Risk of Breast Cancer.

BACKGROUND: For women at increased risk of breast cancer, the National Comprehensive Cancer Network (NCCN) guidelines recommend clinical encounters every 6-12 months. While screening mammography has corresponded with a relative risk reduction in breast cancer mortality of approximately 20%, evidence validating clinical breast examination (CBE) as an efficacious screening modality is deficient. Our study aimed to assess the conventional merit of regular CBE for breast cancer detection among individuals at increased risk of breast cancer development. METHODS: Women > 18 years with documented high-risk encounters at Corewell Health West from 1 January 2018 to 31 December 22 were retrospectively reviewed. High-risk criteria included genetic predisposition, 5-year (> 1.7%) or lifetime (> 20%) Tyrer-Cuzick and/or Gail Model risk estimations, thoracic radiotherapy before age 30 years, lobular carcinoma in-situ, or atypical hyperplasia. Patients with a history of breast cancer or bilateral prophylactic mastectomy prior to 2018 were excluded. RESULTS: Of the 9171 cumulative high-risk encounters among 2493 women, only one breast cancer was detected by CBE. CBE resulted in 1 (0.04%) cancer diagnosis compared with 30 (1.2%) detected on screening imaging and 10 (0.4%) self-reported. Of the 30 image-detected cancers, 28 (93.3%) had no detectable clinical findings at the time of preoperative consultation. Self-reported and CBE-detected cancers were more likely to be of higher clinical stage compared with imaging-detected malignancies. CONCLUSIONS: The role of routine CBE as a cancer detection modality in the high-risk patient population appears to be limited. Telemedicine can be offered to individuals who have completed screening imaging but are unable to commit and/or are inconvenienced by in-person high-risk breast cancer assessments.

Noise increases the correspondence between artificial and human vision.

The best performing computer vision systems are based on deep neural networks (DNNs). A study in this issue of PLOS Biology shows that DNNs trained on noisy stimuli are better than standard DNNs at mirroring both human behavioral and neural visual responses.

Perceived Control, Functional Status, Depressive Symptoms, and Anxiety: Mediating and Moderating Influences on Health-Related Quality of Life in Patients With Heart Failure.

BACKGROUND: Health-related quality of life (HRQoL) is poor in patients with heart failure. Psychological (ie, depressive symptoms [DS], anxiety, and perceived control) and physical (ie, functional status) factors are associated with HRQoL. The dynamic relationships among these variables and their impact on HRQoL remain unclear, limiting the ability to design effective interventions. PURPOSE: Our aim was to evaluate a moderated mediation model, in which the association between perceived control and HRQoL was hypothesized to be mediated by DS and anxiety in the presence of a moderator, functional status. METHODS: Patients (N = 426) with heart failure completed the Control Attitudes Scale-Revised to measure perceived control, Duke Activity Status Index for functional status, Patient Health Questionnaire-9 for DS, Brief Symptom Inventory for anxiety, and Minnesota Living with Heart Failure Questionnaire for HRQoL. We performed a moderated parallel mediation analysis. RESULTS: Higher levels of perceived control were associated with better HRQoL through lower levels of anxiety and DS in the presence of functional status (index of moderated mediation for DS, b = 0.029; 95% confidence interval, 0.016-0.045; for anxiety: b = 0.009, 95% confidence interval, 0.002-0.018). The effect of perceived control on psychological symptoms was stronger at low and moderate functional statuses; however, this effect diminished with increasing functional status. CONCLUSION: Functional status moderated the indirect effects of perceived control on HRQoL through DS and anxiety in patients with heart failure. Efforts to improve HRQoL by targeting perceived control may be more effective when considering DS and anxiety in patients with low to moderate levels of functional status.

Scaling of fast-start performance and its thermal dependence in mummichog Fundulus heteroclitus.

Fast-start predator-escape performance and its sensitivity to temperature (24, 30, and 36°C) were evaluated in mummichog Fundulus heteroclitus across a range of body sizes spanning YOY to adult (35-68 mm standard length). Mummichogs exhibit isometry of body dimensions and areas of the dorsal and anal fins but negative allometry of the caudal fin area. These scaling relationships are consistent with observed decreases in fast-start angular velocities with increasing body size. Linear velocity, on the contrary, does not vary with size, and both large and small mummichogs are capable of traversing similar distances in a given amount of time. In addition, temperature influences fast-start performance in similar ways over the size range, though the magnitude of the effect varies with size for some performance measures. In general, fast-start performance increases with test temperature, but mummichogs acclimated to warmer temperatures exhibit lower performance at each test temperature. Altogether, our results suggest that mummichogs across the adult size range may suffer decreases in their predator-escape performance as increasing sea temperatures combine with short-term temperature fluctuations in the estuaries these fish occupy.

