Plasma exchange and intravenous immunoglobulin for the peri-operative management of type 2 heparin-induced thrombocytopaenia in a patient requiring urgent surgery for critical limb ischaemia.

We report the case of a 61-year-old female who developed heparin-induced thrombocytopaenia following treatment of a submassive pulmonary embolism, and who then required an above knee amputation for critical limb ischaemia. Heparin-induced thrombocytopaenia is a rare, immune-mediated complication associated with an in-hospital mortality rate of 10%. It is more common in surgical patients, with patients undergoing orthopaedic surgery more likely to develop it than patients undergoing cardiac surgery, but heparin-dependent immunoglobulin G antibodies are more likely to be formed in the latter. Peri-operative management remains a challenge. Ideally, it is preferable to wait for the platelet count to improve; but in certain cases, surgery cannot be delayed. Heparin-induced thrombocytopaenia is usually managed with direct thrombin inhibitors, such as argatroban and bivalirudin. Newer therapeutic modalities, such as plasmapheresis and intravenous immunoglobulin, as used in this case, can rapidly remove antibodies, but the certainty of evidence is low. Our case adds to the literature regarding the use of these modalities and highlights the multidisciplinary team approach required to manage such complex cases.

A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

OBJECTIVE: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. PATIENTS & METHODS: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. RESULTS: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. CONCLUSIONS: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.

Pathologic and clinical tumor size discordance in early-stage cervical cancer: Does it matter?

OBJECTIVE: The objective of this study was to assess the rate of discordance between clinical and pathologic tumor size for women with stage IB1 cervical cancer (FIGO 2009 criteria), assess risk factors for discordance, and determine the impact of discordance on oncologic outcomes. METHODS: This was a secondary analysis of a prior multi-institutional retrospective review of patients diagnosed with stage IB1 (FIGO 2009 staging) cervical cancer undergoing radical hysterectomy between 2010 and 2017. Demographic, clinicopathologic, and oncologic data were collected. Pathologic upstaging was defined as having a preoperative diagnosis of stage IB1 cervical cancer with pathology demonstrating a tumor size >4 cm. Demographic and clinicopathologic data was compared using chi-square, fisher exact or 2-sided t-test. Survival was estimated using the Kaplan-Meier method. RESULTS: Of the 630 patients, 77 (12%) were upstaged. Patients who were upstaged had lower rates of preoperative conization (p < .001) or preoperative tumor sizes ≤2 cm (p < .001). Upstaged patients had increased odds of deep stromal invasion, lymphovascular space invasion, positive margins and positive lymph nodes. Almost 88% of upstaged patients received adjuvant therapy compared to 29% of patients with tumors ≤4 cm (odds 18.49, 95% CI 8.99-37.94). Finally, pathologic upstaging was associated with an increased hazard of recurrence (hazard ratio [HR] 1.95, 95% CI 1.03-3.67) and all-cause death (HR 2.31, 95% CI 1.04-5.11). CONCLUSIONS: Pathologic upstaging in stage IB1 cervical cancer is relatively common. Upstaging is associated with an 18-fold increased risk of receipt of adjuvant therapy. Patients undergoing preoperative conization and those with tumors <2 cm had lower risks of upstaging. Improvement in preoperative assessment of tumor size may better inform primary treatment decisions.

Understanding and managing fish populations: keeping the toolbox fit for purpose.

Wild fish populations are currently experiencing unprecedented pressures, which are projected to intensify in the coming decades. Developing a thorough understanding of the influences of both biotic and abiotic factors on fish populations is a salient issue in contemporary fish conservation and management. During the 50th Anniversary Symposium of The Fisheries Society of the British Isles at the University of Exeter, UK, in July 2017, scientists from diverse research backgrounds gathered to discuss key topics under the broad umbrella of 'Understanding Fish Populations'. Below, the output of one such discussion group is detailed, focusing on tools used to investigate natural fish populations. Five main groups of approaches were identified: tagging and telemetry; molecular tools; survey tools; statistical and modelling tools; tissue analyses. The appraisal covered current challenges and potential solutions for each of these topics. In addition, three key themes were identified as applicable across all tool-based applications. These included data management, public engagement, and fisheries policy and governance. The continued innovation of tools and capacity to integrate interdisciplinary approaches into the future assessment and management of fish populations is highlighted as an important focus for the next 50 years of fisheries research.

The effects of stress and sex on selection, genetic covariance, and the evolutionary response.

