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Jongseok Lee,1 Daehyun Jo,2 Shinmi Song,1 Dahee Park,1 Dohyeong Kim,1 Jinyoung Oh1 1Department of Anesthesiology and Pain Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Pain Center, Pohang Wooridul Hospital, Pohang-si, Gyeongsangbuk-do, Republic of KoreaCorrespondence: Jinyoung OhDepartment of Anesthesiology and Pain Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-Ro, Gangnan-Gu, Seoul, Republic of KoreaTel +82-2-2019-3600Fax +82-2-2019-4833Email sgcms3@gmail.comPurpose: Dispersion of contrast media into the anterior epidural space is correlated with better outcomes after transforaminal epidural injection (TFEI). Needle tip position is an important factor affecting the pattern of contrast media dispersion. It is difficult to advance the needle medially to the interpedicle line with a conventional approach, especially in a severe spinal stenosis. But, with Kambin’s triangle approach, the needle can be advanced more medially even in the severe stenosis. We aimed to compare contrast media dispersion patterns according to the needle tip position in TFEI with Kambin’s triangle approach.Patients and Methods: This single-center retrospective study analyzed fluoroscopic data of patients who underwent TFEI from March 2019 to July 2019. Data on the history of lumbar spinal fusion surgery and MRI findings were collected. The needle tip position was evaluated in three positions on fluoroscopic images (final anteroposterior [AP] view): extraforaminal (EF), lateral foramen (LF), and medial foramen (MF). Contrast media dispersion into the epidural space (epidural pattern) in the AP view was evaluated as a dependent variable. The relationship between the contrast media dispersion pattern and needle tip position was analyzed, and other factors affecting the contrast media dispersion pattern were identified.Results: Ninety-eight TFEI cases were analyzed (51 LF, 35 MF, and 12 EF). An epidural pattern of dispersion was observed more frequently in the LF and MF groups than in the EF group. The LF and MF groups showed no significant difference in epidural pattern frequency. On logistic regression analysis, needle tip position emerged as a major factor influencing epidural pattern, while other factors including spine conditions had no significant effect.Conclusion: Positioning the needle tip medial to the pedicle helps in the spread of the contrast media into the epidural space during TFEI with Kambin’s approach. Factors other than the needle tip position did not significantly affect the contrast media dispersion pattern.Keywords: fluoroscopy, spinal stenosis, disc herniation, epidural space, needle tip, contrast media

