Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency. METHODS: We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group. RESULTS: No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group. CONCLUSIONS: In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

Outlining the challenges of Covid-19 health crises in Africa's maritime industry: the case of maritime operations in marine warranty surveying practice.

The relevance of carrying out marine warranty surveys (MWS) as mandatory insurable practice in mitigating associated operational risks within the offshore oil and gas industry, during the Covid-19 crises, was examined against the potential health risk and the various Covid-19 restrictions resulting from newly formed regulations. The health risk concerns to the surveyor and the impact of the Covid-19 policy restrictions for the surveyor's business measured are against the risk of excluding MWS in assessing the suitability of procedures, analyses, and vessels involved in typical offshore marine operations. The purpose of any MWS undertakings ensures that all risks in operations, with potential to destroy property, life, and environment, are minimized-if not eliminated. A series of remote interviews across Africa and direct field observations were respectively conducted at the Takoradi port to develop an understanding of the MWS service product, to ascertain the conditions resulting from current challenges, and to determine contingencies and innovations to ensure full service. The study finds MWS service as paramount to the energy industry with its range of risk control checks for high-value assets and operations. Surveyors demonstrated high-levels of awareness for Covid-19 crises and regulatory policies while in adherence but noted challenges of high-cost and delays as by-products of the restrictions. Surveyors deemed site attendances as crucial in their practice at all time, though recognized the several social and technologically innovative approaches adopted industry-wide to facing the pandemic. The study highlights the need for 'essential worker' status and the introduction of innovative insurance packages. Supplementary Information: The online version contains supplementary material available at 10.1007/s40152-021-00220-7.

Agalsidase alfa and kidney dysfunction in Fabry disease.

In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of agalsidase alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR <135 ml/min per 1.73 m(2)) treated with placebo was 85.4 +/- 29.6 ml/min per 1.73 m(2); during 6 mo of placebo, the mean annualized rate of change in GFR was -7.0 +/- 32.9 ml/min per 1.73 m(2). Among 85 nonhyperfiltrating patients treated with agalsidase alfa, the annualized rate of change was -2.9 +/- 8.7 ml/min per 1.73 m(2). Treatment with agalsidase alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (< 1 or > or = 1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that agalsidase alfa may stabilize kidney function in these patients.

The microbial flora of Aphis gossypii: patterns across host plants and geographical space.

The cotton aphid, Aphis gossypii, has a worldwide distribution and causes damage to numerous economically important crops. The bacterial symbionts associated with cotton aphids, sampled mainly from malvaceous and cucurbitaceous plants within Japan and Australia, were characterised using molecular profiling approaches. The goal was to document the aphid symbionts present and determine if patterns of microbial diversity are consistent with the existence of host plant related cryptic species in A. gossypii. The bacterial profiles of the aphids are diverse and reflect local geography more than host plant use.

Diagnosis and Management of Oral Allergy Syndrome, the Itchy Tongue Allergic Reaction.

Oral allergy syndrome (OAS) is a relatively common condition that is strongly associated with seasonal allergic rhinitis. Symptoms include pruritus of the oral mucosa and, in particular, the posterior tongue. Patients with OAS experience symptoms immediately after eating certain fruits, vegetables, spices, and nuts. Typically, for patients with this condition, offending foods may be cooked to avoid the symptoms. For diagnosis and management of OAS, dental clinicians should take a thorough history and be alerted to the possibility of OAS when symptoms such as pruritus of oral mucosal tissues appear immediately after the patient eats foods associated with OAS and has a concomitant history of seasonal allergic rhinitis. Because there is a relatively rare possibility of more serious symptomatology, clinicians should consider referral to the patient's primary care provider or an appropriate medical specialist. This article presents a case series comprising five patients diagnosed with OAS.

The efficacy of a petroleum spray oil against Aphis gossypii Glover on cotton. Part 1: mortality rates and sources of variation.