The capacity of a population to adapt to selection (evolvability) depends on whether the structure of genetic variation permits the evolution of fitter trait combinations. Selection, genetic variance and genetic covariance can change under environmental stress, and males and females are not genetically independent, yet the combined effects of stress and dioecy on evolvability are not well understood. Here, we estimate selection, genetic (co)variance and evolvability in both sexes of Tribolium castaneum flour beetles under stressful and benign conditions, using a half-sib breeding design. Although stress uncovered substantial latent heritability, stress also affected genetic covariance, such that evolvability remained low under stress. Sexual selection on males and natural selection on females favoured a similar phenotype, and there was positive intersex genetic covariance. Consequently, sexual selection on males augmented adaptation in females, and intralocus sexual conflict was weak or absent. This study highlights that increased heritability does not necessarily increase evolvability, suggests that selection can deplete genetic variance for multivariate trait combinations with strong effects on fitness, and tests the recent hypothesis that sexual conflict is weaker in stressful or novel environments.

Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults.

VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing HIV-1 monoclonal antibody (mAb) isolated from the B cells of an HIV-infected patient. It is directed against the HIV-1 CD4 binding site and is capable of potently neutralizing the majority of diverse HIV-1 strains. This Phase I dose-escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose-limiting toxicities. Mean 28-day serum trough concentrations after the first infusion were 35 and 57 µg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 µg/ml for the same two doses. Over the 5-40 mg/kg i.v. dose range (n = 18), the clearance was 0.016 l/h and terminal half-life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half-life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV-1 prevention efficacy studies.

Assessing the alignment of sexual and natural selection using radiomutagenized seed beetles.

A major unsolved question in evolutionary biology concerns the relationship between natural and sexual selection. Sexual selection might augment natural selection, for example if mutations that harm female fecundity also reduce male mating success. Conversely, sexual selection might favour traits that impair naturally selected fitness components. We induced detrimental mutations in Callosobruchus maculatus beetles using X-ray irradiation and then experimentally measured the effect of precopulatory sexual selection on offspring number and survival rate. Sexual selection treatment had a negative effect on egg-to-adult survivorship, although the number of progeny reaching adulthood was unaffected, perhaps because eggs and juveniles that failed to develop lessened competition on the survivors. We hypothesize that the negative effect of sexual selection arose because sexually competitive males transmitted a smaller nuptial gift or carried alleles that conferred reduced survival. Although we found no evidence that sexual selection on males can purge alleles that are detrimental to naturally selected fitness components, such benefits might exist in other environmental or genetic contexts.

Polyandrous females found fitter populations.

Multiple mating by females (polyandry) requires an evolutionary explanation, because it carries fitness costs in many species. When mated females disperse alone to a new habitat, their offspring may have no option but to mate with their siblings and incur inbreeding depression. However, some of the offspring of polyandrous females may only be half siblings, reducing inbreeding depression when isolated groups of siblings only have each other as mates. We investigated this putative benefit of polyandry over monandry by initiating multiple genetically isolated populations of Callosobruchus maculatus beetles, each founded by a single female, who received a complete ejaculate from either one or two males. The early generations had comparable fitness, but the F4 and F5 descendants of doubly inseminated females were more numerous and had higher egg-to-adult survival than the descendants of singly inseminated females. This fitness benefit was of similar magnitude whether beetles were reared on their standard food plant, or on a less favourable food source. Our results suggest that polyandrous females produce fitter descendants in inbred founder populations and therefore that polyandry may affect movement ecology and invasion biology.

The evolution of queen pheromones in the ant genus Lasius.

Queen pheromones are among the most important chemical messages regulating insect societies yet they remain largely undiscovered, hindering research into interesting proximate and ultimate questions. Identifying queen pheromones in multiple species would give new insight into the selective pressures and evolutionary constraints acting on these ubiquitous signals. Here, we present experimental and comparative evidence that 3-methylalkanes, hydrocarbons present on the queen's cuticle, are a queen pheromone throughout the ant genus Lasius. Interspecific variation in the chemical profile is consistent with 3-methylalkanes evolving more slowly than other types of hydrocarbons, perhaps due to differential selection or evolutionary constraints. We argue that the sensory ecology of the worker response imposes strong stabilizing selection on queen pheromones relative to other hydrocarbons. 3-Methylalkanes are also strongly physiologically and genetically coupled with fecundity in at least one Lasius species, which may translate into evolutionary constraints. Our results highlight how honest signalling could minimize evolutionary conflict over reproduction, promoting the evolution and maintenance of eusociality.

A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults.

Ebola virus causes irregular outbreaks of severe hemorrhagic fever in equatorial Africa. Case mortality remains high; there is no effective treatment and outbreaks are sporadic and unpredictable. Studies of Ebola virus vaccine platforms in non-human primates have established that the induction of protective immunity is possible and safety and human immunogenicity has been demonstrated in a previous Phase I clinical trial of a 1st generation Ebola DNA vaccine. We now report the safety and immunogenicity of a recombinant adenovirus serotype 5 (rAd5) vaccine encoding the envelope glycoprotein (GP) from the Zaire and Sudan Ebola virus species, in a randomized, placebo-controlled, double-blinded, dose escalation, Phase I human study. Thirty-one healthy adults received vaccine at 2×10(9) (n=12), or 2×10(10) (n=11) viral particles or placebo (n=8) as an intramuscular injection. Antibody responses were assessed by ELISA and neutralizing assays; and T cell responses were assessed by ELISpot and intracellular cytokine staining assays. This recombinant Ebola virus vaccine was safe and subjects developed antigen specific humoral and cellular immune responses.

