A Prospective Open-Label Observational Study of a Buffered Soluble 70 mg Alendronate Effervescent Tablet on Upper Gastrointestinal Safety and Medication Errors: The GastroPASS Study.

Upper gastrointestinal (GI) side effects are a main reason for discontinuing bisphosphonate treatment, an important therapeutic option for osteoporosis patients. Consequently, the development of novel formulations with improved tolerability is warranted. In this multicenter prospective, observational, postauthorization safety study conducted in Italy and Spain, postmenopausal women (PMW) with osteoporosis (naïve to bisphosphonates) were treated weekly with a buffered soluble alendronate 70 mg effervescent (ALN-EFF) tablet (Binosto®) and followed for 12 ± 3 months. Information was collected on adverse events (AEs), medication errors, persistence, and compliance using the Morisky-Green questionnaire. Patients (N = 1028) aged 67 ± 9 years (mean ± SD) received ALN-EFF weekly. The cumulative incidence of upper GI AEs (oesophageal toxicity, gastritis, gastric ulcers, and duodenitis) related to ALN-EFF (primary endpoint) was 9.6% (95% confidence interval [CI] 7.9-11.6%), the vast majority being of mild intensity. The most frequently occurring upper GI AEs related to ALN-EFF were dyspepsia (2.7%), gastroesophageal reflux disease (2.4%), and nausea (2.2%). None of the relevant upper GI AEs listed in the primary endpoint and no serious AEs were reported. At least one medication error occurred in 29.9% (95% CI 27.1-32.8%) of patients. However, the majority of medication errors were associated with administration instructions applicable to any oral bisphosphonate and only seven medication errors were associated with the ALN-EFF formulation. ALN-EFF was discontinued in 209 of 1028 (20.3%) patients. The most frequent reasons for discontinuation were AEs related to ALN-EFF (46.9%) and patients' decision (42.6%). Compliance with ALN-EFF was high, reflected by a mean Morisky-Green score of 92.8 ± 18.6. PMW with osteoporosis treated with ALN-EFF in a real-world setting experienced few upper GI AEs. In addition, they had a low discontinuation and high compliance compared with other formulations, suggesting that ALN-EFF may increase patient satisfaction and therefore long-term adherence and efficacy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

LMNA-Related Muscular Dystrophy with Clinical Intrafamilial Variability.

The LMNA gene is associated to a huge broad of phenotypes, including congenital Emery-Dreifuss muscular dystrophy and late-onset LMNA-related muscular dystrophy. In these forms, muscle weakness, contractures, and cardiac impairment are common. In an autosomal dominant pedigree including 5 affected patients, NGS molecular analysis performed in 6 relatives identifies the heterozygous c.1129C>T p.Arg377Cys variant in the exon 6 of the LMNA gene in three of them. Clinical, laboratorial, imaging investigation of these affected patients showed a significant clinical variability: the father presented subclinical imaging muscular dystrophy masqueraded as radiculopathy. One of his sons presented cardiac arrhythmia, muscular weakness, elbow contractures, and intranuclear pseudoinclusions on muscle biopsy. A second son presented only decreased tendon reflexes. Two other brothers presenting myalgia and cramps were not carriers of the same mutation in the LMNA gene. Early diagnosis, considering these variable phenotype and genotype, is important for genetic counseling, as well as cardiac, and rehabilitation management.

Muscle phenotypic variability in limb girdle muscular dystrophy 2 G.

Limb girdle muscular dystrophy type 2 G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46 years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8 years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41 years old, and now, at 54 years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy.

[Fitness of Bemisia tabaci (Gennadius) B Biotype (Hemiptera: Aleyrodidae) populations with different levels of susceptibility to the thiametoxam insecticide]. / Aptitud biológica de poblaciones de Bemisia tabaci (Gennadius) Biotipo B (Hemiptera: Aleyrodidae) con diferente susceptibilidad al insecticida thiametoxam.

In two field-collected populations of de Bemisia tabaci (Gennadius) B biotype previously selected with the neonicotinoid insecticide thiamethoxam (NEO-R, NEO-N), and a population susceptible to insecticides (SUSC), the level of response to the insecticide thiametoxam, as well as the life and fertility tables were determined. At LC95, the NEO-R population showed a resistance ratio (RR95) value of 8.8-fold, an intrinsic rate of increase (r m) of 0.72. The fitness of the NEO-R and NEO-N populations in relation to the SUSC was 1.5 and 2.0, respectively. The RR95 value for NEO-N was 1.9-fold; it's r m value was 0.082, while in the SUSC population was 0.041. The developmental time of egg and adult were longer in NEO-R population, while the nymph and pupa lasted longer in the NEO-N and SUSC populations. The developmental time was different in the three NEO-R, NEO-N, and SUSC populations with 19.7 d (315.84 degree days or dd), 15.7 d (250.4 dd) and 18.5 d (296.6 d), respectively. The populations previously selected with thiamethoxam did not reproduce faster than their susceptible counterpart.