Cen Wei,1,* Huaqing Wei,2,* Xun Wu,3 Guangyao Nong,1 Chenglin Wu,4 Jinli Lee,5 Ning Meng,3 Dahai Yu,6 Jiping Su,7 Mengzhu Guo,6 Jiangyuan Qin,8 Xuemin Fan3 1ENT & HN Surgery Department, Wuming Hospital of Guangxi Medical University, Nanning 530199, People’s Republic of China; 2Department of Cardiology, Wuming Hospital of Guangxi Medical University, Nanning 530199, People’s Republic of China; 3Department of Maxillofacial Surgery, Guangxi Medical University College of Stomatology, Nanning 530021, People’s Republic of China; 4Department of ENT, Sixth Affiliated Hospital of Guangxi Medical University, Nanning 537000, People’s Republic of China; 5Department of Gastroenterology, 923 Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army, Nanning 530021, People’s Republic of China; 6Department of Stomatology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, People’s Republic of China; 7ENT & HN Surgery Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530199, People’s Republic of China; 8Department of Otolaryngology, Guangxi General Hospital of Chinses People’s Armed Police Force, Nanning 530000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xun WuDepartment of Maxillofacial Surgery, Guangxi Medical University College of Stomatology, No. 10 Shuangyong Road, Nanning City, Guangxi Province 530021, People’s Republic of ChinaEmail kc4704@163.comGuangyao NongENT & HN Surgery Department, Wuming Hospital of Guangxi Medical University, No. 26 Yongning Road Wuming District, Nanning City, Guangxi Province 530199, People’s Republic of ChinaTel +86 771-6023602Fax +86 771-6213919Email lmqvqaymlhn43@163.comObjective: The functions of lncRNA-IUR in laryngeal squamous cell carcinoma (LSCC) were investigated in this study.Methods: RT-qPCR and paired t-test were used to measure and compare expression levels of IUR, miR-24 and p53 in LSCC and non-tumor tissues. Human LSCC cell line UM-SCC-17A was used and transfected by pcDNA3.1 vector to overexpress IUR and miR-24. The transwell assay and wound healing assay illustrated the effect of overexpression of IUR or miR-24 in the cell invasion and migration of LSCC. Subcutaneous tumor model in nude mice was carried out to demonstrate the mechanism between IUR and miR-24 in regulating tumor growth.Results: We found that IUR was downregulated in LSCC. Low expression levels of IUR were correlated with the poor survival of LSCC patients. Overexpression experiments showed that overexpression of IUR led to increased, while overexpression of miR-24 led to decreased expression levels of p53 in LSCC cells. And bioinformatics analysis showed that IUR may sponge miR-24. Cell proliferation assay showed that overexpression of IUR and p53 led to decreased proliferation rate of LSCC cells, while overexpression of miR-24 led to increased proliferation rate of LSCC cells. We also illustrated that overexpression of IUR promoted cell migration and invasion while miR-24 had opposite effects. In addition, subcutaneous tumor model in nude mice showed that overexpression of miR-24 attenuated the effects of overexpression of IUR on the expression of p53 and cancer cell proliferation.Conclusion: IUR sponges miR-24 to upregulate p53 in LSCC, thereby inhibiting cancer cell proliferation.Keywords: laryngeal squamous cell carcinoma, IUR, miR-24, p53

Abstract Background Cardiac arrest (CA) is the most common cause of acute neurologic insult in children. Many survivors have significant neurocognitive deficits at 1 year of recovery. Epoxyeicosatrienoic acids (EETs) are multifunctional endogenous lipid signaling molecules that are involved in brain pathobiology and may be therapeutically relevant. However, EETs are rapidly metabolized to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), limiting their bioavailability. We hypothesized that sEH inhibition would improve outcomes after CA in an infant swine model. Male piglets (3–4 kg, 2 weeks old) underwent hypoxic-asphyxic CA. After resuscitation, they were randomized to intravenous treatment with an sEH inhibitor (TPPU, 1 mg/kg; n = 8) or vehicle (10% poly(ethylene glycol); n = 9) administered at 30 min and 24 h after return of spontaneous circulation. Two sham-operated groups received either TPPU (n = 9) or vehicle (n = 8). Neurons were counted in hematoxylin- and eosin-stained sections from putamen and motor cortex in 4-day survivors. Results Piglets in the CA + vehicle groups had fewer neurons than sham animals in both putamen and motor cortex. However, the number of neurons after CA did not differ between vehicle- and TPPU-treated groups in either anatomic area. Further, 20% of putamen neurons in the Sham + TPPU group had abnormal morphology, with cell body attrition and nuclear condensation. TPPU treatment also did not reduce neurologic deficits. Conclusion Treatment with an sEH inhibitor at 30 min and 24 h after resuscitation from asphyxic CA does not protect neurons or improve acute neurologic outcomes in piglets.

Tryptophan (Trp) is not only a nutrient enhancer but also has systemic effects. Trp metabolites signaling through the well-known aryl hydrocarbon receptor (AhR) constitute the interface of microbiome-gut-brain axis. However, the pathway through which Trp metabolites affect central nervous system (CNS) function have not been fully elucidated. AhR participates in a broad variety of physiological and pathological processes that also highly relevant to intestinal homeostasis and CNS diseases. Via the AhR-dependent mechanism, Trp metabolites connect bidirectional signaling between the gut microbiome and the brain, mediated via immune, metabolic, and neural (vagal) signaling mechanisms, with downstream effects on behavior and CNS function. These findings shed light on the complex Trp regulation of microbiome-gut-brain axis and add another facet to our understanding that dietary Trp is expected to be a promising noninvasive approach for alleviating systemic diseases.

