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Understanding social network structures can contribute to the introduction of new HIV prevention strategies with socially marginalized populations like transgender women (TW). We conducted 20 semi-structured interviews and four focus groups (n = 32) with TW from selected social networks in Lima, Peru between May and July, 2015. Participants described layers of social influence from diverse actors in their social networks. The majority identified a close relative as their primary social support, with whom they confided secrets but avoided issues of transgender identity, sexuality, and sex work. Participants described close circles of TW friends with whom they shared information about gender identity, body modification, and sexual partners, but avoided issues like HIV. Community leadership included political leaders (who advocated for transgender rights) as well as social leaders (who introduced TW to hormone therapy, body modification, and commercial sex). Detailed analysis of TW social networks can contribute to implementation and acceptability of new HIV prevention technologies.

Alternatives to convenience sampling (CS) are needed for HIV/STI surveillance of most-at-risk populations in Latin America. We compared CS, time space sampling (TSS), and respondent driven sampling (RDS) for recruitment of men who have sex with men (MSM) and transgender women (TW) in Lima, Peru. During concurrent 60-day periods from June-August, 2011, we recruited MSM/TW for epidemiologic surveillance using CS, TSS, and RDS. A total of 748 participants were recruited through CS, 233 through TSS, and 127 through RDS. The TSS sample included the largest proportion of TW (30.7 %) and the lowest percentage of subjects who had previously participated in HIV/STI research (14.9 %). The prevalence of newly diagnosed HIV infection, according to participants' self-reported previous HIV diagnosis, was highest among TSS recruits (17.9 %) compared with RDS (12.6 %) and CS (10.2 %). TSS identified diverse populations of MSM/TW with higher prevalences of HIV/STIs not accessed by other methods.

Knowledge of a sex partner's HIV serostatus can influence sexual behavior and inform harm-reduction strategies. We sought to determine how often Peruvian men who have sex with men (MSM) and transgender women (TW) knew the HIV serostatus of their sex partners, if this knowledge was associated with any predictive factors or unprotected anal intercourse (UAI), and if UAI was associated with partner serostatus. We analyzed data from the 2008 Peruvian MSM Sentinel Surveillance Survey. Data were collected by CASI about each participant's three most recent male sex partners. Primary outcome was knowledge of a partner's HIV test result. Multivariate analysis assessed the effect of age, education, sexual identity, number of male partners, alcohol use during intercourse, type of partnership and length of partnership using logistic regression. 735 participants provided data on 1,643 of their most recent sex partners from the last 3 months. 179/735 (24.4%) of all participants knew HIV test results for at least one of their 3 most recent partners, corresponding to 230/1643 (14.0%) of all sexual partnerships in the last 3 months. In multivariate analysis, casual (OR: 0.27, 95% CI: 0.17-0.42) and exchange sex (OR: 0.31, 95% CI: 0.11-0.88) partners, compared to stable partners, were negatively associated with knowledge of partner serostatus, whereas relationships lasting longer than one night (

A 23-month-old female was referred for hearing aid fitting after failing newborn hearing screening and being diagnosed with significant hearing loss through subsequent diagnostic testing. Auditory brainstem response (ABR) and behavioral testing revealed a moderate-to-severe bilateral mixed hearing loss. Prior to the hearing aid evaluation, tympanostomy tubes had been placed bilaterally with little or no apparent change in hearing sensitivity. Initial testing during the hearing aid fitting confirmed earlier findings, but abnormal middle ear results were observed, requiring referral for additional otologic management. Following medical clearance, binaural digital programmable hearing aids were fit using Desired Sensation Level parameters. Behavioral testing and probe microphone measures showed significant improvements in audibility. Decrease in hearing sensitivity was observed six months following hearing aid fitting. Radiological studies, ordered due to the mixed component and decreased hearing sensitivity, revealed large vestibular aqueduct syndrome (LVAS). Based on the diagnosis of LVAS, a cochlear implant was placed on the right ear; almost immediate speech-language gains were observed. [ABSTRACT FROM AUTHOR]

Mozambique is a developing African country recuperating from a lengthy civil war. As a result, documenting the incidence of hearing loss has remained a low priority. This paper provides results from work being carried out by the Mozambique Audiology Program (MAP), which is a philanthropic effort established in 1997 to introduce audiology services and identify auditory disorders in the country. Some decades before the MAP, another program reported extremely high incidence rates of otitis media in 1000 primary school students in the capital city of Maputo. This paper presents the MAP results from mass hearing screenings conducted over a two year period on a cohort group of 2685 students ranging in age from 3-18 years at a preschool and primary school in Chicuque and Maxixe, Mozambique. This current study showed a prevalence of 5% of the total 2685 students across ages with varying degrees of hearing loss resulting from multiple etiologies. External auditory canal obstruction was the greatest otoscopic abnormality (regardless of age), followed by severely limited tympanic membrane mobility (i.e. flat tympanogram) in the absence of EAC obstruction in those students identified with hearing loss. Of the 145 student identified with hearing loss, there were 27 found to have active drainage. Some of the benefits of conducting mass hearing screening in this population are discussed. [ABSTRACT FROM AUTHOR]