Surgeon Perspectives on Determinants of Same-Day Mastectomy: A Roadmap for Implementing Change.

BACKGROUND: Same-day discharge after mastectomy without immediate reconstruction (MwoR) has been shown to be safe, with improved patient satisfaction when compared with patients discharged 1 or more days after surgery. Nevertheless, only 16% of patients undergoing MwoR in Michigan are discharged on the day of surgery, with significant variation between facilities (3-88%). Our objective was to explore determinants of same-day discharge and offer strategies for broader implementation of this practice. METHODS: We conducted semi-structured interviews with surgeons performing MwoR across the state of Michigan. Recruitment utilized purposeful and snowball sampling methods. The Tailored Implementation in Chronic Disease (TICD) framework was used to inform the creation of the interview guide. Interviews were transcribed and then analyzed using directed content analysis guided by the TICD framework. Salient determinants were organized into patient, provider, and system-level factors. RESULTS: Participants (n = 26) included general surgeons, breast surgeons, and surgical oncologists. Most surgeons (n = 18, 69%) reported that they discharged fewer than 60% of patients the same day after MwoR. The most common barriers included patient knowledge at the patient level; awareness of evidence, surgeon dogma, and peer influence at the provider level; and team processes and operating room logistics at the system level. CONCLUSION: We identified surgeon-defined determinants of same-day discharge after MwoR. For the identified barriers, potential implementation strategies could include incorporation of preoperative drain teachings for patients, utilizing consensus statements and opinion leaders to disseminate evidence supporting same-day mastectomies, and conducting workshops with relevant stakeholders to establish consistent facility practice patterns among surgical teams.

Prophylactic mastectomy and occult malignancy: Surgical and imaging considerations.

BACKGROUND: Sentinel node biopsy (SLNB) is not routinely recommended for patients undergoing prophylactic mastectomy (PM), yet omission remains a subject of debate among surgeons. A modern patient cohort was examined to determine occult malignancy (OM) incidence within PM specimens to reinforce current recommendations. METHODS: All PM performed over a 5-year period were retrospectively identified, including women with unilateral breast cancer who underwent synchronous or delayed contralateral PM or women with elevated cancer risk who underwent bilateral PM. RESULTS: The study population included 772 patients (598 CPM, 174 BPM) with a total of 39 OM identified: 17 invasive cancers (14 CPM, 3 BPM) and 22 DCIS (19 CPM, 3 BPM). Of the 86 patients for whom SLNB was selectively performed, 1 micrometastasis was identified. In the CPM cohort, risk of OM increased with age, presence of LCIS of either breast, or presence of a non-BRCA high-penetrance gene mutation, while preoperative magnetic resonance imaging was associated with lower likelihood of OM. CONCLUSIONS: Given the low incidence of invasive OM in this updated series, routine SLNB is of low value for patients undergoing PM. For patients with indeterminate radiographic findings, discordant preoperative biopsies, LCIS, or non-BRCA high-penetrance gene mutations, selective SLNB implementation could be considered.

Training healthcare professionals to be ready for practice in an era of social distancing: a realist evaluation.

BACKGROUND: Programme changes due to the COVID-19 pandemic have impacted variably on preparation for practice of healthcare professional students. Explanations for such variability need exploration. The aim of our study was to understand what clinical learning, whilst under socially distanced restrictions, worked and why (or why not). METHODS: We conducted a realist evaluation of the undergraduate healthcare programmes at one UK university in 2020-21. Initial programme theories to be tested in this study were derived from discussions with programme leads about the changes they implemented due to the pandemic. Study participants were students and teaching faculty. Online interview transcripts were coded, identifying why interventions had worked or not. This resulted in a set of 'context-mechanism-outcome' (CMO) statements about each intervention. The initial programme theories were refined as a result. RESULTS AND DISCUSSION: 29 students and 22 faculty members participated. 18 CMO configurations were identified relating to clinical skills learning and 25 relating to clinical placements. Clinical skills learning was successful whether in person, remote or hybrid if it followed the steps of: demonstration-explanation-mental rehearsal-attempt with feedback. Where it didn't work there was usually a lack of observation and corrective feedback. Placements were generally highly valued despite some deficiencies in student experience. Being useful on placements was felt to be good preparation for practice. If student numbers are to expand, findings about what works in distance learning of clinical skills and the value of various modes of induction to clinical workplace activity may also be relevant post-pandemic.