Petroleum spray oils (PSOs) kill insect pests on contact, and the composition of modern PSOs is substantially different from the ones introduced earlier. The effects of direct application of a new nC24 PSO on the cotton aphid, Aphis gossypii Glover, were therefore determined. This covered not only aphid mortality rates but also the way in which the oils affected aphid behaviour at the time of contact with the oil. Direct application of the nC24 oil proved to be highly effective in controlling A. gossypii at a range of concentrations between 1 and 10% v/v. The oil killed cotton aphids quickly, with most of the mortality occurring within the first 10 min of spraying. The fast killing action of the oils prevented any behavioural responses by the aphids. Aphids killed by the oils became flaccid and their legs and antennae extended horizontally relative to the body axis. With time, their cuticle became very shiny and began to darken. The quick death of the aphids suggested a contact mode of action of the oils, an interpretation supported by the lack of any negative effect on aphids not initially reached by the oils. However, those aphids not hit by the oils, but that subsequently encountered oil-treated areas when they moved elsewhere, also died, indicating that the oil deposits are also toxic to the aphids. The mode of action of the oil thus seems to be versatile, and the means by which it kills the aphids may be more complex than anoxia, which is the widely claimed mechanism attributed to PSOs. This oil now needs to be tested for any possible indirect effects on the cotton aphid (e.g. through its host-plant acceptance behaviour). The implications of the present findings for cotton aphid control and assessment of PSO efficacy in the field are discussed.

The efficacy of a petroleum spray oil against Aphis gossypii Glover on cotton. Part 2: indirect effects of oil deposits.

The primary mode of action of petroleum spray oils (PSOs) on pest insects is through direct contact. Indirect effects are, however, also possible, and deposits of the oils may influence pest populations by killing insects and/or by influencing their behaviour. The indirect effects of deposits of a new nC24 oil against the cotton aphid, Aphis gossypii Glover, were therefore determined. The effects of oil deposits on the acceptance of cotton as host plant by the aphids were assessed, as well as aphid mortality rates and their success in the establishment of colonies. The efficacy of deposits of a heavier oil (nC27) was also evaluated. Deposits of PSO were toxic to A. gossypii and remained effective until 8 days after spraying. Mortality decreased with time, so that, the older the deposit, the lower was the mortality. Significantly higher aphid mortalities were achieved on younger leaves than on mature ones. Thus, leaf age proved a significant factor in the efficacy of the deposits. Consecutive prophylactic applications (at 9 day intervals) did not have a cumulative effect, and their killing power proved to be independent of one another. Thus, applying the oil prior to aphid infestations would confer only minimal protection. The mortality inflicted by the deposits was not improved by increasing the molecular mass of the oil used (nC27 oil), but the toxic life of the oil deposit was increased. Oil deposits did not deter alates from landing on oil-sprayed plants. Oil deposits did, however, affect subsequent alate and nymphal survival, and thus the establishment of aphid colonies. The impact that the oils could have on the longer-term development of aphid populations in the field was thus demonstrated. First- and second-instar nymphs were the most susceptible life stages, with > 50% mortality compared with < 10% for the other stages. These nymphs did not show the typical signs of oil-induced mortality observed in aphids killed by direct oil applications, which suggests an alternative mode of action to that of the directly applied oil. Anoxia does not seem to be involved in either process, and alternative modes of action of the oil deposits are discussed. The implications of these findings for cotton aphid control are also considered, primarily in relation to the timing and frequency of oil application.

Development of a Microbial-Based Integrated Pest Management Program for Helicoverpa spp. (Lepidoptera: Noctuidae) and Beneficial Insects on Conventional Cotton Crops in Australia.

Entomopathogenic fungi, when used as a microbial control agent against cotton pests, such as Helicoverpa spp., may have the potential to establish and spread in the environment and to have an impact on both pests and beneficial insects. Information on the effect of entomopathogenic fungi on pests and beneficial insects is crucial for a product to be registered as a biopesticide. The effect of the entomopathogenic fungus BC 639 (Aspergillus sp.) against Helicoverpa spp. and beneficial insects (mostly predatory insects) was studied in the laboratory and in cotton field trials. The results show that when Helicoverpa spp. second instar larvae were exposed to increasing concentrations (from 10² to 108) of the entomopathogenic fungus BC 639, the optimum dose required to kill over 50% of the insects was 1.0 ´ 107 spores/mL. In the field trials, the number of Helicoverpa spp. per metre on plots treated with 1.0 or 0.50 L/ha of BC 639 was the same as on plots treated with the recommended rate of the commercial insecticide, Indoxacarb. However, when plots were treated with 0.25 L/ha of BC 639, this was not as effective at controlling Helicoverpa spp. as 1.0 or 0.5 L/ha BC 639 or Indoxacarb. BC 639 had less effect on predatory insects when applied at lower rates (0.50 and 0.25 L/ha) than at higher rates (1.0 L/ha). Thus, BC 639 was more selective against predators when applied at lower rates than at the higher rate, but was also more selective than Indoxacarb. Thus, the ability of BC 639 to control Helicoverpa spp. effectively with a minimal effect on predatory insects indicates its potential for enhancing integrated pest management programs and to sustain cotton production.