This study sought to quantify the effects of varying the degree of ear canal occlusion on pure-tone threshold sensitivity. Thresholds were obtained from each ear of five normal-hearing adults without occlusion, with complete occlusion, and with partial occlusion estimated to be 40-60% and 60-80%. A commercial lubricant was used in the completely occluded condition to eliminate possible acoustic leakage. Results showed a reduction of threshold sensitivity in all occluded conditions, with the greatest effect in frequencies above 1000 Hz. Only in the completely occluded condition were frequencies below 1000 Hz affected. In the partially occluded conditions, thresholds decreased by an average 7.5 dB and 13.0 dB across frequency for the 40-60% and 60-80% conditions respectively. At frequencies above 1000 Hz, the average threshold shifts for the two partially occluded conditions were 10.0 dB and 16.8 dB respectively. The implications of these findings on routine pure-tone audiometric procedures, with specific relevance for industrial hearing conservation programs, are discussed. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) with binary or single phenotype data have successfully identified disease-associated genotypes and determinants of antimicrobial resistance. We describe a novel phenotype-to-genotype approach for a major bacterial pathogen that involves simultaneously testing for associations among multiple disease-related phenotypes and linkages between phenotypic variation and genetic determinants. High-throughput assays quantified variation among 163 Neisseria meningitidis serogroup W ST-11 clonal complex isolates for 11 phenotypic traits. A comparison of carriage and two disease subgroups detected significant differences between groups for eight phenotypic traits. Candidate genotypic testing indicated that indels in csw , a capsular biosynthesis gene, were associated with reduced survival in antibody-depleted heat-inactivated serum. GWAS testing detected 341 significant genetic variants (3 single-nucleotide polymorphisms and 338 unitigs) across all traits except serum bactericidal antibody-depleted assays. Growth traits were associated with variants of capsular biosynthesis genes, carbonic anhydrase, and an iron-uptake system while adhesion-linked variation was in pilC2 , marR, and mutS . Multiple phase variation states or combinatorial phasotypes were associated with significant differences in multiple phenotypes. Controlling for group effects through regression and recursive random forest approaches detected group-independent effects for nalP with biofilm formation and fetA with a growth trait. Through random forest testing, nine phenotypes were weakly predictive of MenW:cc11 sub-lineage, original or 2013, for disease isolates while three characteristics separated carriage and disease isolates with >80% accuracy. This study demonstrates the power of combining high-throughput phenotypic testing of pathogenically relevant isolate collections with genomics for identifying genetic determinants of specific disease-relevant phenotypes and the pathobiology of microbial pathogens.IMPORTANCENext-generation sequencing technologies have led to the creation of extensive microbial genome sequence databases for several bacterial pathogens. Mining of these databases is now imperative for unlocking the maximum benefits of these resources. We describe a high-throughput methodology for detecting associations between phenotypic variation in multiple disease-relevant traits and a range of genetic determinants for Neisseria meningitidis , a major causative agent of meningitis and septicemia. Phenotypic variation in 11 disease-related traits was determined for 163 isolates of the hypervirulent ST-11 lineage and linked to specific single-nucleotide polymorphisms, short sequence variants, and phase variation states. Application of machine learning algorithms to our data outputs identified combinatorial phenotypic traits and genetic variants predictive of a disease association. This approach overcomes the limitations of generic meta-data, such as disease versus carriage, and provides an avenue to explore the multi-faceted nature of bacterial disease, carriage, and transmissibility traits.

Scientists' limited understanding of tropical plant communities obscures the true extent of species loss caused by habitat destruction 1 . The Centinelan extinction hypothesis 2,3 posits an extreme but widely referenced scenario wherein forest clearing causes the immediate extinction of species known only from a single geographic location. It remains unclear, however, whether the disappearance of such microendemics reflects their global extinction or insufficient collection effort at larger scales. Here we test these hypotheses by synthesizing decades of floristic data from the heavily deforested tropical cloud forest (TCF) at Centinela, Ecuador. We find that 99% of its putative microendemics have been collected elsewhere and are not extinct. Our field work also revealed new species, highlighting the enduring conservation value of TCFs and the intense efforts required to illuminate such plant diversity 'darkspots' 4 . Field and herbarium research remain essential to the conservation action needed to forestall large-scale plant extinctions in Earth's beleaguered cloud forests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The high rate of recurrence after radiation therapy in triple-negative breast cancer (TNBC) indicates that novel approaches and targets are needed to enhance radiosensitivity. Here, we report that neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) that is enriched on sub-populations of TNBC cells with stem cell properties, is an effective therapeutic target for sensitizing TNBC to radiotherapy. Specifically, VEGF/NRP2 signaling induces nitric oxide synthase 2 (NOS2) transcription by a mechanism dependent on Gli1. NRP2-expressing tumor cells serve as a hub to produce nitric oxide (NO), an autocrine and paracrine signaling metabolite, which promotes cysteine-nitrosylation of Kelch-like ECH-asssociated protein 1 (KEAP1) and, consequently, nuclear factor erythroid 2-related factor 2 (NFE2L2)-mediated transcription of antioxidant response genes. Inhibiting VEGF binding to NRP2, using a humanized monoclonal antibody (mAb), results in NFE2L2 degradation via KEAP1 rendering cell lines and organoids vulnerable to irradiation. Importantly, treatment of patient-derived xenografts with the NRP2 mAb and radiation resulted in significant tumor necrosis and regression compared to radiation alone. Together, these findings reveal a targetable mechanism of radioresistance and they support the use of NRP2 mAb as an effective radiosensitizer in TNBC.

Recent exploratory field expeditions to the western slopes of the Ecuadorian Andes resulted in the discovery of a new species of Amalophyllon (Gesneriaceae). Amalophyllonmiraculum J.L.Clark, sp. nov. is described from two localities in the Centinela region in the Santo Domingo de los Tsáchilas province. The new species is differentiated from congeners by the pendent habit, basal rosette of leaves, leaf blades with deeply serrate margins, and miniature size. Based on IUCN guidelines, a preliminary conservation status is assigned as Critically Endangered (CR)., Competing Interests: The authors have declared that no competing interests exist., (John L. Clark, Andrea Fernández, J. Nicolás Zapata, Camilo Restrepo-Villarroel, Dawson M. White, Nigel C. A. Pitman.)