Offspring from sequential matings between Bacillus thuringiensis-resistant and Bacillus thuringiensis-susceptible Heliothis virescens moths (Lepidoptera: Noctuidae).

The tobacco budworm, Heliothis virescens (F.) (Lepidoptera: Noctuidae), is an economically important pest of the Americas. Females of this species copulate multiple times during their lifetimes, and the presence of sperm from multiple males inside them could allow for a diversity of paternal genotypes in the offspring, unless there was complete precedence of sperm from the first mating. If a female copulates with a male that is insecticide-susceptible and another male that is insecticide-resistant, her progeny could vary in their resistance phenotypes. In some cases, this could impact the evolution of insecticide resistance in a population. We designed a series of experiments to determine whether Bacillus thuringiensis susceptibility is maintained when an H. virescens female that is homozygous for a genetically recessive form of B. thuringiensis resistance copulates with a Cry1Ac-susceptible and a Cry1Ac-resistant males. During the lifetime of double-copulated females, a proportion of F1 progeny were Cry1Ac-resistant. This indicates that when a B. thuringiensis-resistant H. virescens female copulates with two males, with one male being resistant to Cry1Ac, some of the progeny will carry resistance to this insecticide. Due to the polyandrous nature of this species, the above-mentioned scenario is not unrealistic; therefore, results from this study may help understand and manage the evolution of B. thuringiensis-resistance in field populations.

Aptitud biológica de poblaciones de Bemisia tabaci (Gennadius) Biotipo B (Hemiptera: Aleyrodidae) con diferente susceptibilidad al insecticida thiametoxam / Fitness of Bemisia tabaci (Gennadius) B Biotype (Hemiptera: Aleyrodidae) populations with different levels of susceptibility to the thiametoxam insecticide

In two field-collected populations of de Bemisia tabaci (Gennadius) B biotype previously selected with the neonicotinoid insecticide thiamethoxam (NEO-R, NEO-N), and a population susceptible to insecticides (SUSC), the level of response to the insecticide thiametoxam, as well as the life and fertility tables were determined. At LC95, the NEO-R population showed a resistance ratio (RR95) value of 8.8-fold, an intrinsic rate of increase (r m) of 0.72. The fitness of the NEO-R and NEO-N populations in relation to the SUSC was 1.5 and 2.0, respectively. The RR95 value for NEO-N was 1.9-fold; it's r m value was 0.082, while in the SUSC population was 0.041. The developmental time of egg and adult were longer in NEO-R population, while the nymph and pupa lasted longer in the NEO-N and SUSC populations. The developmental time was different in the three NEO-R, NEO-N, and SUSC populations with 19.7 d (315.84 degree days or dd), 15.7 d (250.4 dd) and 18.5 d (296.6 d), respectively. The populations previously selected with thiamethoxam did not reproduce faster than their susceptible counterpart.

Bacillus thuringiensis Cry1Ac resistance frequency in tobacco budworm (Lepidoptera: Noctuidae).

The tobacco budworm, Heliothis virescens (F.) (Lepidoptera: Noctuidae), is one of the most important pests of cotton, Gossypium hirsutum L, that has become resistant to a wide range of synthetic insecticides. CrylAc-expressing cotton has proven its effectiveness against this insect since its introduction in North America in 1996. However, the constant exposure of tobacco budworm to this protein toxin may result in the development of resistance to it. To estimate the frequency of alleles that confer resistance to a 1.0 microg of Bacillus thuringiensis Cry1Ac diagnostic concentration in field-collected insects, the second generation (F2) of 1,001 single-pair families from seven geographical regions representing 2,202 alleles from natural populations was screened in 2006 and 2007 without finding major resistant alleles. Neonates of 56 single-pair families were able to develop to second instar on the diagnostic concentration in the initial screen, but only seven of these lines did so again in a second confirmatory screen. Minor resistance alleles to Cry1Ac may be quite common in natural populations of H. virescens. Our estimated resistance allele frequencies (0.0036-0.0263) were not significantly different from a previously published estimate from 1993. There is no evidence that H. virescens populations have become more resistant to Cry1Ac.

Disability and use of healthcare resources in Brazilian patients with Parkinson's disease.

PURPOSE: To assess disability and healthcare resource use in Parkinson's disease (PD) patients. METHODS: A cross-sectional survey of 144 Brazilian PD patients consecutively admitted at a Neurological outpatient clinic. Clinical evaluation was done using the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn & Yahr staging (H&Y). The Schwab and England (SE) activity of daily living (ADL) scale was used to assess the level of dependence in the ADL. Information about the utilization of health resources was obtained interviewing the patient by means of a structured questionnaire. RESULTS: A total of 66% of patients (mean age 62 years; males, 53%) had a Hoehn & Yahr stage < or = 2. Mean UPDRS score was 46.2, and median SE scale score was 80. Disabled PD patients significantly received more visits by a general practitioner (p < 0.001). Patients with comorbid conditions significantly used more domiciliary nurse care and physiotherapist assistance (p < 0.01). The most frequent reason for hospitalization was the treatment of clinical complications and drug dose adjustment. Pharmacological treatment costs were associated with the severity of the disease (p < 0.05). CONCLUSION: Utilization of healthcare resources was influenced by functional status and comorbid conditions.

