Patterns of genetic diversity and gene flow associated with an aridity gradient in populations of common mole-rats, Cryptomys hottentotus hottentotus.

Genetic adaptation is the change of a population towards a phenotype that best fits the present ecological conditions in which it inhabits. As environmental conditions change, allele frequencies shift, resulting in different populations of the same species possessing genetic variation and divergent phenotypes. Cooperatively breeding common mole-rats (Cryptomys hottentotus hottentotus) inhabit environments along an aridity gradient in South Africa, which provides an opportunity for local genetic adaptations to occur. Using one mitochondrial gene (cytochrome b) and 3,540 SNP loci across the whole genome, we determined the phylogenetic relationship, population structure and genetic diversity of five populations of C. h. hottentotus located along an aridity gradient. Mitochondrial data identified population-specific clades that were less distinct in the two mesic populations, potentially indicating historical or recent gene flow, or the retention of ancestral haplotypes. Arid and semi-arid populations formed a distinct cluster from the non-arid populations. Genetic diversity and gene flow were higher in arid-dwelling individuals, suggesting greater connectivity and interactions between colonies in arid regions in comparison to mesic ones. Using an Aridity Index, we determined that isolation by environment, rather than isolation by geographical distance, best explains the genetic distance between the populations. Further analyses using target loci may determine if there are differing underlying genetic adaptations among populations of C. h. hottentotus. These analyses could help unravel population differences in response to environmental factors within a sub-species of bathyergid mole-rat and determine the adaptive capacity of this small non-migratory subterranean rodent species in response to aridification in the face of climate change.

The dissection of a despotic society: exploration, dominance and hormonal traits.

Naked mole-rats (Heterocephalus glaber) live in large colonies with one breeding female (queen), one to three breeding males (BMs) and the remainder are non-reproductive subordinates. The animals have a linear dominance rank with the breeders at the top of the hierarchy. We investigated how dominance rank in naked mole-rats differs with exploration (the propensity to explore a novel environment) and related endocrine markers. Exploration behaviour, faecal progestagen metabolite (fPM), faecal glucocorticoid metabolite (fGCM), faecal androgen metabolite (fAM) and plasma prolactin concentrations were quantified in breeding, high-, middle- and low-ranked females and males from five naked mole-rat colonies. There were no significant differences between the dominance rank and exploration behaviour. Interestingly, the queens and high-ranking females had higher fGCM and fAM concentrations compared with middle- and low-ranked females. The queens had significantly higher fPM concentrations than all other ranked females, since they are responsible for procreation. In the males, the BMs had higher fGCM concentrations compared with high- and low-ranked males. In addition, BMs and middle-ranking males had overall higher prolactin levels than all other ranked males, which could be linked to cooperative care. Overall, the results suggest that physiological reproductive suppression is linked to high dominance rank.

The Relationship Between Transfusion in Cardiac Surgery Patients and Adverse Outcomes.

OBJECTIVES: To understand if red blood cell (RBC) transfusions are independently associated with a risk of mortality, prolonged intubation, or infectious, cardiac, or renal morbid outcomes. DESIGN: A retrospective review. SETTING: A single-institution university hospital. PARTICIPANTS: A total of 2,458 patients undergoing coronary bypass artery graft and/or valvular surgery from July 2014 through January 2018. INTERVENTIONS: No interventions were done. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of an adverse event or prolonged intubation. Infectious, cardiac, and renal composite outcomes were also defined. These composites, along with mortality, were analyzed individually and then combined to form the "any adverse events" composite. Preoperative demographic and intraoperative parameters were analyzed as univariate risk factors for adverse outcomes. Logistic regression was used to screen variables, with a p value criterion of p < 0.05 for entry into the model selection procedure. A backward selection algorithm was used with variable entry and retention criteria of p < 0.05 to select the final multivariate model. Multivariate logistic regression models were used to determine whether there was an association between the volume of RBC transfusion and the defined adverse event after adjusting for covariates. A p value < 0.01 was considered statistically significant in the final model of each aim to adjust for multiple comparisons. The final logistic models for each of the following outcomes indicate an increased risk of that outcome per each additional unit of RBC transfused. For prolonged intubation, the odds ratio (OR) was 1.493 (p < 0.0001), OR = 1.358 (p < 0.0001) for infectious composite outcomes, OR = 1.247 (p < 0.0001) for adverse renal outcomes, and OR = 1.467 (p < 0.0001) for any adverse event. CONCLUSIONS: The authors demonstrated a strong independent association between RBC transfusion volume and adverse outcomes after cardiac surgery. Efforts should be undertaken, such as preoperative anemia management and control of coagulopathy, in order to minimize the need for RBC transfusion.

