Phenotypic Variation Through Ontogeny: Thyroid Axis Disruption During Larval Development in the Frog Pleurodema borellii

Studies of the effects of thyroid hormones on larval development in the frog Xenopus spp. have provided baseline information to identify developmental constraints and elucidate genetic and hormonal mechanisms driving development, growth, and life history transitions. However, this knowledge requires data based on other anurans to complete a comprehensive approach to the understanding of larval developmental diversity and phenotypic variation through ontogeny. Mesocosm experiments provide realistic data about environmental conditions and timing; this information is useful to describe anuran larval development and/or analyze endocrine disruption. In this study, mesocosm experiments of the larval development of the frog Pleurodema borellii were conducted to explore the consequences of thyroid axis disruption; the sensitivity of tadpoles to the methimazole (2.66 mg/l) and thyroxine (T4) (1.66 μg/l) was compared. These concentrations were selected based on previous studies in Pleurodema borellii. We test the effects of methimazole and thyroxine on development in early exposure (from beginning of larval development) and late exposure, 18 days after hatching, with doses administered every 48 h. Tadpoles were evaluated 31 days after hatching. Methimazole caused moderate hypertrophy of the thyroid gland, alteration in the growth rates, differentiation without inhibition of development, and an increase of developmental variability. Thyroxine produced slight atrophy of the thyroid gland, accelerated growth rates and differentiation, and minor developmental variability. In tadpoles at stages previous to metamorphose, skull development (differentiation of olfactory capsules, appearance of dermal bones, and cartilage remodeling) seemed to be unaltered by the disruptors. Moreover, similar abnormal morphogenesis converged in specimens under methimazole and thyroxine exposures. Abnormalities occurred in pelvic and pectoral girdles, and vent tube, and could have been originated at the time of differentiation of musculoskeletal tissues of girdles. Our results indicate that premetamorphic stages (Gosner Stages 25–35) are sensitive to minimal thyroid axis disruption, which produces changes in developmental rates; these stages would also be critical for appendicular musculoskeletal morphogenesis to achieve the optimal condition to start metamorphosis.

Intermittent opioid use and ischemic placental disease: Study quantifies risks, raises questions

Discomfort and, to a lesser extent, pain are common complaints during pregnancy, and some patients may turn to opioids for pain relief. Esposito and colleagues (Am J Epidemiol. 2021, in press) report associations between intermittent exposure to opioids during pregnancy and the risk of ischemic placental disease (IPD) – a syndrome that includes preeclampsia, placental abruption, small for gestational age (SGA) births, and preterm delivery. They found that early opioid exposure in pregnancy was associated with a modestly increased risk for abruption, SGA births, and preterm delivery, and both early and late exposure was associated with the greatest risk for these outcomes. Surprisingly, preeclampsia was not associated with opioid use. Through quantitative bias analysis, the authors cleverly tackle a number of biases to assess their roles in explaining the associations, including unmeasured confounding, outcome misclassification, and residual confounding; none exerted strong influences on the associations. Although the findings appear fairly robust on the surface, the lack of association between intermittent opioid use and preeclampsia, and important differences in characteristics of patients in the opioid exposed group compared to the unexposed group, suggest that further study is needed to clarify the relationship between intermittent opioid use, lifestyle factors, and IPD risk.

Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation

Prenatal exposure to maternal immune activation (MIA) is a risk factor for a variety of neurodevelopmental and psychiatric disorders. The timing of MIA-exposure has been shown to affect adolescent and adult offspring neurodevelopment, however, less is known about these effects in the neonatal period. To better understand the impact of MIA-exposure on neonatal brain development, we first assess neonate communicative abilities with the ultrasonic vocalization task, followed by high-resolution ex vivo magnetic resonance imaging (MRI) on the neonatal (postnatal day 8) brain. Early exposed offspring displayed decreased communicative ability, while brain anatomy appeared largely unaffected, apart from some subtle alterations. By integrating MRI and behavioural assays to investigate the effects of MIA-exposure on neonatal neurodevelopment we show that offspring neuroanatomy and behaviour are only subtly affected by both early and late exposure. This suggests that the deficits often observed in later stages of life may be dormant, not yet developed in the neonatal period, or not as easily detectable using a cross-sectional approach.

