Safety and immunogenicity of a polyvalent DNA-protein HIV vaccine with matched Env immunogens delivered as a prime-boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial.

BACKGROUND: An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens. METHODS: HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection. The DNA vaccine comprised five plasmids: four copies expressing Env gp120 (clades A, B, C, and AE) and one gag p55 (clade C). The protein vaccine included four DNA vaccine-matched GLA-SE-adjuvanted recombinant gp120 proteins. Participants were enrolled across six clinical sites in the USA and were randomly assigned to placebo or one of two vaccine groups (ie, prime-boost or coadministration) in a 5:1 ratio in part A and a 7:1 ratio in part B. Vaccines were delivered via intramuscular needle injection. The primary outcomes were safety and tolerability, assessed via frequency, severity, and attributability of local and systemic reactogenicity and adverse events, laboratory safety measures, and early discontinuations. Part A evaluated safety. Part B evaluated safety and immunogenicity of two regimens: DNA prime (administered at months 0, 1, and 3) with protein boost (months 6 and 8), and DNA-protein coadministration (months 0, 1, 3, 6, and 8). All randomly assigned participants who received at least one dose were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT03409276) and is closed to new participants. FINDINGS: Between April 19, 2018 and Feb 13, 2019, 60 participants (12 in part A [five men and seven women] and 48 in part B [21 men and 27 women]) were enrolled. All 60 participants received at least one dose, and 14 did not complete follow-up (six of 21 in the prime-boost group and eight of 21 in the coadminstration group). 11 clinical adverse events deemed by investigators as study-related occurred in seven of 48 participants in part B (eight of 21 in the prime-boost group and three of 21 in the coadministration group). Local reactogenicity in the vaccine groups was common, but the frequency and severity of reactogenicity signs or symptoms did not differ between the prime-boost and coadministration groups (eg, 20 [95%] of 21 in the prime-boost group vs 21 [100%] of 21 in the coadministration group had either local pain or tenderness of any severity [p=1·00], and seven [33%] vs nine [43%] had either erythema or induration [p=0·97]), nor did laboratory safety measures. There were no delayed-type hypersensitivity reactions or vasculitis or any severe clinical adverse events related to vaccination. The most frequently reported systemic reactogenicity symptoms in the active vaccine groups were malaise or fatigue (five [50%] of ten in part A and 17 [81%] of 21 in the prime-boost group vs 15 [71%] of 21 in the coadministration group in part B), headache (five [50%] and 18 [86%] vs 12 [57%]), and myalgia (four [40%] and 13 [62%] vs ten [48%]), mostly of mild or moderate severity. INTERPRETATION: Both vaccine regimens were safe, warranting evaluation in larger trials. FUNDING: US National Institutes of Health and US National Institute of Allergy and Infectious Diseases.

Challenges with non-descriptive compliance labeling of end-stage renal disease patients in accessibility for renal transplantation.

Non-descriptive and convenient labels are uninformative and unfairly project blame onto patients. The language clinicians use in the Electronic Medical Record, research, and clinical settings shapes biases and subsequent behaviors of all providers involved in the enterprise of transplantation. Terminology such as noncompliant and nonadherent serve as a reason for waitlist inactivation and limit access to life-saving transplantation. These labels fail to capture all the circumstances surrounding a patient's inability to follow their care regimen, trivialize social determinants of health variables, and bring unsubstantiated subjectivity into decisions regarding organ allocation. Furthermore, insufficient Medicare coverage has forced patients to ration or stop taking medication, leading to allograft failure and their subsequent diagnosis of noncompliant. We argue that perpetuating non-descriptive language adds little substantive information, increases subjectivity to the organ allocation process, and plays a major role in reduced access to transplantation. For patients with existing barriers to care, such as racial/ethnic minorities, these effects may be even more drastic. Transplant committees must ensure thorough documentation to correctly encapsulate the entirety of a patient's position and give voice to an already vulnerable population.

Dyadic practice for the acquisition of laparoscopic skills (DALS)-A randomized controlled trial.