New insights into morphological adaptation in common mole-rats (Cryptomys hottentotus hottentotus) along an aridity gradient.

Morphological adaptation is the change in the form of an organism that benefits the individual in its current habitat. Mole-rats (family Bathyergidae), despite being subterranean, are impacted by both local and broad-scale environmental conditions that occur above ground. Common mole-rats (Cryptomys hottentotus hottentotus) present an ideal mammalian model system for the study of morphological variation in response to ecology, as this species is found along an aridity gradient and thus can be sampled from geographically non-overlapping populations of the same species along an environmental longitudinal cline. Using the mass of five internal organs, ten skeletal measurements and 3D morphometric analyses of skulls, we assessed the morphology of wild non-breeding individuals from five common mole-rat populations in South Africa. We found that the body mass and mean relative mass of the spleen and kidneys in arid populations was larger, and individuals from arid regions possessed shorter legs and larger inter-shoulder widths compared to individuals from mesic regions. Additionally, arid populations demonstrated greater skull depth, and shape change of features such as angular processes of the lower jaw than mesic individuals, indicating that these distinct geographic populations show differences corresponding to the aridity gradient, potentially in response to environmental factors such as the variation in food sources found between different habitats, in addition to different soil compositions found in the different regions. Arid populations potentially require a stronger jaw and neck musculature associated with mastication to chew xeric-adapted plants and to dig through hard soil types, whereas mesic populations excavate through soft, looser soil and may make use of their front limbs to aid the movement of soils when digging. Aridity influences the morphology of this species and could indicate the impact of environmental changes on speciation and mammalian skull morphology.

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

The role of ambient temperature and light as cues in the control of circadian rhythms of Damaraland mole-rat.

Light is considered the primary entrainer for mammalian biological rhythms, including locomotor activity (LA). However, mammals experience different environmental and light conditions, which include those predominantly devoid of light stimuli, such as those experienced in subterranean environments. In this study, we investigated what environmental cue (light or ambient temperature (Ta)) is the strongest modulator of circadian rhythms, by using LA as a proxy, in mammals that experience a lifestyle devoid of light stimuli. To address this question, this study exposed a subterranean African mole-rat species, the Damaraland mole-rat (Fukomys damarensis), to six light and Ta cycles in different combinations. Contrary to previous literature, when provided with a reliable light cue, Damaraland mole rats exhibited nocturnal, diurnal, or arrhythmic LA patterns under constant Ta. While under constant darkness and a 24-hour Ta cycle mimicking the burrow environment, all mole-rats were most active during the coolest 12-hour period. This finding suggests that in a subterranean environment, which receives no reliable photic cue, the limited heat dissipation and energy constraints during digging activity experienced by Damaraland mole-rats make Ta a reliable and consistent "time-keeping" variable. More so, when providing a reliable light cue (12 light: 12 dark) to Damaraland mole-rats under a 24-hour Ta cycle, this study presents the first evidence that cycles of Ta affect the LA rhythm of a subterranean mammal more strongly than cycles of light and darkness. Once again, Damaraland mole-rats were more active during the coolest 12-hour period regardless of whether this fell during the light or dark phase. However, conclusive differentiation of entrainment to Ta from that of masking was not achieved in this study, and as such, we have recommended future research avenues to do so.

Adult stem cell activity in naked mole rats for long-term tissue maintenance.

The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent, provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity and tissue function with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5+) in their native in vivo state, we find an expanded pool of Lgr5+ cells in NMRs, and these cells specifically at the crypt base (Lgr5+CBC) exhibit slower division rates compared to those in short-lived mice but have a similar turnover as human LGR5+CBC cells. Instead of entering quiescence (G0), NMR Lgr5+CBC cells reduce their division rates by prolonging arrest in the G1 and/or G2 phases of the cell cycle. Moreover, we also observe a higher proportion of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment efficiently, triggering a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone.

Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis.

Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53-/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53-/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis.

Non-Invasive Quantification of Faecal and Urine Reproductive Hormone Metabolites in the Naked Mole-Rat (Heterocephalus glaber).