As a corridor for population movement out of Africa, the southern Levant is a natural laboratory for research exploring the dynamics of the Middle-to-Upper Paleolithic transition. Yet, the number of well-preserved sites dating to the initial millennia of the Early Upper Paleolithic (EUP; ∼45-30 ka) remains limited, restricting the resolution at which we can study the biocultural and techno-typological changes evidenced across the transition. With EUP deposits dating to 45-39 ka cal BP, Mughr el-Hamamah, Jordan, offers a key opportunity to expand our understanding of EUP lifeways in the southern Levant. Mughr el-Hamamah is particularly noteworthy for its large faunal assemblage, representing the first such assemblage from the Jordan Valley. In this paper, we present results from taxonomic and taphonomic analyses of the EUP fauna from Mughr el-Hamamah. Given broader debates about shifts in human subsistence across the Middle-to-Upper Paleolithic transition, we also assess evidence for subsistence intensification, focusing especially on the exploitation of gazelle and the use of small game. Taphonomic data suggest that the fauna was primarily accumulated by human activity. Ungulates dominate the assemblage; gazelle (Gazella sp.) is the most common taxa, followed by fallow deer (Dama mesopotamica) and goat (Capra sp.). Among the gazelle, juveniles account for roughly one-third of the sample. While the focus on gazelle and the frequency of juveniles are consistent with broader regional trends, evidence for the regular exploitation of marrow from gazelle phalanges suggests that the EUP occupants of Mughr el-Hamamah processed gazelle carcasses quite intensively. Yet, the overall degree of dietary intensification appears low-small game is rare and evidence for human capture of this game is more equivocal. As a whole, our results support a growing body of data showing gradual shifts in animal exploitation strategies across the Middle-to-Upper Paleolithic transition in the southern Levant., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Despite high rates of HIV transmission among men who have sex with men (MSM) in Lima, Peru, limited data exist on the sexual network characteristics or risk factors for secondary HIV transmission among MSM with uncontrolled HIV infection. We report the frequency of serodiscordant, condomless anal intercourse (CAI) and associated sexual network characteristics among MSM in Lima with detectable HIV viremia and compare to those with undetectable viremia., Methods: This cross-sectional analysis includes MSM who tested positive for HIV-1 during screening for a trial of partner management and STI control (June 2022-January 2023). Participants were tested for HIV, gonorrhoea, chlamydia, and syphilis, and completed questionnaires on their demographic characteristics, sexual identity and behaviour, sexual network structures and engagement in HIV care., Findings: Of 665 MSM, 153 (23%) had detectable (>200 copies/mL) viremia. 75% (499/662) of men living with HIV were previously diagnosed, with 94% (n = 469/499) reporting that they were on ART, and 93% (n = 436/469) virally suppressed. 96% (n = 147/153) of men with detectable viremia reported serodiscordant CAI with at least one of their last three sexual partners, and 74% (n = 106/144) reported the same with all three of their recent partners. In contrast, 62% (n = 302/489) of men with undetectable viral load reported serodiscordant CAI with all of their last three partners (p < 0.01)., Interpretation: 23% of men living with HIV in Peru had detectable viremia, of whom almost all (96%) reported recent serodiscordant CAI. The primary gap in the HIV care cascade lies in awareness of HIV serostatus, suggesting that improved access to HIV testing could be a key prevention strategy in Peru., Funding: Funding for this study was provided by NIH/NIMH grants R01 MH118973 (PI: Clark) and R25 MH087222 (PI: Clark)., Competing Interests: None of the authors on this paper have financial or other conflicts of interest to disclose., (© 2024 The Authors.)

Background: Neisseria gonorrheae and Chlamydia trachomatis are associated with mucosal inflammation and human immunodeficiency virus 1 (HIV-1) transmission. We assessed levels of inflammatory cytokines in men who have sex with men (MSM) with and without rectal gonorrhea and/or chlamydia in Lima, Peru., Methods: We screened 605 MSM reporting condomless receptive anal intercourse for rectal N. gonorrheae/C. trachomatis using nucleic acid testing. We identified 101 cases of gonorrhea and/or chlamydia and randomly selected 50 N. gonorrheae/C. trachomatis positive cases and matched 52 negative controls. We measured levels of IL-1β, IL-6, IL-8, and TNF-α in rectal secretions. Tests for HIV-1, rectal N. gonorrheae/C. trachomatis, and mucosal cytokines were repeated after 3 and 6 months. Cytokine levels in cases and uninfected controls were compared using Wilcoxon rank-sum tests and linear regression., Results: MSM with gonorrhea/chlamydia had elevated levels of all cytokines in rectal mucosa compared with matched controls (all P values <.001). Following antibiotic treatment there were no significant differences in cytokine levels at 3- or 6-month follow-up evaluations (all P values >.05)., Discussion: Rectal gonorrhea/chlamydia infection is associated with transient mucosal inflammation and cytokine recruitment. Our data provide proof of concept for rectal sexually transmitted infection screening as an HIV prevention strategy for MSM. Clinical Trials Registration. NCT03010020., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intraspecific processes impact macroevolutionary patterns through individual variation, selection, and ecological specialisation. According to the niche variation hypothesis, the broader ecological niche of gen- eralist species results in an increased morphological variation among individuals, either because they are constituted of diversified specialised individuals each exploiting a fraction of the species' niche, or because they are constituted of true generalist individuals that experience relaxed selection. To test this hypoth- esis, we surveyed the individual floral morphology of species of Antillean Gesneriaceae, a group that has transitioned between specialisation for hummingbird pollination and generalisation multiple times throughout its evolutionary history. We characterised the profiles of corollas using geometric morpho- metrics and compared the intraspecific shape variance of specialists and generalists in a phylogenetic context. We used three approaches that differently accounted for the high dimensionality of morphologi- cal traits, the ancestral reconstruction of pollination syndromes over time, and the error associated with the estimation of the intraspecific variance. Our findings provide partial support for the niche variation hypothesis. If considering the whole shape in the analysis corroborated this idea, decomposing the shape into principal components indicated that not all aspects of the corolla exhibit the same pattern of vari- ation. Specifically, pollination generalists tend to display greater intraspecific variation than specialists in terms of tubularity, but not of curvature. Accounting for the error in the variance estimation also reduced the support for the hypothesis, suggesting that larger sample sizes may be required to reach stronger conclusions. This study emphasises the reciprocal influence between plants and their pollinators on floral morphology at different biodiversity scales, and suggests that ecological strategies of species can affect patterns of morphological variation at macroevolutionary scales., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Evolutionary Biology.)