BACKGROUND: Laparoscopic simulation is integral to surgical education but requires significant resources. We aimed to compare the effectiveness of dyadic practice (DP), involving two individuals working together, to individual practice (IP) for novices acquiring laparoscopic skills and assess their learning experience. METHODS: We conducted a Randomized Controlled Trial comparing DP and IP for novice medical students who completed a laparoscopic simulation workshop. Participants were assessed individually pre-course (test 1), post-course (test 2), and 8-week retention (test 3) using a validated quantitative method. A post-course questionnaire and interview, analyzed with thematic analysis, assessed the learning experience. RESULTS: In total, 31 DP and 35 IP participants completed the study. There was no difference in mean scores between DP and IP groups in all three tests: test 1 (p = 0.55), test 2 (p = 0.26), test 3 (p = 0.35). In trend analysis, the DP group improved post-course (test 1 vs. 2: p = 0.02) and maintained this level at the retention test (2 vs. 3: p = 0.80, 1 vs. 3: p = 0.02). Whilst the IP group also improved post-course (test 1 vs. 2: p < 0.001), this improvement was not retained (2 vs. 3: p = 0.003, 1 vs. 3: p = 0.32). Thematic analysis revealed that DP participants valued peer support, peer feedback and observation time, but also acknowledged the limitations of reduced practical time and issues with teamwork. CONCLUSION: DP is non-inferior to IP for novices learning laparoscopic skills, is well received and may lead to superior long-term skill retention.

A guide to outcome evaluation of simulation-based education programmes in low and middle-income countries.

Evaluation is a vital part of any learning activity and is essential to optimize and improve educational programmes. It should be considered and prioritized prior to the implementation of any learning activity. However, comprehensive programme evaluation is rarely conducted, and there are numerous barriers to high-quality evaluation. This review provides a framework for conducting outcome evaluation of simulation-based education programmes in low and middle-income countries (LMICs). The basis of evaluation, including core ideas of theory, purpose and structure are outlined, followed by an examination of the levels and healthcare applications of the Kirkpatrick model of evaluation. Then, methods of conducting evaluation of simulation-based education in LMICs are discussed through the lens of a successful surgical simulation programme in Myanmar, a lower-middle-income country. The programme involved the evaluation of 11 courses over 4 years in Myanmar and demonstrated evaluation at the highest level of the Kirkpatrick model. Reviewing this programme provides a bridge between evaluation theory and practical implementation. A range of evaluation methods are outlined, including surveys, interviews, and clinical outcome measurement. The importance of a mixed-methods approach, enabling triangulation of quantitative and qualitative analysis, is highlighted, as are methods of analysing data, including statistical and thematic analysis. Finally, issues and challenges of conducting evaluation are considered, as well as strategies to overcome these barriers. Ultimately, this review informs readers about evaluation theory and methods, grounded in a practical application, to enable other educators in low-resource settings to evaluate their own activities.

Structural analysis of a U-superfamily conotoxin containing a mini-granulin fold: Insights into key features that distinguish between the ICK and granulin folds.

We are entering an exciting time in structural biology where artificial intelligence can be used to predict protein structures with greater accuracy than ever before. Extending this level of accuracy to the predictions of disulfide-rich peptide structures is likely to be more challenging, at least in the short term, given the tight packing of cysteine residues and the numerous ways that the disulfide bonds can potentially be linked. It has been previously shown in many cases that several disulfide bond connectivities can be accommodated by a single set of NMR-derived structural data without significant violations. Disulfide-rich peptides are prevalent throughout nature, and arguably the most well-known are those present in venoms from organisms such as cone snails. Here, we have determined the first three-dimensional structure and disulfide connectivity of a U-superfamily cone snail venom peptide, TxVIIB. TxVIIB has a VI/VII cysteine framework that is generally associated with an inhibitor cystine knot (ICK) fold; however, AlphaFold predicted that the peptide adopts a mini-granulin fold with a granulin disulfide connectivity. Our experimental studies using NMR spectroscopy and orthogonal protection of cysteine residues indicate that TxVIIB indeed adopts a mini-granulin fold but with the ICK disulfide connectivity. Our findings provide structural insight into the underlying features that govern formation of the mini-granulin fold rather than the ICK fold and will provide fundamental information for prediction algorithms, as the subtle complexity of disulfide isomers may be not adequately addressed by the current prediction algorithms.

Pretransplant malignancy in pediatrics is not a risk factor for renal graft failure.