Baseline susceptibility of tobacco budworm (Lepidoptera: Noctuidae) to Cry1F toxin from Bacillus thuringiensis.

Transgenic cotton, Gossypium hirsutum L., lines expressing both Cry1F and Cry1Ac insecticidal proteins from Bacillus thuringiensis (Bt) have been commercially available in the United States since 2005. Both Bt proteins are highly effective against tobacco budworm, Heliothis virescens (F.), and other lepidopteran pests of cotton. Although CrylAc has been available in Bt cotton since 1996, the Cry1F component is relatively new. As part of the proactive resistance management program for Cry1F/Cry1Ac cotton, a susceptibility-monitoring program is being implemented. Baseline variation in the susceptibility to Cry1F in field populations of tobacco budworm was measured. There was a three-fold variation in the amount of Cry1F needed to kill 50% of the neonates from 15 different field populations from the southern and central United States. Future variation in susceptibility of tobacco budworm populations to Cry1F or even resistance evolution could be documented based on this baseline data. A candidate diagnostic concentration was determined that may be efficiently used to identify individuals that potentially carry major alleles conferring field-relevant resistance to Cry1F before such alleles spread through field populations.

Plant host effect on the development of Heliothis virescens F. (Lepidoptera: Noctuidae).

Heliothis virescens F. is an important polyphagous pest that can develop on >100 plant species, including 20 economic crops. Populations of this insect are believed to be locally maintained on a few crops and weed hosts in Washington County, MS. To find the intrinsic value of these plants for the development of H. virescens populations, we fed different laboratory and wild colonies with fresh and lyophilized plant tissue under a constant temperature. Development time of this insect under laboratory conditions varied up to 10 d between plant hosts and was dependent on the type of plant tissue provided: fresh or lyophilized. Life table parameters such as net reproductive rate, finite rate of increase, and generation time indicated that Trifolium repens, a wild host growing around agricultural fields year round, could be one of the most suitable local plant hosts for the development of H. virescens. Two species of Geranium, previously reported as the source of the first H. virescens generation in the region, had lower intrinsic value as a food source than did T. repens. Gossyipium hirsutum, perhaps the most important crop source of H. virescens in the region, produced low net reproductive rate and finite rate of increase parameters. Sampling conducted in agricultural fields during 2006 and 2007 found no larvae on the above mentioned wild hosts as it was previously reported. Results indicated that H. virescens populations in this region were not supported by the wild plant species growing around agricultural fields during the time when the survey took place.

Monitoring Bacillus thuringiensis-susceptibility in insect pests that occur in large geographies: how to get the best information when two countries are involved.

The adoption of cotton producing insecticidal proteins of Bacillus thuringiensis, commonly referred to as Bt cotton, around the world has proven to be beneficial for growers and the environment. The effectiveness of this important genetically-modified crop can be jeopardized by the development of resistance to Bt cotton by pests it is meant to control, with the possibility that this phenomenon could develop in one country and spread to another by means of insect migration. To preserve the effectiveness of this agricultural biotechnology, regulatory agencies have developed plans to mitigate the development of resistance, and research institutions constantly monitor for shifts in Bt-susceptibility in important pests. If Bt-resistance is detected, this finding needs to be corroborated by an independent laboratory according to current regulatory requirements; a process that presents numerous challenges. We investigated the biological activity of Bt-incorporated diet on Helicoverpa virescens L. after it was stored for several days at different temperatures. Diet stored up to nine days at different temperatures (-14 to 27 degrees C) produced the same biological effect on H. virescens as freshly-prepared diet. Elevating the temperature of Bt stock solution to 76 degrees C as compared to 26 degrees C yielded significantly higher reading of apparent Cry1Ac concentration from MVP II, but not enough to elicit a significant biological response when these stock solutions were incorporated into insect artificial diet. These findings are important particularly when the confirmation of resistance is done at a distant location, such as Mexico, or when diet is shared between laboratories, and must be stored for later use, as in the case of international collaboration.

Unusual early-onset Huntingtons disease.

Huntington's disease is an autosomal dominant progressive neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral disorders leading to functional disability. In contrast to patients with adult onset, in which chorea is the major motor abnormality, children often present with spasticity, rigidity, and significant intellectual decline associated with a more rapidly progressive course. An unusual early-onset Huntington's disease case of an 11-year-old boy with severe hypokinetic/rigid syndrome appearing at the age of 2.5 years is presented. Clinical diagnosis was confirmed by polymerase chain reaction study of the expanded IT-15 allele with a compatible size of 102 cytosine-adenosine-guanosine repeats L-Dopa mildly ameliorated rigidity, bradykinesia, and dystonia. We conclude that Huntington's disease should be included in the differential diagnoses of regressive syndromes of early childhood.