Objectives: Sexual networks are known to structure sexually transmitted infection (STI) transmission among men who have sex with men (MSM). We sought to estimate the risks of STI diagnosis for various partnership types within these networks., Methods: Our cross-sectional survey analysed data from 1376 MSM screened for a partner management intervention in Lima, Peru. Participants were tested for HIV, syphilis, gonorrhoea (NG) and chlamydia (CT) and completed surveys on their demographics, sexual identity/role, HIV status, partnership types and sexual network from the prior 90 days. χ 2 and Wilcoxon rank-sum tests compared participants without an STI to those diagnosed with (1) syphilis, (2) NG and/or CT (NG/CT) and (3) syphilis and NG/CT coinfection (coinfection)., Results: 40.8% (n=561/1376) of participants were diagnosed with an STI (syphilis: 14.9%, NG/CT: 16.4%, coinfection: 9.5%). 47.9% of all participants were living with HIV and 8.9% were newly diagnosed. A greater proportion of participants with syphilis and coinfection were living with HIV (73.5%, p<0.001; 71.0%, p<0.001) compared with those with NG/CT (47.8%) or no STI (37.8%). Participants with syphilis more often reported sex-on-premises venues (SOPVs) as the location of their last sexual encounter (51.7%, p=0.038) while those with NG/CT tended to meet their last sexual partner online (72.8%, p=0.031). Respondents with coinfection were the only STI group more likely to report transactional sex than participants without an STI (31.3%, p=0.039)., Conclusions: Sexual networks and partnership types of Peruvian MSM are associated with differential risks for STIs. Participants diagnosed with syphilis tended to meet single-encounter casual partners at SOPV, while MSM with NG/CT were younger and often contacted casual partners online. Coinfection had higher frequency of transactional sex. These findings suggest the potential importance of public health interventions through combined syphilis/HIV screening at SOPV, syphilis screening at routine clinic appointments for MSM living with HIV and directed advertisements and/or access to NG/CT testing through online platforms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Published data on combined breast and gynecologic [breast/gyn] surgical pathology fellowship training programs are limited. Our study aimed to survey the landscape of such fellowships in the United States (US), including specific information about their characteristics and the educational activities therein. Using web searches, we identified programs offering combined breast/gyn surgical pathology fellowship training. We developed a 26-item questionnaire asking program directors to report on the characteristics of their fellowship training structure. The search revealed 25 academic based programs offering one-year combined breast/gyn fellowship training, predominantly located (40 %) in the Northeast area. The following data was obtained: 44 % of the programs were accredited by the ACGME, 82 % required >19 weeks of breast and gyn service, and 69.6 % accepted the common application, 54.5 % of programs require completion of a research project for graduation. An annual average of 3000 breast and 3000 gyn cases appears to be the usual volume of cases. Interestingly, only 36 % of the program directors are graduates of a combined breast/gyn fellowship program. In conclusion, we present the most comprehensive and up-to-date census of combined breast/gyn pathology fellowships in the US. Our study provides valuable information on the current state of combined breast/gyn pathology fellowship training. The information will be helpful to current and prospective trainees, as well as program leaders., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Hearing loss is an important global public health issue which can be alleviated through treatment with hearing aids. However, most people who would benefit from hearing aids do not receive them, in part due to challenges in accessing hearing aids and related services, which are most salient in low- and middle-income countries (LMIC) and other resource-limited settings. Innovative approaches for hearing aid service delivery can overcome many of the challenges related to access, including that of limited human resources trained to provide ear and hearing care. The purpose of this systematic scoping review is to synthesize evidence on service delivery approaches for hearing aid provision in LMIC and resource-limited settings. We searched 3 databases (PubMed, Scopus, Ovid MEDLINE) for peer-reviewed articles from 2000 to 2022 that focused on service delivery approaches related to hearing aids in LMIC or resource-limited settings. Fifteen peer-reviewed articles were included, which described hospital-based (3 studies), large-scale donation program (1 studies), community-based (7 studies), and remote (telehealth; 4 studies) service delivery approaches. Key findings are that hearing aid services can be successfully delivered in hospital- and community-based settings, and remotely, and that both qualified hearing care providers and trained non-specialists can provide quality hearing aid services. Service delivery approaches focused on community-based and remote care, and task sharing among qualified hearing care providers and trained non-specialists can likely improve access to hearing aids worldwide, thereby reducing the burden of untreated hearing loss., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. Author De Wet Swanepoel declares: Consultation, equity and potential royalties, hearX Group, Pretoria, South Africa. Author Carrie Nieman declares: Volunteer membership on the nonprofit board of directors for the Hearing Loss Association of America and Access HEARS. No other authors have competing interests to declare., (Copyright: © 2024 Dillard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Social networks contribute to normative reinforcement of HIV prevention strategies, knowledge sharing, and social capital, but little research has characterized the social networks of transgender women (TW) in Latin America. We conducted a mixed methods analysis of three network clusters of TW in Lima, Peru, to evaluate network composition, types of support exchanged, and patterns of communication., Methods: We recruited TW residing in or affiliated with three "casas trans" (houses shared among TW) in Lima between April-May 2018. Eligible participants were 18 or older, self-reported HIV-negative, and reported recent intercourse with a cis-male partner. Participants completed demographic questionnaires, social network interviews, and semi-structured interviews to assess egocentric network structures, support exchanged, and communication patterns. Quantitative and qualitative data were analyzed using Stata v14.1 and Atlas.ti, respectively., Results: Of 20 TW, median age was 26 years and 100% reported involvement in commercial sex work. Respondents identified 161 individuals they interacted with in the past month (alters), of whom 33% were TW and 52% family members. 70% of respondents reported receiving emotional support from family, while 30% received financial support and instrumental support from family. Of the 13 (65%) respondents who nominated someone as a source of HIV prevention support (HPS), the majority (69%) nominated other TW. In a GEE regression analysis adjusted for respondent education and region of birth, being a family member was associated with lower likelihood of providing financial support (aOR 0.21, CI 0.08-0.54), instrumental support (aOR 0.16, CI 0.06-0.39), and HPS (aOR 0.18, CI 0.05-0.64). In qualitative interviews, most respondents identified a cis-female family member as their most trusted and closest network member, but other TW were more often considered sources of day-to-day support, including HPS., Conclusion: TW have diverse social networks where other TW are key sources of knowledge sharing and support, and family members may also represent important and influential components. Within these complex networks, TW may selectively solicit and provide support from different network alters according to specific contexts and needs. HIV prevention messaging could consider incorporating network-based interventions with TW community input and outreach efforts for supportive family members., (© 2023. The Author(s).)

Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast cancer stem cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate integrin α6 mRNA splicing. Specifically, TRPC6-mediated calcium entry represses the epithelial splicing factor ESRP1 (epithelial splicing regulatory protein 1), which enables expression of the integrin α6B splice variant. TRPC6 and α6B function in tandem to facilitate stemness and persistence by activating TAZ and, consequently, repressing Myc. Therapeutic inhibition of TRPC6 sensitizes triple-negative breast cancer (TNBC) cells and tumors to chemotherapy by targeting the splicing of α6 integrin mRNA and inducing Myc. These data reveal a Ca 2+ -dependent mechanism of chemotherapy-induced persistence, which is amenable to therapy, that involves integrin mRNA splicing., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent field research on the eastern slopes of the Andes resulted in the discovery of a new species of Bomarea from the Cerro Candelaria Reserve in the Tungurahua province of Ecuador. Bomareapastazensis is the second smallest species in the genus and differs from the smallest by the presence of glutinous trichomes on the ovary, glabrous sepals, and greenish-yellow petals with purple spots. Based on IUCN guidelines, a preliminary conservation status is assigned as Vulnerable (VU)., Competing Interests: The authors have declared that no competing interests exist., (John L. Clark, Alisson Fierro-Minda, Nolan Exe, Mia Johnson, Carrie M. Tribble, Lou Jost.)

A narrowly endemic new species of Gesneria is described from the Sierra de Bahoruco in the Dominican Republic's Barahona Peninsula of southern Hispaniola. Gesneriatuberifera J.L.Clark & T.Clase, sp. nov. differs from all other congeners by the presence of a tuber and tubular red corollas with yellow lobes. Images and a discussion are provided to summarize the presence of tubers in other Gesneriaceae and differentiate Gesneriatuberifera from congeners that share a lithophytic habit. Based on IUCN guidelines, a preliminary conservation status of Endangered (EN) is assessed for G.tuberifera ., Competing Interests: The authors have declared that no competing interests exist., (John L. Clark, Teodoro Clase.)

Objectives: Gender-affirming hormonal therapies (GAHT) and HIV increase cardiovascular risk for transgender women (TW), yet there is a paucity of data quantifying cardiometabolic changes following GAHT initiation, particularly among TW with HIV., Methods: The Féminas study enrolled TW from October 2016 to March 2017 in Lima, Peru. Participants reported sexual activity that was high risk for HIV acquisition or transmission. All were tested for HIV/ sexually transmitted infection and were given access to GAHT (oestradiol valerate and spironolactone), HIV pre-exposure prophylaxis (PrEP) or antiretroviral therapy (ART) for 12 months. Biomarker measurement was done on stored serum, whereas fasting glucose and lipids were measured in real time., Results: In all, 170 TW (32 with HIV, 138 without HIV) had median age 27 years and 70% prior GAHT use. At baseline, PCSK9, sCD14, sCD163, IL-6, sTNFRI/II, CRP and EN-RAGE levels were significantly higher in TW with HIV than in TW without HIV. High-density lipoprotein and total cholesterol were lower and insulin and glucose parameters were similar. All TW with HIV started ART, but only five achieved virological suppression at any time. No TW without HIV initiated PrEP. Over 6 months, all participants initiated GAHT and had worsening insulin, glucose and HOMA-IR. Large d-dimer decreases also occurred. Similar changes occurred in TW with and without HIV., Conclusions: In this unique cohort of TW, GAHT decreased d-dimer but worsened insulin sensitivity. Because PrEP uptake and ART adherence were very low, observed effects are primarily attributed to GAHT use. Further study is needed to better understand cardiometabolic changes in TW by HIV serostatus., (© 2023 British HIV Association.)