The naked mole-rat (Heterocephalus glaber) occurs in colonies with a distinct dominance hierarchy, including one dominant, breeding female (the queen), 1-3 breeding males, and non-reproductive subordinates of both sexes that are reproductively suppressed while in the colony. To non-invasively evaluate reproductive capacity in the species, we first had to examine the suitability of enzyme immunoassays (EIAs) for determining progestogen and androgen metabolite concentrations in the naked mole-rat, using urine and faeces. A saline control and gonadotrophin-releasing hormone (GnRH) were administered to twelve (six males and six females) naked mole-rats which were previously identified as dispersers and housed singly. The results revealed that urine is possibly not an ideal matrix for progestogen and androgen metabolite quantification in naked mole-rats as no signal was detected in the matrix post GnRH administration. A 5α-Progesterone EIA and an Epiandrosterone EIA were identified as suitable for quantifying faecal progesterone metabolites (fPMs) and faecal androgen metabolites (fAMs) in males and females, respectively. The results suggest that there are individual variations in baseline fPM and fAM concentrations, and only two out of six females and no males exhibited an increase in fPM concentrations greater than 100% (-20% SD) post GnRH administration. Conversely, only four out of six females and three out of six males had an increase in fAM concentrations greater than 100% (-20% SD) following GnRH administration. These results imply that some naked mole-rat individuals have a reduced reproductive capacity even when they are separated from the queen.

A cohort study and matched pair analysis evaluating the effects of the COVID-19 pandemic on access to dental care for people with inherited bleeding disorders.

INTRODUCTION: Patients with inherited bleeding disorders (IBDs) can experience challenges in accessing dental care. The COVID-19 pandemic saw the cessation of routine dentistry in England. This study aims to highlight whether access to dental care for patients with IBDs was impacted by the pandemic, and whether the severity of their IBD impacts patients experience of dental care. METHODS: Patients over the age of 18 with Haemophilia A and B, Von Willibrands (VWD), Bernard-Soulier syndrome (BSS) and Glanzmann's disease were recruited. One hundred and seventy-eight patients were called and invited to complete a questionnaire. Full cohort and matched pair analysis was performed. RESULTS: Seventy participants completed the questionnaire (62 males, mean age 39.9), 26 had a mild IBD and 44 severe. Mild and severe patients were matched on IBD, gender, deprivation index and age. Thirty-one percent of patients tried to seek dental advice during the pandemic. Eighty-one percent of mild patients saw a dentist routinely prior to the pandemic, compared to 58% of severe patients. Doctors were more likely to discuss the importance of dental prevention with patients with severe IBDs (p = .0042). CONCLUSION: Fewer patients with severe IBDs accessed regular dental care compared to their matched pair counterparts prior to the pandemic. This could indicate that access to care is more difficult for those with severe IBDs. Patients felt that oral health is relevant to their IBD. While doctors were more likely to discuss the importance of preventing dental disease with patients who have severe IBDs, the profession needs to ensure this translates into routine engagement.

The Evolution and Ecology of Oxidative and Antioxidant Status: A Comparative Approach in African Mole-Rats.

The naked mole-rat of the family Bathyergidae has been the showpiece for ageing research as they contradict the traditional understanding of the oxidative stress theory of ageing. Some other bathyergids also possess increased lifespans, but there has been a remarkable lack of comparison between species within the family Bathyergidae. This study set out to investigate how plasma oxidative markers (total oxidant status (TOS), total antioxidant capacity (TAC), and the oxidative stress index (OSI)) differ between five species and three subspecies of bathyergids, differing in their maximum lifespan potential (MLSP), resting metabolic rate, aridity index (AI), and sociality. We also investigated how oxidative markers may differ between captive and wild-caught mole-rats. Our results reveal that increased TOS, TAC, and OSI are associated with increased MLSP. This pattern is more prevalent in the social-living species than the solitary-living species. We also found that oxidative variables decreased with an increasing AI and that wild-caught individuals typically have higher antioxidants. We speculate that the correlation between higher oxidative markers and MLSP is due to the hypoxia-tolerance of the mole-rats investigated. Hormesis (the biphasic response to oxidative stress promoting protection) is a likely mechanism behind the increased oxidative markers observed and promotes longevity in some members of the Bathyergidae family.

The best of both worlds: no apparent trade-off between immunity and reproduction in two group-living African mole-rat species.