Comparing Exogenous Methods to Induce Plant-Resistance Against a Bark-Feeding Insect

Exogenous application of the plant hormone methyl jasmonate (MeJA) can trigger induced plant defenses against herbivores, and has been shown to provide protection against insect herbivory in conifer seedlings. Other methods, such as mechanical damage to seedlings, can also induce plant defenses, yet few have been compared to MeJA and most studies lack subsequent herbivory feeding tests. We conducted two lab experiments to: (1) compare the efficacy of MeJA to mechanical damage treatments that could also induce seedling resistance, (2) examine if subsequent insect damage differs depending on the time since induction treatments occurred, and (3) assess if these induction methods affect plant growth. We compared Scots pine (Pinus sylvestris) seedlings sprayed with MeJA (10 or 15 mM) to seedlings subjected to four different mechanical bark damage treatments (two different bark wound sizes, needle-piercing damage, root damage) and previous pine weevil (Hylobius abietis) damage as a reference treatment. The seedlings were exposed to pine weevils 12 or 32 days after treatments (early and late exposure, hereafter), and resistance was measured as the amount of damage received by plants. At early exposure, seedlings treated with needle-piercing damage received significantly more subsequent pine weevil feeding damage than those treated with MeJA. Seedlings treated with MeJA and needle-piercing damage received 84% less and 250% more pine weevil feeding, respectively, relative to control seedlings. The other treatments did not differ statistically from control or MeJA in terms of subsequent pine weevil damage. For the late exposure group, plants in all induction treatments tended to receive less pine weevil feeding (yet this was not statistically significant) compared to control seedlings. On the other hand, MeJA significantly slowed down seedling growth relative to control and all other induction treatments. Overall, the mechanical damage treatments appeared to have no or variable effects on seedling resistance. One of the treatments, needle-piercing damage, actually increased pine weevil feeding at early exposure. These results therefore suggest that mechanical damage shows little potential as a plant protection measure to reduce feeding by a bark-chewing insect.

Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental and psychiatric disorders. MIA-induced deficits in adolescent and adult offspring have been well characterized, however, less is known about the effects of MIA-exposure on embryo development. To address this gap, we performed high-resolution ex vivo magnetic resonance imaging (MRI) to investigate the effects of early (gestational day [GD]9) and late (GD17) MIA-exposure on embryo (GD18) brain structure. We identify striking neuroanatomical changes in the embryo brain, particularly in the late exposed offspring. We further examined hippocampal neuroanatomy using electron microscopy and identified differential effects due to MIA-timing. An increase in apoptotic cell density was observed in the GD9 exposed offspring, while an increase in the density of dark neurons and glia, putative markers for increased neuroinflammation and oxidative stress, was observed in GD17 exposed offspring, particularly in females. Overall, our findings integrate imaging techniques across different scales to identify differential impact of MIA-timing on the earliest stages of neurodevelopment.