BACKGROUND: In adults, pretransplant malignancy (PTM) negatively impacts patient survival due to immunosuppression regimens influencing post-transplantation tumor growth. Few reports investigate the outcomes of pediatric kidney transplantation with PTM. We compare transplant outcomes for pediatric patients with PTM to matched controls, including cancer types extending beyond Wilms tumor. METHODS: The United Network of Organ Sharing Database was queried to identify pediatric transplant recipients with histories of PTM. All PTM patients were matched to non-PTM patients, at a 1:1 ratio, with 0.001 match tolerance. Matching variables included transplant year, recipient age, recipient gender, recipient race, donor type, and prior transplant. Death-censored graft and patient survival were analyzed. All statistics were reported with 95% confidence intervals (CI). RESULTS: After propensity matching, 285 PTM and 285 non-PTM patients were identified, with transplant dates from 1990 to 2020. Median Kidney Donor Profile Index values were comparable between cohorts, 17% and 12%, respectively (p = .065). Kaplan-Meier analysis revealed that PTM patients did not have a significantly different rate of death-censored graft failure, compared to the non-PTM group [HR 0.76; 95% CI (0.54-1.1)]. There was also no difference in the overall survival between the two groups of patients [HR 1.1; 95% CI (0.66-2.0)]. CONCLUSION: A history of pediatric malignancy has minimal independent effect on their post-transplant survival. Additionally, pediatric patients with PTM demonstrated equivalent rates of graft survival. Thus, in contrast to adults, renal failure in children with history of pediatric malignancies should not be considered a complicating factor for renal transplantation.

Peptide toxins that target vertebrate voltage-gated sodium channels underly the painful stings of harvester ants.

Harvester ants (genus Pogonomyrmex) are renowned for their stings which cause intense, long-lasting pain, and other neurotoxic symptoms in vertebrates. Here, we show that harvester ant venoms are relatively simple and composed largely of peptide toxins. One class of peptides is primarily responsible for the long-lasting local pain of envenomation via activation of peripheral sensory neurons. These hydrophobic, cysteine-free peptides potently modulate mammalian voltage-gated sodium (NaV) channels, reducing the voltage threshold for activation and inhibiting channel inactivation. These toxins appear to have evolved specifically to deter vertebrates.

Identification of sodium channel toxins from marine cone snails of the subgenera Textilia and Afonsoconus.

Voltage-gated sodium (NaV) channels are transmembrane proteins that play a critical role in electrical signaling in the nervous system and other excitable tissues. µ-Conotoxins are peptide toxins from the venoms of marine cone snails (genus Conus) that block NaV channels with nanomolar potency. Most species of the subgenera Textilia and Afonsoconus are difficult to acquire; therefore, their venoms have yet to be comprehensively interrogated for µ-conotoxins. The goal of this study was to find new µ-conotoxins from species of the subgenera Textilia and Afonsoconus and investigate their selectivity at human NaV channels. Using RNA-seq of the venom gland of Conus (Textilia) bullatus, we identified 12 µ-conotoxin (or µ-conotoxin-like) sequences. Based on these sequences we designed primers which we used to identify additional µ-conotoxin sequences from DNA extracted from historical specimens of species from Textilia and Afonsoconus. We synthesized six of these µ-conotoxins and tested their activity on human NaV1.1-NaV1.8. Five of the six synthetic peptides were potent blockers of human NaV channels. Of these, two peptides (BuIIIB and BuIIIE) were potent blockers of hNaV1.3. Three of the peptides (BuIIIB, BuIIIE and AdIIIA) had submicromolar activity at hNaV1.7. This study serves as an example of the identification of new peptide toxins from historical DNA and provides new insights into structure-activity relationships of µ-conotoxins with activity at hNaV1.3 and hNaV1.7.

Cancer screening and management in the transgender population: Review of literature and special considerations for gender affirmation surgery.

BACKGROUND: Literature focused on cancer screening and management is lacking in the transgender population. AIM: To action to increase contributions to the scientific literature that drives the creation of cancer screening and management protocols for transgender and gender nonconforming (TGNC) patients. METHODS: We performed a systematic search of PubMed on January 5th, 2022, with the following terms: "TGNC", OR "transgender", OR "gender non-conforming", OR "gender nonbinary" AND "cancer screening", AND "breast cancer", AND "cervical cancer", AND "uterine cancer", AND "ovarian cancer", AND "prostate cancer", AND "testicular cancer", AND "surveillance", AND "follow-up", AND "management". 70 unique publications were used. The findings are discussed under "Screening" and "Management" categories. RESULTS: Screening: Current cancer screening recommendations default to cis-gender protocols. However, long-term gender-affirming hormone therapy and loss to follow-up from the gender-specific specialties contribute to a higher risk for cancer development and possible delayed detection. The only known screening guidelines made specifically for this population are from the American College of Radiology for breast cancer. Management: Prior to undergoing Gender Affirmation Surgery (GAS), discussion should address cancer screening and management in the organs remaining in situ. Cancer treatment in this population requires consideration for chemotherapy, radiation, surgery and/or reconstruction. Modification of hormone therapy is decided on a case-by-case basis. The use of prophylactic vs aesthetic techniques in surgery is still debated. CONCLUSION: When assessing transgender individuals for GAS, a discussion on the future oncologic risk of the sex-specific organs remaining in situ is essential. Cancer management in this population requires a multidisciplinary approach while the care should be highly individualized with considerations to social, medical, surgical and gender affirming surgery related specifications. Special considerations have to be made during planning for GAS as surgery will alter the anatomy and may render the organ difficult to sample for screening purposes. A discussion with the patient regarding the oncologic risk of remaining organs is imperative prior to GAS. Other special considerations to screening such as the conscious or unconscious will to unassociated with their remaining organs is also a key point to address. We currently lack high quality studies pertinent to the cancer topic in the gender affirmation literature. Further research is required to ensure more comprehensive and individualized care for this population.