Co-operatively breeding mammals often exhibit a female reproductive skew and suppression of the subordinate non-breeding group members. According to evolutionary theory and the immunity-fertility axis, an inverse relationship between reproductive investment and survival (through immunocompetence) is expected. As such, this study investigated if a trade-off between immunocompetence and reproduction arises in two co-operatively breeding African mole-rat species, namely the Damaraland mole-rat (Fukomys damarensis) and common mole-rat (Cryptomys hottentotus hottentotus), which possess female reproductive division of labour. This study also attempted to investigate the relationship between the immune and endocrine systems in Damaraland mole-rats. There was no trade-off between reproduction and immunocompetence in co-operatively breeding African mole-rat species, and in the case of the Damaraland mole-rats, breeding females (BFs) possessed increased immunocompetence compared with non-breeding females (NBFs). Furthermore, the increased levels of progesterone possessed by Damaraland mole-rat BFs compared with NBFs appear to be correlated to increased immunocompetence. In comparison, BF and NBF common mole-rats possess similar immunocompetence. The species-specific differences in the immunity-fertility axis may be due to variations in the strengths of reproductive suppression in each species. This article is part of the theme issue 'Evolutionary ecology of inequality'.

Considerations for shared decision management in previously untreated patients with hemophilia A or B.

Recent advances in therapeutics are now providing a wide range of options for adults and children living with hemophilia. Although therapeutic choices are also increasing for the youngest individuals with severe disease, challenges remain about early management decisions, as supporting data are currently limited. Parents and healthcare professionals are tasked with helping children achieve an inclusive quality of life and maintain good joint health into adulthood. Primary prophylaxis is the gold standard to optimize outcomes and is recommended to start before 2 years of age. A range of topics need to be discussed with parents to aid their understanding of the decisions they can make and how these will affect the management of their child/children. For those with a family history of hemophilia, prenatal considerations include the possibility of genetic counseling, prenatal investigations, and planning for delivery, together with monitoring of the mother and neonate, as well as diagnosis of the newborn and treatment of any birth-associated bleeding. Subsequent considerations, which are also applicable to families where infant bleeding has resulted in a new diagnosis of sporadic hemophilia, involve explaining bleed recognition and treatment options, practical aspects of initiating/continuing prophylaxis, dealing with bleeds, and ongoing aspects of treatment, including possible inhibitor development. Over time, optimizing treatment efficacy, in which individualizing therapy around activities can play a role, and long-term considerations, including retaining joint health and tolerance maintenance, become increasingly important. The evolving treatment landscape is creating a need for continually updated guidance. Multidisciplinary teams and peers from patient organizations can help provide relevant information. Easily accessible, multidisciplinary comprehensive care remains a foundation to care. Equipping parents early with the knowledge to facilitate truly informed decision-making will help achieve the best possible longer-term health equity and quality of life for the child and family living with hemophilia. Plain language summary: Points to be taken into account to help families make decisions to best care for children born with hemophilia Medical advances are providing a range of treatment options for adults and children with hemophilia. There is, however, relatively limited information about managing newborns with the condition. Doctors and nurses can help parents to understand the choices for infants born with hemophilia. We describe the various points doctors and nurses should ideally discuss with families to enable informed decision-making. We focus on infants who require early treatment to prevent spontaneous or traumatic bleeding (prophylaxis), which is recommended to start before 2 years of age. Families with a history of hemophilia may benefit from discussions before pregnancy, including how an affected child would be treated to protect against bleeds. When mothers are pregnant, doctors can explain investigations that can provide information about their unborn child, plan for the birth, and monitor mother and baby to minimize bleed risks at delivery. Testing will confirm whether the baby is affected by hemophilia. Not all infants with hemophilia will be born to families with a history of the condition. Identification of hemophilia for the first time in a family (which is 'sporadic hemophilia') occurs in previously undiagnosed infants who have bleeds requiring medical advice and possibly hospital treatment. Before any mothers and babies with hemophilia are discharged from hospital, doctors and nurses will explain to parents how to recognize bleeding and available treatment options can be discussed. Over time, ongoing discussions will help parents to make informed treatment decisions:• When and how to start, then continue, prophylaxis.• How to deal with bleeds (reinforcing previous discussions about bleed recognition and treatment) and other ongoing aspects of treatment. ○ For instance, children may develop neutralizing antibodies (inhibitors) to treatment they are receiving, requiring a change to the planned approach.• Ensuring treatment remains effective as their child grows, considering the varied needs and activities of their child.

Validation of Enzyme Immunoassays via an Adrenocorticotrophic Stimulation Test for the Non-Invasive Quantification of Stress-Related Hormone Metabolites in Naked Mole-Rats.