674 Late antibiotic administration during durvalumab treatment may be associated with clinical benefit

BackgroundEarly concurrent antibiotic usage in patients receiving immune checkpoint inhibitors (ICIs) is linked to decreased progression-free survival (PFS) and overall survival (OS), likely mediated by lower gut microbial diversity and skewed taxonomic abundance. The relationship of late antibiotic exposure to ICI efficacy has not been explored.MethodsData from a single-arm, Phase 1/2 study (Study 1108) were retrospectively analyzed in 945 patients with metastatic disease in 18 tumor types (largest subsets: non-small-cell lung cancer [NSCLC], 31.5% and urothelial cancer [UC], 20.8%) receiving durvalumab 10 mg/kg Q2W between 8/2012–6/2017. Early antibiotic exposure was defined as 30 days prior to until 30 days after durvalumab initiation. Late exposure was any time >30 days after durvalumab initiation. Demographics, infection type, and antibiotic data (route, duration, class) were collected. Median PFS and OS were compared between no antibiotics (n=525), early antibiotics (n=239), and late antibiotics (n=181) by Kaplan-Meier methods and log-rank tests. The Cox proportional hazards model was used for multivariable adjustments. In a translational in vivo analysis, Balb/c mice implanted with CT26 tumors were prospectively treated with oral levofloxacin 1 mg/mL for 7 days either 1 week prior to, concurrently with, or 1 week after initiating anti-PD-L1 or control IgG therapy (n=40 per group). The primary endpoint was tumor growth kinetics.Resultsß-lactams (51.3%) and fluoroquinolones (39.3%) were most commonly prescribed overall. Early antibiotic exposure was associated with reduced mOS compared to no exposure (7.2 vs 9.8 months, p=0.049). Unexpectedly, patients with late antibiotic exposure had markedly improved mOS versus those with no exposure (19.8 vs 9.8 months, p<0.001), which persisted after adjusting for baseline tumor volume, demographics, treatment-induced immune-related adverse events, and neutrophil to lymphocyte ratio (table 1). In NSCLC and UC cohorts, these results were preserved. To account for time-on-treatment bias, an independent model using antibiotic start time as a time-dependent covariate also showed improved benefit with late antibiotics (HR 0.91, 95% CI 0.87–0.95, p<0.001). Compared to control IgG, mice receiving prior or concurrent levofloxacin with anti-PD-L1 had similar survival, while mice receiving late levofloxacin with anti-PD-L1 had improved survival (p=0.004).Abstract 674 Table 1mPFS and mOS by antibiotic exposure* Early antibiotics defined as 30 days prior to until 30 days after durvalumab initiation** Late exposure was any time greater than 30 days after durvalumab initiationConclusionsThis large retrospective analysis is consistent with previous studies showing associations of early antibiotics with shorter survival during ICI therapy. For the first time, we report that late antibiotics do not negatively impact survival and may actually benefit survival. Future studies will evaluate immune phenotyping and microbiome characterization to clarify mechanistic underpinnings. These findings will require confirmation in prospective clinical studies.Trial Registrationclinicaltrials.gov NCT01693562Ethics ApprovalThis study was conducted according to the Declaration of Helsinki and approved by the independent ethics committee/institutional review board at each participating center.ConsentInformed consent was obtained from all patients.

Kiwis and COVID-19: The Aotearoa New Zealand Response to the Global Pandemic

This fast-moving global COVID-19 pandemic caught many nations unprepared and has exposed numerous flaws in global health, public health, and economic and social welfare infrastructures. It may seem premature to write about responses, but there are lessons to be learned from the response of Aotearoa New Zealand. Although its geopolitical situation as an island nation meant that it had late exposure to COVID-19, NZ has been commended because it closed its borders (to non-nationals); lockdown; traced; tested contacts; told people to pick a ‘bubble’ (immediate and usual family or household) and stay within that bubble; and promoted clear public messages. Government assistance was available for employers to retain staff, and additional support was provided for businesses and individuals. A strong and empathetic prime minister communicated regularly with the public and developed a sense of common national purpose. However, COVID-19 still exposed the impact of social inequalities. Implications for the next steps of recovery are considered in the paper.

Management and Prevention of Complications of Guided Bone Regeneration

Guided bone regeneration using titanium-reinforced expanded teflon non-absorbable membranes (e-PTFE) has proven, through rigorous studies on many occasions, that it is a safe and predictable method to achieve bone growth at mandible and maxilla level, both vertically and horizontally. However, the technique itself is one that requires special operative skills and is not without postoperative complications. The purpose of this paper is to review most of these postoperative complications, their management and the key operative elements that help preventing them. Complications are presented both from the perspective of the meta-analysis performed from the present literature and from the point of view of the author’s personal experience, personal casuistry being presented. This paper will discuss all this starting with the complications without negative impact on the bone regeneration such as, late exposure of the membrane and ending with the most serious ones, such as the suppuration of the augmented anatomical regions. All of these can be avoided or minimized by using a correct operating technique. In addition, once installed, we can minimize the negative effects on bone regeneration by a proper management applied at the right time.