Background: Intravenous digoxin loading dose recommendations differ between clinical guidelines and Food and Drug Administration packaging for acute rate control., Objective: The objective of this study was to assess the safety and efficacy of intravenous digoxin loading in patients who received ≤12 µg/kg and >12 µg/kg of digoxin using ideal body weight (IBW)., Methods: This single center retrospective cohort study with exempt status from the local Institutional Review Board included patients who received intravenous digoxin and had a serum digoxin concentration (SDC) drawn. Digoxin doses >36 hours after the first dose were excluded. Patients who received a total of >12 µg/kg and ≤12 µg/kg IBW were compared. The primary endpoint was frequency of SDCs ≥1.2 ng/mL, which have been shown to be associated with increased mortality., Results: A total of 244 patients were included (144 receiving >12 µg/kg and 100 receiving ≤12 µg/kg). There were significantly more SDC ≥1.2 ng/mL in the >12 µg/kg group than the ≤12 µg/kg group (50.6% vs. 30.0%; adjusted odds ratio, 3.19; 95% confidence interval [CI]: 1.79-5.84), with no difference in rate control failure. Major limitations of the study include retrospective nature and possible selection bias., Conclusion and Relevance: Compared to patients who received digoxin doses ≤12 µg/kg IBW, patients who received >12 µg/kg IBW had higher rates of SDC ≥1.2 ng/mL. This suggests that appropriate weight-based dosing with 8 to 12 µg/kg IBW has the potential to be a safer approach to digoxin loading, rather than frequently used dosing strategies that result in doses >12 µg/kg.

We evaluated COVID-19's impact on HIV care indicators among INI/FIOCRUZ's HIV Clinical Cohort in Rio de Janeiro, Brazil: (1) Adequate care visits: two visits ≥ 90 days apart; (2) Adequate viral load monitoring: ≥ 2 viral load results ≥ 90 days apart; (3) Consistent viral suppression: all viral loads < 40 copies/mL; and (4) ART medication possession ratio (MPR) ≥ 95%. Chi-square tests compared the fraction of participants meeting each indicator per period: pre-pandemic (3/1/2019-2/29/2020) and post-pandemic (3/1/2020-2/28/2021). Logistic regression models were used to assess disparities in adequate care visits. Among 906 participants, care visits and viral load monitoring decreased pre-pandemic to post-pandemic: 77.0-55.1% and 36.6-11.6% (both p < 0.001), respectively. The optimal MPR rate improved from 25.5 to 40.0% (p < 0.001). Post-pandemic period (aOR 0.33, CI 0.28-0.40), transgender women (aOR 0.34, CI 0.22-0.53), and those aged 18-24 years (aOR 0.67, CI 0.45-0.97) had lower odds of adequate care visits. COVID-19 disrupted care access disproportionately for transgender women and younger participants., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Syndemic psychosocial and reproductive factors affecting women's retention in HIV care remain understudied. We analyzed correlates of non-retention in a cohort of women with HIV in Brazil from 2000‒2015. Participants self-reported exposure to physical/sexual violence, illicit drug use, adolescent pregnancy, or induced abortion. Lifetime history of these psychosocial stressors were used to create a syndemic score based on the presence or absence of these conditions. All dichotomous variables were summed (range 0 to 4), with greater scores indicating more syndemic factors experienced. Logistic regression models identified predictors of non-retention, defined as < 2 HIV viral load or CD4 results within the first year of enrollment. Of 915 women, non-retention was observed for 18%. Prevalence of syndemic factors was adolescent pregnancy (53.2%), physical/sexual violence (38.3%), induced abortion (27.3%), and illicit drug use (17.2%); 41.2% experienced ≥ 2 syndemic conditions. Syndemic scores of 2 and 3 were associated with non-retention, as well as low education, years with HIV and seroprevalent syphilis. Psychosocial and reproductive syndemics can limit women's retention in HIV care. Syphilis infection predicted non-retention and could be explored as a syndemic factor in future studies., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

A new species of Amanoa (Phyllanthaceae) is described from the sandstone Nangaritza Plateau in the Cordillera del Cóndor Region in southern Ecuador. Amanoacondorensis J.L.Clark & D.A.Neill is a small tree, 4 m tall that is only known from the type collection. The new species is distinct by a shrub habit, presence of coriaceous leaves with an acuminate apex, and congested inflorescences. The relatively high elevation of the type locality, presence of an androphore, and the habit as shrub or low tree are an unusual combination for Amanoa . The conservation status of A.condorensis is assessed as Critically Endangered (CR), based on IUCN Criteria., Competing Interests: No conflict of interest was declared.