Small size in mammals usually restricts long-term, frequent monitoring of endocrine function using plasma as a matrix. Thus, the non-invasive monitoring of hormone metabolite concentrations in excreta may provide an invaluable approach. The aim of the current study was to examine the suitability of enzyme immunoassays (EIAs) for monitoring responses to stressors in the naked mole-rat (Heterocephalus glaber, NMR) using urine and feces as hormone matrices. A saline control administration, and a high- and low-dose adrenocorticotropic hormone (ACTH) challenge were performed on six male and six female disperser morph NMRs. The results revealed that a 5α-pregnane-3ß,11ß,21-triol-20-one EIA detecting glucocorticoid metabolites (GCMs) with a 5α-3ß-11ß-diol structure is the most suitable assay for measuring concentrations in male urine samples, whereas an 11-oxoaetiocholanolone EIA detecting GCMs with a 5ß-3α-ol-11-one structure appears the most suitable EIA for quantifying GCMs in female urine. An 11-oxoaetiocholanolone EIA detecting 11,17 dioxoandrostanes was the most suitable EIA for quantifying GCMs in the feces of both sexes. There were sex-related differences in response to the high- and low-dose ACTH challenge. We recommend using feces as a more suitable matrix for non-invasive GCM monitoring for NMRs which can be valuable when investigating housing conditions and other welfare aspects.

The relationship between hypoxia exposure and circulating cortisol levels in social and solitary African mole-rats: An initial report.

Hypoxemia from exposure to intermittent and/or acute environmental hypoxia (lower oxygen concentration) is a severe stressor for many animal species. The response to hypoxia of the hypothalamic-pituitary-adrenal axis (HPA-axis), which culminates in the release of glucocorticoids, has been well-studied in hypoxia-intolerant surface-dwelling mammals. Several group-living (social) subterranean species, including most African mole-rats, are hypoxia-tolerant, likely due to regular exposure to intermittent hypoxia in their underground burrows. Conversely, solitary mole-rat species, lack many adaptive mechanisms, making them less hypoxia-tolerant than the social genera. To date, the release of glucocorticoids in response to hypoxia has not been measured in hypoxia-tolerant mammalian species. Consequently, this study exposed three social African mole-rat species and two solitary mole-rat species to normoxia, or acute hypoxia and then measured their respective plasma glucocorticoid (cortisol) concentrations. Social mole-rats had lower plasma cortisol concentrations under normoxia than the solitary genera. Furthermore, individuals of all three of the social mole-rat species exhibited significantly increased plasma cortisol concentrations after hypoxia, similar to those of hypoxia-intolerant surface-dwelling species. By contrast, individuals of the two solitary species had a reduced plasma cortisol response to acute hypoxia, possibly due to increased plasma cortisol under normoxia. If placed in perspective with other closely related surface-dwelling species, the regular exposure of the social African mole-rats to hypoxia may have reduced the basal levels of the components for the adaptive mechanisms associated with hypoxia exposure, including circulating cortisol levels. Similarly, the influence of body mass on plasma cortisol levels cannot be ignored. This study demonstrates that both hypoxia-tolerant rodents and hypoxia-intolerant terrestrial laboratory-bred rodents may possess similar HPA-axis responses from exposure to hypoxia. Further research is required to confirm the results from this pilot study and to further confirm how the cortisol concentrations may influence responses to hypoxia in African mole-rats.

Emicizumab prophylaxis in haemophilia A with inhibitors: Three years follow-up from the UK Haemophilia Centre Doctors' Organisation (UKHCDO).

INTRODUCTION: The UK National Haemophilia Database (NHD) collects data from all UK persons with haemophilia A with inhibitors (PwHA-I). It is well-placed to investigate patient selection, clinical outcomes, drug safety and other issues not addressed in clinical trials of emicizumab. AIMS: To determine safety, bleeding outcomes and early effects on joint health of emicizumab prophylaxis in a large, unselected cohort using national registry and patient reported Haemtrack (HT) data between 01 January 2018 and 30 September 2021. METHODS: Prospectively collected bleeding outcomes were analysed in people with ≥6 months emicizumab HT data and compared with previous treatment if available. Change in paired Haemophilia Joint Health Scores (HJHS) were analysed in a subgroup. Adverse events (AEs) reports were collected and adjudicated centrally. RESULTS: This analysis includes 117 PwHA-I. Mean annualised bleeding rate (ABR) was .32 (95% CI, .18; .39) over a median 42 months treatment with emicizumab. Within-person comparison (n = 74) demonstrated an 89% reduction in ABR after switching to emicizumab and an increase in zero treated bleed rate from 45 to 88% (p < .01). In a subgroup of 37 people, total HJHS improved in 36%, remained stable in 46% and deteriorated in 18%, with a median (IQR) within-person change of -2.0 (-9, 1.5) (p = .04). Three arterial thrombotic events were reported, two possibly drug related. Other AEs were generally non-severe and usually limited to early treatment, included cutaneous reactions (3.6%), headaches (1.4%), nausea (2.8%) and arthralgia (1.4%). CONCLUSIONS: Emicizumab prophylaxis is associated with sustained low bleeding rates and was generally well-tolerated in people with haemophilia A and inhibitors.

Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).

A comprehensive profile of reproductive hormones in eusocial Damaraland mole-rats (Fukomys damarensis).

In species where sociality and group cohesion are primarily determined by the maintenance of a reproductive division of labour and cooperative behaviours, the eusocial Damaraland mole-rat (Fukomys damarensis) presents a model which provides behavioural and endocrine distinctions between sex (males and females) and reproductive class (breeders and non-breeders). Although previous studies have demonstrated the endocrine aspects of reproductive suppression and behaviour in Damaraland mole-rats, they have focused on one hormone separately and on different conspecifics and samples across time. Unfortunately, this could introduce extrinsic biases when using these studies to compile complete hormonal profiles for comparisons. This study, therefore, set out to obtain a profile of the reproductive hormones from breeding and non-breeding male and female Damaraland mole-rats at a single point in time, from which circulating plasma prolactin and urinary progesterone, testosterone, and cortisol were measured. As expected, plasma prolactin and urinary cortisol did not differ between the breeders and non-breeders. However, breeders (both male and female) possessed increased urinary testosterone and progesterone concentrations compared to their non-breeding counterparts. These results, in conjunction with the variation in the expression of the respective hormonal receptors within the brains of breeders and non-breeders suggest that elevated testosterone and progesterone in breeders establish a neural dominance phenotype, which ultimately aids in controlling breeding activities. This study has emphasised the need for holistic, comprehensive profiling of reproductive endocrine systems.

Tissue Oxidative Ecology along an Aridity Gradient in a Mammalian Subterranean Species.

Climate change has caused aridification which can alter habitat vegetation, soil and precipitation profiles potentially affecting resident species. Vegetation and soil profiles are important for subterranean mole-rats as increasing aridity causes soils to become harder and geophytes less evenly distributed, and the inter-geophyte distance increases. Mole-rats obtain all water and dietary requirements from geophytes, and thus digging in harder soils may amplify stressors (hyperthermia, dehydration- or exercise-induced damage). This study assessed the oxidative status of the wild common mole-rat along an aridity gradient (arid, semi-arid and mesic). Kidney and liver oxidative markers, including total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Liver oxidative status did not demonstrate any significance with the degree of the aridity gradient. Aridity affected the TAC and OSI of the kidney, with individuals in the most arid habitats possessing the highest TAC. The evolution of increased group size to promote survival in African mole-rats in arid habitats may have resulted in the additional benefit of reduced oxidative stress in the kidneys. The SOD activity of the kidneys was higher than that of the liver with lower oxidative damage, suggesting this species pre-emptively protects its kidneys as these are important for water balance and retention.

Aggression, Boldness, and Exploration Personality Traits in the Subterranean Naked Mole-Rat (Heterocephalus glaber) Disperser Morphs.

Animal personality traits (consistent behavioral differences between individuals in their behavior across time and/or situation) affect individual fitness through facets, such as dispersal. In eusocial naked mole-rat (Heterocephalus glaber) colonies, a disperser morph may arise with distinct morphological, behavioral, and physiological characteristics. This study aimed to quantify the personality traits of a cohort of disperser morphs of naked mole-rat (NMR). Behavioral tests were performed on twelve disperser morphs (six males and six females) in an observation tunnel system that was novel and unfamiliar. Novel stimuli (fresh snakeskin, tissue paper, and conspecific of the same sex) were introduced for fifteen minutes, and the behavioral acts of the individual were recorded. A total of 30 behaviors were noted during the behavioral tests of which eight were used to quantify aggression, boldness, and exploration. The NMR disperser morphs showed consistent individual differences in boldness, and exploration across time and test, indicating a distinct personality. In addition, new naked mole-rat responses including disturbance behaviors; confront, barricade, and stay-away, were recorded. Further investigations into the relationships between animal personality traits and social hierarchy position in entire colonies are needed for more informative results as we further investigate the role of personality in cooperatively breeding societies.