Spermicide, cryptic female choice and the evolution of sperm form and function.

Sperm competition and cryptic female choice profoundly affect sperm morphology, producing diversity within both species and individuals. One type of within-individual sperm variation is sperm heteromorphism, in which each male produces two or more distinct types of sperm simultaneously, only one of which is typically fertile (the "eusperm"). The adaptive significance of nonfertile "parasperm" types is poorly understood, although numerous sperm-heteromorphic species are known from many disparate taxa. This paper examines in detail two female-centred hypotheses for the evolution and maintenance of this unconventional sperm production strategy. First, we use game theoretical models to establish that parasperm may function to protect eusperm from female-generated spermicide, and to elucidate the predictions of this idea. Second, we expand on the relatively undeveloped idea that parasperm are used by females as a criterion for cryptic female choice, and discuss the predictions generated by this idea compared to other hypotheses proposed to explain sperm heteromorphism. We critically evaluate both hypotheses, suggest ways in which they could be tested, and propose taxa in which they could be important.

Modulation of sexual signalling by immune challenged male mealworm beetles (Tenebrio molitor, L.): evidence for terminal investment and dishonesty.

Organisms partition resources into life-history traits in order to maximise fitness over their expected lifespan. For the males of many species fitness is determined by qualitative and quantitative aspects of costly sexual signals: The notion that epigamic traits are costly forms the cornerstone of those theories that propose parasites drive sexual selection. Consequently studies examining this notion assume sexual signalling is honest (i.e. driven by cost) when they seek to identify correlations or causal links between male immune function and attractiveness. We demonstrate that immune challenged males of the mealworm beetle, Tenebrio molitor, increased their investment in epigamic pheromone signals: these males became significantly more attractive to females whilst increasing the activity of a key immune effector system. In other words males increase terminal reproductive effort (invest in attractiveness) in response to a survival threat (immune insult). Consequently the signal preferred by the female is dishonest when considering the male's condition.

Calibration of a compaction simulator for the measurement of tablet thickness during compression.

For the calibration of a compaction simulator for punch displacement measurements, the displacement of the punch must be related to the voltage output of a linear variable displacement transducer (LVDT) which is attached to the punch via its movable core, with correction for any deformation of the machine parts which are inherently incorporated in the LVDT readings. Contrary to common assumptions the relationship between the displacement of the movable core and the voltage output of the LVDTs used is not linear. Similarly, the deformation of the machine parts did not follow Hooke's law of linear elasticity but exhibited characteristics of nonlinear elasticity. The data demonstrate the need for careful validation of the calibration of a compaction simulator when accurate punch displacements are required.

[Simultaneous test of ventricular function and myocardial perfusion, during exercise, using a new agent labeled with Tc99m]. / Test simultáneo de función ventricular y perfusión miocárdica, durante el ejercicio, mediante un nuevo agente marcado con Tc99m.

One a tribute of a Tc 99m labeled myocardial agent is the possibility to measure both ventricular function and myocardial perfusion with a single injection. To assess this, normal volunteers, 14 patients with coronary artery disease (CAD) and two suffering from cardiomyopathy with normal coronaries, were injected with 8-10 mci carbomethoxy-isopropyl-isonitrile or 20 mci Rp-30 Tc 99m at peak semi-recumbent bicycle exercise and again at rest. Thirty msec per frame first pass data, and 5 min static anterior, 40(0-) and 70(0-) left anterior oblique images were obtained. Standard Thallium 201 stress test were also done, within one month, and were at the same level of exercise. The left ventricular ejection fraction (EF) increased with exercise (69%-76%) in normal patients. All studies showed normal myocardial perfusion on exercise. In CAD patients the EF increased in some patients who had ischemia. Perfusion images with Tc 99m during exercise and at rest had an identical correlation with Thallium 201. The results support the concept of dual ventricular function and perfusion studies using a single Tc 99m labelled myocardial agent, and suggest that this could become the standard radionuclide stress tests in the future.

Temporal evolution of brain distribution of IMP and HIPDM. Concise communication.

Early and late brain distribution of iodine-labelled N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine (HIPDM) and iodine labelled N-isopropyl-p-iodoamphetamine (IMP) were compared in rat and one human patient with a recent stroke in the right middle cerebral artery area. In rat, an important 'redistribution' of cerebral activity was observed in various areas of the brain, mainly white matter, whereas no such observation was made with HIPDM. In the patient, the right area was hypoactive during the early SPECT with IMP and HIPDM, and redistribution was observed in the late SPECT only with IMP. We suggest that while HIPDM appears to reflect regional cerebral perfusion, IMP distribution is dependent upon metabolic brain activity.