Methamphetamine (MA) use is associated with HIV transmission among men who have sex with men (MSM) and lapses in medication adherence. Contingency Management (CM) is effective in reducing MA use, but studies of CM to support adherence to HIV prevention or treatment are limited. We conducted a pilot trial of a CM intervention to reduce MA use and improve PrEP/ART adherence among MSM prescribed a tenofovir (TFV)-based regimen for HIV prevention or treatment. Participants were randomly assigned to receive escalating incentives for either MA abstinence or TFV adherence (based on point-of-care urine testing), and to a monitoring schedule of either 2 or 3 visits/week for 4 weeks. 19 MSM were randomized to either CM for MA use or CM for PrEP/ART adherence (median age: 38; IQR: 28-46) and 15 were living with HIV. Participants attended 95.7% (67/70) of scheduled visits in the 2x/week arm and 74.8% (74/99) in the 3x/week arm. TFV adherence was higher among participants in the TFV adherence arm with 93.5% (n = 72/77) of urine samples positive for TFV, compared to 76.6% (n = 49/64) in the MA abstinence arm (p = 0.007). Participants in the MA abstinence arm had more urine samples negative for MA metabolites (20.3%, n = 13/64) than those receiving CM for TFV adherence (6.5%, n = 5/77; p = 0.021). A CM model for MA abstinence and PrEP/ART adherence using twice-weekly visits and urine testing for MA and TFV for MSM who use MA is feasible and potentially effective as an integrated harm reduction strategy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Despite a growing body of literature on sexual harassment and inappropriate patient sexual behavior towards clinicians within the broader fields of psychology and medicine, literature, guidance, and supervision frameworks specific to neuropsychology are lacking. This gap in the literature is significant, given that neuropsychology is a specialty field faced with vulnerabilities to sexual harassment, and neuropsychologists may weigh unique factors into their decision-making of whether and/or when to respond. This decision-making may be further complicated for trainees. Method: A review of the literature addressing sexual harassment by patients in neuropsychology was completed. In this paper, we summarize the relevant literature on sexual harassment within psychology and academic medicine and provide a framework for discussing sexual harassment in neuropsychology supervision. Results: Research suggests high rates of inappropriate sexual behavior and/or sexual harassment from patients towards trainees, especially amongst trainees who identify as female and/or hold marginalized identities. Trainees report inadequate training in how to deal with sexual harassment by patients and there are perceived barriers for discussing the topic in supervision. Further, most professional organizations do not have formal policies regarding how to handle incidents. Conclusions: As of this writing, guidance and/or position statements from prominent neuropsychological associations could not be found. Research and guidance specific to neuropsychology is needed to help clinicians navigate these challenging clinical situations, provide effective supervision on the topic to trainees, and normalize discussion and reporting of sexual harassment.

Background: Pre-exposure prophylaxis (PrEP) is an important tool for HIV prevention in Latin America and the Caribbean (LAC). Yet, little is known about the PrEP policies landscape in the region. Addressing this gap, this scoping review assessed current PrEP policies throughout LAC to better understand existing PrEP implementation gaps and identify opportunities to improve access., Methods: We conducted a scoping review, using a modified PRISMA extension, through 28 July 2022, to identify country-level PrEP policies. Data were collected in English, Spanish, French, and Portuguese utilizing online platforms for screening and data extraction (Google Forms, Zotero, and Excel). Extracted data were divided by data source, including country-level government policies, gray literature, and peer-reviewed literature, with at least one full-text reviewer and data extractor per publication. An iterative summative content analysis was performed to compare and interpret themes across phases and data sources., Results: Of the 33 countries in LAC, 22 (67%) had policies approving daily oral PrEP for HIV prevention, which outlined specific key populations, including men who have sex with men, transgender women, sex workers, and serodiscordant couples. Generic tenofovir disoproxil fumarate/emtricitabine has been approved in 15 of the 33 countries, and 13 of the 33 countries have incorporated PrEP into their public health system. No countries were found to have approved cabotegravir. Costing data were reported by only one country, Ecuador, in its national health ministry guidelines. Findings also document a lag between the media/gray-literature announcement of PrEP and implementation of policies., Conclusion: Findings underscore significant advances in PrEP policies in the region and signal opportunities for greater PrEP implementation. Since 2017, an increasing number of countries have begun to provide PrEP to communities at heightened need, although significant gaps remain. Policy approval is a key step to further increasing access to PrEP in LAC, necessary to reduce the burden of HIV in LAC, specifically among marginalized populations., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, or publication of this article: KK reports employment at Universidad Peruana Cayetano Heredia and Keck School of Medicine at University of Southern California., (© The Author(s), 2023.)

Background: Methamphetamine (MA) use is associated with sexual risk behavior as well as systemic and mucosal inflammation, suggesting parallel biological and behavioral mechanisms of HIV transmission among men who have sex with men (MSM) who use MA. Data evaluating the combined biological effects of MA use with concomitant rectal gonococcal and/or chlamydial (GC/CT) infection on inflammation are limited., Setting: Secondary analysis of stored rectal and plasma specimens from 100 MSM participating in an NIDA-funded longitudinal cohort in Los Angeles, CA., Methods: This cross-sectional analysis evaluated systemic and rectal inflammatory markers under 2 conditions: (1) recent MA use (by urine drug screen) and (2) rectal GC/CT infection. We evaluated 50 participants with recent MA use (25 with and 25 without rectal GC/CT) and 50 MSM without MA use (25 with and 25 without rectal GC/CT). Log-transformed plasma and rectal immune markers were regressed on MA exposure and rectal GC/CT, controlling for HIV status and age., Results: Median age was 32 (range 19-45) years, and 58% of participants were living with HIV. Plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-1ß, and rectal IL-6 were associated with rectal GC/CT and MA use, independent of HIV status. Higher levels of rectal TNF-α, IL-1ß, and IL-17a were associated with rectal GC/CT., Conclusions: Systemic and rectal inflammation was positively associated with rectal GC/CT and MA use. Condomless sex in the setting of GC/CT- and MA-induced immune activation may provide a basis for synergistic biobehavioral mechanisms that promote HIV/STI transmission among MSM who use MA., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