Psychometric Testing of the Control Attitudes Scale-Revised for Patients With a Left Ventricular Assist Device.

BACKGROUND: Perceived control, an indicator of the patient's ability to cope and thrive with a chronic illness, is a common target of nursing interventions. As of 2019, more than 25 000 patients had been implanted with a left ventricular assist device (LVAD) as a treatment of advanced heart failure. Patients with an LVAD experience significant life changes that affect anxiety, depression, health-related quality of life, and, presumably, perceived control. To adequately intervene and improve perceived control, a reliable and valid measure is needed. OBJECTIVES: The objectives of this analysis were to (1) assess item discrimination and anticipated range of scores of the Control Attitudes Scale-Revised (CAS-R), (2) assess the internal consistency and validity of the CAS-R, and (3) examine perceived control in a sample of patients with an LVAD. METHODS: Two cohorts of patients with an LVAD (n = 113) were combined to evaluate the psychometric qualities of the CAS-R. Correlations among patient-reported outcomes and perceived control were used to evaluate validity. Cronbach α was used to test internal consistency. Item response theory was used to measure item discrimination and anticipated scores. Descriptive statistics describe perceived control in the sample. RESULTS: Overall, the CAS-R demonstrated good internal consistency and convergent validity with other patient-reported outcomes. Using the item response theory, we saw that the CAS-R was a good predictor of lower-moderate scorers but was not good at differentiating high performers. There were several items that were poor discriminators and could be altered or discarded to create a more predictive instrument. CONCLUSIONS: The CAS-R is a valid and reliable instrument to measure perceived control in patients who have LVAD implants; however, more work could be done to improve item-level information.

Mediation by Fatalism of the Association Between Symptom Burden and Self-care Management in Patients With Heart Failure.

BACKGROUND: Clinicians and researchers often assume that symptom burden is associated with self-care management (SCM) in patients with heart failure (HF). However, that association is often not borne out in simple regression analyses and may be because another variable mediates the association. Fatalism is an appropriate candidate for mediation and is the belief that circumstances are predetermined without opportunity for control by individuals. OBJECTIVE: Our objective was to determine whether fatalism mediated the relationship of symptom burden with SCM among adults with HF. METHODS: We conducted a secondary analysis (N = 95) from a clinical trial. We used Self-care of HF Index to measure SCM, the Memorial Symptom Assessment Scale-HF for symptom burden, and the Cardiovascular Disease Fatalism Instrument to measure fatalism. We used the PROCESS macro to evaluate mediation. RESULTS: Symptom burden was not directly associated with SCM (effect coefficient [C'] = 0.0805; 95% confidence interval, -0.048 to 0.209; P = .217). There was, however, an indirect pathway between symptom burden and SCM through fatalism (ab = -0.040; 95% confidence interval, -0.097 to -0.002). Those with higher symptom burden were more fatalistic (a = 0.004, P = .015), and greater fatalism was associated with worse SCM (b = -9.132, P = .007). CONCLUSION: Symptom burden, not directly associated with SCM, is associated through the mediator of fatalism. Interventions to improve SCM should include strategies to mitigate fatalistic views. Self-care management interventions should focus on promoting internal locus of control or increasing perceptions of perceived control to decrease fatalism and improve engagement in self-care.

Thinking beyond the ventral stream: Comment on Bowers et al.

Bowers et al. rightly emphasise that deep learning models often fail to capture constraints on visual perception that have been discovered by previous research. However, the solution is not to discard deep learning altogether, but to design stimuli and tasks that more closely reflect the problems that biological vision evolved to solve, such as understanding scenes and preparing skilled action.

Toward a more expansive and inclusive definition of women's health: A content analysis of Twitter conversations.

To develop a nuanced understanding of women's health on social media, we conducted a content analysis of Twitter data in early 2020, during the early days of the COVID-19 pandemic. Included tweets (N = 1,714) fell into 15 overarching themes. "Politics and Women's Health" was most discussed, demonstrating the politicization of women's health, followed by "Maternal, Reproductive, and Sexual Health." COVID-19 was a crosscutting issue for 12 themes, suggesting widespread effects on women's health. Overall, diverse conversations unfolded on social media, including variation geographically, highlighting the need for a more expansive and inclusive definition of women's health. This work supports further investigation into the role of politics and COVID-19 across women's health domains.