Clinical and Demographic Factors Associated With COVID-19, Severe COVID-19, and SARS-CoV-2 Infection in Adults: A Secondary Cross-Protocol Analysis of 4 Randomized Clinical Trials.

Importance: Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders. Objective: To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection. Design, Setting, and Participants: This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023. Exposures: Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment. Main Outcomes and Measures: Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection. Results: A total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001). Conclusions and Relevance: In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.

Horizontal gene transfer underlies the painful stings of asp caterpillars (Lepidoptera: Megalopygidae).

Larvae of the genus Megalopyge (Lepidoptera: Zygaenoidea: Megalopygidae), known as asp or puss caterpillars, produce defensive venoms that cause severe pain. Here, we present the anatomy, chemistry, and mode of action of the venom systems of caterpillars of two megalopygid species, the Southern flannel moth Megalopyge opercularis and the black-waved flannel moth Megalopyge crispata. We show that megalopygid venom is produced in secretory cells that lie beneath the cuticle and are connected to the venom spines by canals. Megalopygid venoms consist of large aerolysin-like pore-forming toxins, which we have named megalysins, and a small number of peptides. The venom system differs markedly from those of previously studied venomous zygaenoids of the family Limacodidae, suggestive of an independent origin. Megalopygid venom potently activates mammalian sensory neurons via membrane permeabilization and induces sustained spontaneous pain behavior and paw swelling in mice. These bioactivities are ablated by treatment with heat, organic solvents, or proteases, indicating that they are mediated by larger proteins such as the megalysins. We show that the megalysins were recruited as venom toxins in the Megalopygidae following horizontal transfer of genes from bacteria to the ancestors of ditrysian Lepidoptera. Megalopygids have recruited aerolysin-like proteins as venom toxins convergently with centipedes, cnidarians, and fish. This study highlights the role of horizontal gene transfer in venom evolution.

Ant venoms contain vertebrate-selective pain-causing sodium channel toxins.

Stings of certain ant species (Hymenoptera: Formicidae) can cause intense, long-lasting nociception. Here we show that the major contributors to these symptoms are venom peptides that modulate the activity of voltage-gated sodium (NaV) channels, reducing their voltage threshold for activation and inhibiting channel inactivation. These peptide toxins are likely vertebrate-selective, consistent with a primarily defensive function. They emerged early in the Formicidae lineage and may have been a pivotal factor in the expansion of ants.

Racial Disparity in Gender Affirming Surgery: A Comparative Study on Plastic Surgeon Social Media Use.

In the past 5 years, social media use among plastic surgeons has grown to become a common modality used to promote one's practice. However, surgeons lack the necessary ethical training to understand how their published content impacts patient opinions and behavior. Social media trends among plastic surgeons may contribute to the reduced rate of Black (non-White) patients accessing gender affirming surgery. Methods: In total, 250 gender affirming surgeons and 51,698 individual posts from social media platform, Instagram, were manually extracted and analyzed. Posts were assessed for inclusion and categorized by the subject's skin color (White versus non-White) using the Fitzpatrick scale. Results: Of the 3101 included posts, 375 (12.1%) portrayed non-White subjects. Of the 56 included surgeons, White surgeons were found to be 2.3 times less likely to include non-White subjects in their posts, compared with non-White surgeons. Regionally, surgeons practicing in the Northeast had the most racially diverse social media accounts, with over 20% of all posts including a non-White subject. Analyzing data over the past 5 years demonstrated no relative increase in the amount of non-White subjects being displayed on social media, while social media use by gender affirming surgeons had increased by over 200%. Conclusions: The low number of non-White individuals portrayed by surgeons on social media perpetuates the racial disparity seen in patients accessing gender affirming surgery. Surgeons must be conscious of the demographic they portray on social media, as a lack of representation may influence patients' self-identify and decision to utilize gender affirming surgical treatment.

Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function.

Voltage-gated sodium (NaV) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons.

Characterisation of Elevenin-Vc1 from the Venom of Conus victoriae: A Structural Analogue of α-Conotoxins.

Elevenins are peptides found in a range of organisms, including arthropods, annelids, nematodes, and molluscs. They consist of 17 to 19 amino acid residues with a single conserved disulfide bond. The subject of this study, elevenin-Vc1, was first identified in the venom of the cone snail Conus victoriae (Gen. Comp. Endocrinol. 2017, 244, 11-18). Although numerous elevenin sequences have been reported, their physiological function is unclear, and no structural information is available. Upon intracranial injection in mice, elevenin-Vc1 induced hyperactivity at doses of 5 or 10 nmol. The structure of elevenin-Vc1, determined using nuclear magnetic resonance spectroscopy, consists of a short helix and a bend region stabilised by the single disulfide bond. The elevenin-Vc1 structural fold is similar to that of α-conotoxins such as α-RgIA and α-ImI, which are also found in the venoms of cone snails and are antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). In an attempt to mimic the functional motif, Asp-Pro-Arg, of α-RgIA and α-ImI, we synthesised an analogue, designated elevenin-Vc1-DPR. However, neither elevenin-Vc1 nor the analogue was active at six different human nAChR subtypes (α1ß1εδ, α3ß2, α3ß4, α4ß2, α7, and α9α10) at 1 µM concentrations.

Intra-colony venom diversity contributes to maintaining eusociality in a cooperatively breeding ant.

BACKGROUND: Eusociality is widely considered to evolve through kin selection, where the reproductive success of an individual's close relative is favored at the expense of its own. High genetic relatedness is thus considered a prerequisite for eusociality. While ants are textbook examples of eusocial animals, not all ants form colonies of closely related individuals. One such example is the ectatommine ant Rhytidoponera metallica, which predominantly forms queen-less colonies that have such a low intra-colony relatedness that they have been proposed to represent a transient, unstable form of eusociality. However, R. metallica is among the most abundant and widespread ants on the Australian continent. This apparent contradiction provides an example of how inclusive fitness may not by itself explain the maintenance of eusociality and raises the question of what other selective advantages maintain the eusocial lifestyle of this species. RESULTS: We provide a comprehensive portrait of the venom of R. metallica and show that the colony-wide venom consists of an exceptionally high diversity of functionally distinct toxins for an ant. These toxins have evolved under strong positive selection, which is normally expected to reduce genetic variance. Yet, R. metallica exhibits remarkable intra-colony variation, with workers sharing only a relatively small proportion of toxins in their venoms. This variation is not due to the presence of chemical castes, but has a genetic foundation that is at least in part explained by toxin allelic diversity. CONCLUSIONS: Taken together, our results suggest that the toxin diversity contained in R. metallica colonies may be maintained by a form of group selection that selects for colonies that can exploit more resources and defend against a wider range of predators. We propose that increased intra-colony genetic variance resulting from low kinship may itself provide a selective advantage in the form of an expanded pharmacological venom repertoire. These findings provide an example of how group selection on adaptive phenotypes may contribute to maintaining eusociality where a prerequisite for kin selection is diminished.

Renal Cell Carcinoma in End-Stage Kidney Disease and the Role of Transplantation.

Kidney transplant patients have a higher risk of renal cell carcinoma (RCC) compared to non-transplanted end-stage kidney disease (ESKD) patients. This increased risk has largely been associated with the use of immunosuppression; however, recent genetic research highlights the significance of tissue specificity in cancer driver genes. The implication of tissue specificity becomes more obscure when addressing transplant patients, as two distinct metabolic environments are present within one individual. The oncogenic potential of donor renal tissue is largely unknown but assumed to pose minimal risk to the kidney transplant recipient (KTR). Our review challenges this notion by examining how donor and recipient microenvironments impact a transplant recipient's associated risk of renal cell carcinoma. In doing so, we attempt to encapsulate how ESKD-RCC and KTR-RCC differ in their incidence, pathogenesis, outcome, and approach to management.