A narrowly endemic new species of Glossoloma is described from the Cordillera Oriental of the northern Andes, in the Colombian departments of Caquetá and Huila. Glossolomamagenticristatum J.L.Clark, D.Hoyos & Clavijo, sp. nov. differs from most other congeners by a habit that is usually epiphytic with elongate scandent subwoody shoots, the presence of a magenta corolla tube, and a creased calyx formed by tightly appressed adjacent lobes. A brief summary of Gesneriaceae diversity in the Colombia departments of Caquetá and Huila is discussed with an emphasis on the old highway between Florencia and Guadalupe. The conservation status of G.magenticristatum is assessed as Endangered (EN) based on IUCN Criteria.

Background: Alterations in the gut microbiome have been associated with HIV infection, but the relative impact of HIV versus other factors on the gut microbiome has been difficult to determine in cross-sectional studies., Methods: To address this, we examined the gut microbiome, serum metabolome, and cytokines longitudinally within 27 individuals before and during acute HIV using samples collected from several ongoing cohort studies. Matched control participants (n=28) from the same cohort studies without HIV but at similar behavioral risk were used for comparison., Findings: We identified few changes in the microbiome during acute HIV infection, but did find alterations in serum metabolites involving secondary bile acid (lithocholate sulfate, glycocholenate sulfate) and amino acid metabolism (3-methyl-2-oxovalerate, serine, cysteine, N-acetylputrescine). Greater microbiome differences, including decreased Bacteroides spp and increased Megasphaera elsdenii, were seen when comparing pre-HIV infection visits to matched at-risk controls. Those who acquired HIV also had elevated inflammatory cytokines (TNF-α, B cell activating factor, IL-8) and bioactive lipids (palmitoyl-sphingosine-phosphoethanolamide and glycerophosphoinositol) prior to HIV acquisition compared to matched controls., Interpretation: Longitudinal sampling identified pre-existing microbiome differences in participants with acute HIV compared to matched control participants observed over the same period. These data highlight the importance of increasing understanding of the role of the microbiome in HIV susceptibility., Funding: This work was supported by NIH/NIAID (K08AI124979; P30AI117943), NIH/NIDA (U01DA036267; U01DA036939; U01DA036926; U24DA044554), and NIH/NIMH (P30MH058107; R34MH105272)., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare., (Published by Elsevier B.V.)

Exploratory field expeditions to the western slopes of the Ecuadorian Andes resulted in the discovery of a new species of Monopyle (Gesneriaceae). Monopyleglutinosa J.L.Clark & Keene, sp. nov. is described as a narrow endemic from lowland forests along the border of the Reserva Ecológica Los Illinizas in the Province of Cotopaxi. The new species is unique for the presence of glutinous or sticky trichomes on the calyx lobes and outer surface of the inferior ovary. Based on IUCN guidelines, a preliminary conservation status is assigned as Critically Endangered (CR)., (John L. Clark, Franciso Tobar, Jeremy Keene.)

Systemic oppression creates a context in which Latinx LGBTQ+ youth experience social isolation. Social isolation has been associated with mental and physical health disparities, including disproportionate levels of depression, substance use, self-harm, and attempted suicide. These disparities are often magnified in rural and suburban areas with fewer identity-affirming spaces. This community-engaged study reports on the formative process of developing a Latinx LGBTQ+ telenovela (soap opera) allyship intervention based on critical consciousness theory. We conducted eight focus groups with community advisory boards, which included Latinx LGBTQ+ youth ( n = 12), health and social service providers serving LGBTQ+ youth ( n = 10), 4-H Latinx alumni youth ( n = 12), and 4-H Latinx parents ( n = 8). We interviewed nine Latinx LGBTQ+ youth enrolled in a film-making workshop. As a result of our multi-stakeholder approach, we: (1) described how stakeholders reflected on and decoded intersectional isolation on the individual, community, and structural levels; and (2) identified ways that stakeholders suggested taking action by improving access to resources to address social isolation, provide culturally competent healthcare, and co-create an enabling social environment. Our study indicated the importance of tapping into core values and intersectional identities to build solidarity among and within marginalized groups to dismantle oppressive systems.

Background: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19., Methods: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168., Findings: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012)., Interpretation: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered., Funding: National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Paleogenomic research can elucidate the evolutionary history of human and faunal populations. Although the Levant is a key land-bridge between Africa and Eurasia, thus far, relatively little ancient DNA data has been generated from this region, since DNA degrades faster in warm climates. As sediments can be a source of ancient DNA, we analyzed 33 sediment samples from different sedimentological contexts in the Paleolithic layers of Sefunim Cave (Israel). Four contained traces of ancient Cervidae and Hyaenidae mitochondrial DNA. Dating by optical luminescence and radiocarbon indicates that the DNA comes from layers between 30,000 and 70,000 years old, surpassing theoretical expectations regarding the longevity of DNA deposited in such a warm environment. Both identified taxa are present in the zooarchaeological record of the site but have since gone extinct from the region, and a geoarchaeological study suggests little movement of the sediments after their deposition, lending further support to our findings. We provide details on the local conditions in the cave, which we hypothesize were particularly conducive to the long-term preservation of DNA-information that will be pertinent for future endeavors aimed at recovering ancient DNA from the Levant and other similarly challenging contexts., (© 2022. The Author(s).)