Management of early stage HER2 positive breast cancer and increased implementation of axillary imaging to improve identification of nodal metastasis.

BACKGROUND AND OBJECTIVES: Given the significant benefit of targeted therapies for HER2+ breast cancer patients in both the neoadjuvant and adjuvant settings, it is critical to identify all eligible patients for these treatments. We sought to investigate cT1cN0 HER2+ patients to determine the rate of postsurgical nodal positivity, and to identify presurgical factors associated with nodal positivity. We hypothesize there is a subset of underdiagnosed HER2+ patients who would benefit from preoperative axillary imaging and inclusion in neoadjuvant chemotherapy regimens. METHODS: We performed a 10-year retrospective analysis of T1 HER2+ breast cancer patients. Clinicopathologic characteristics were evaluated based on surgical nodal data. RESULTS: We identified 38 patients with cT1cN0 HER2+ cancer. Of this cohort, 24% had positive lymph nodes on final pathology. High tumor grade (p = 0.035) on core needle biopsy and the presence of lymphovascular invasion (p = 0.0036) were associated with an increased likelihood of lymph node positivity. The majority (66%) of lymph node positive patients were clinically T1c. CONCLUSIONS: We identified a 24% nodal positivity rate in clinically node negative T1 HER2+ breast cancer patients. In particular, HER2+ patients with high-grade T1c cancers should undergo preoperative diagnostic axillary imaging to expand potential benefit from targeted therapies.

Earliest known Oldowan artifacts at >2.58 Ma from Ledi-Geraru, Ethiopia, highlight early technological diversity.

The manufacture of flaked stone artifacts represents a major milestone in the technology of the human lineage. Although the earliest production of primitive stone tools, predating the genus Homo and emphasizing percussive activities, has been reported at 3.3 million years ago (Ma) from Lomekwi, Kenya, the systematic production of sharp-edged stone tools is unknown before the 2.58-2.55 Ma Oldowan assemblages from Gona, Ethiopia. The organized production of Oldowan stone artifacts is part of a suite of characteristics that is often associated with the adaptive grade shift linked to the genus Homo Recent discoveries from Ledi-Geraru (LG), Ethiopia, place the first occurrence of Homo ∼250 thousand years earlier than the Oldowan at Gona. Here, we describe a substantial assemblage of systematically flaked stone tools excavated in situ from a stratigraphically constrained context [Bokol Dora 1, (BD 1) hereafter] at LG bracketed between 2.61 and 2.58 Ma. Although perhaps more primitive in some respects, quantitative analysis suggests the BD 1 assemblage fits more closely with the variability previously described for the Oldowan than with the earlier Lomekwian or with stone tools produced by modern nonhuman primates. These differences suggest that hominin technology is distinctly different from generalized tool use that may be a shared feature of much of the primate lineage. The BD 1 assemblage, near the origin of our genus, provides a link between behavioral adaptations-in the form of flaked stone artifacts-and the biological evolution of our ancestors.

A Multibiomarker Latent Class Analysis in Moderate to Advanced Heart Failure: Differentiating Factors.

BACKGROUND: Biomarker science in heart failure (HF) is advancing quickly in our ability to diagnosis and treat patients with this complex syndrome. Researchers are urged to not use single-marker strategies, but instead evaluate biomarkers in patterns to better understand their relationship to one another, as well as disease progression. Latent class mixture modeling allows researchers to determine novel associations between biomarkers. OBJECTIVE: The objectives of this study were to identify and compare latent classes of cardiovascular biomarkers among patients with moderate to advanced HF. METHODS: This was a cross-sectional study of 96 participants with moderate to advanced HF. Latent class mixture modeling was used to identify unique classes of biomarkers and their associations to sociodemographic and clinical variables. RESULTS: The average age of the sample was 54 years, with most of the sample being men (77%) and having an average ejection fraction of 23%. Two unique classes of biomarkers were identified. Latent class 1 had higher levels of all biomarkers, whereas latent class 2 had lower levels. The higher biomarker class had, on average, more neurohormonal activation and fluid retention; however, the higher levels of biomarker class were not more likely to be diagnosed with advanced HF or have more comorbidities. CONCLUSION: By identifying classes of biomarkers, providers may be better able to identify patients who are at risk of progressing into advanced HF quicker or those who are more likely to have more severe complications, such as fluid overload or renal disease.