Chaiho Jeong,1 Hyunsam Kim,1 Jeongmin Lee,2 Jeonghoon Ha,1 Min-Hee Kim,2 Moo Il Kang,1 Dong-Jun Lim1 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Dong-Jun LimDivision of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-Gu, Seoul 06591, Republic of KoreaTel +82-2-2258-6009Fax +82-2-599-3589Email ldj6026@catholic.ac.krBackground: The Korea Thyroid Association published the revised guidelines for thyroid nodules in 2016. However, whether fine-needle aspiration is accurately performed based on indications and whether the results of this procedure are appropriately addressed according to clinical guidelines, particularly in subcentimeter nodules, are unclear.Methods: We retrospectively analyzed the fine-needle aspiration data of 331 thyroid nodules of patients who were referred to a tertiary hospital clinic for fine-needle aspiration. Each nodule was categorized according to ultrasonography findings based on the recommendations of the Korea Thyroid Association for fine-needle aspiration. Only nodules with a final pathological diagnosis of benign or malignant made using the Bethesda system were included.Results: Up to 32% of thyroid nodules that were not indicated for fine-needle aspiration were aspirated. Regarding subcentimeter nodules, only 28 of 123 (22.8%) aspirated nodules were indicated for fine-needle aspiration. Of the 49 malignant subcentimeter nodules, 33 (67.3%) underwent immediate surgery. Meanwhile, 14 (28.6%) nodules were lost to follow-up, and two (4.1%) were under active surveillance. Eighteen (36.7%) malignant subcentimeter nodules were not indicated for fine-needle aspiration but underwent surgical resection instead of active surveillance.Conclusion: Despite the recommendations in the revised guidelines, several thyroid nodules that do not meet the indications for FNA are aspirated in real-world practice. To reduce overtreatment, a widespread knowledge of the correct indications for fine-needle aspiration is important in clinical practice, particularly for subcentimeter nodules.Keywords: thyroid nodule, fine-needle aspiration, thyroid cancer, KTA guidelines

Nathan Yee,1 Emily R Locke,2 Kenneth C Pike,3 Zijing Chen,3 Jungeun Lee,4 Joe C Huang,5 Huong Q Nguyen,6 Vincent S Fan2,7 1Department of Medicine, University of Washington, Seattle, WA, USA; 2Department of Health Services Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; 3Department of Child, Family, and Population Health Nursing, School of Nursing, University of Washington, Seattle, WA, USA; 4College of Nursing, University of Rhode Island, Kingston, RI, USA; 5Division of Gerontology & Geriatric Medicine, University of Washington, Seattle, WA, USA; 6Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA; 7Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USACorrespondence: Vincent S FanDepartment of Health Services Research and Development, Veterans Affairs Puget Sound Health Care System, Pulmonary Section, S-111-Pulm, 1660 S. Columbian Way, Seattle, WA 98108, USATel +1 206 764-2504Fax +1 206 764-2659Email Vincent.fan@va.govBackground: Frailty is a complex clinical syndrome associated with vulnerability to adverse health outcomes. While frailty is thought to be common in chronic obstructive pulmonary disease (COPD), the relationship between frailty and COPD-related outcomes such as risk of acute exacerbations of COPD (AE-COPD) and hospitalizations is unclear.Purpose: To examine the association between physical frailty and risk of acute exacerbations, hospitalizations, and mortality in patients with COPD.Methods: A longitudinal analysis of data from a cohort of 280 participants was performed. Baseline frailty measures included exhaustion, weakness, low activity, slowness, and undernutrition. Outcome measures included AE-COPD, hospitalizations, and mortality over 2 years. Negative binomial regression and Cox proportional hazard modeling were used.Results: Sixty-two percent of the study population met criteria for pre-frail and 23% were frail. In adjusted analyses, the frailty syndrome was not associated with COPD exacerbations. However, among the individual components of the frailty syndrome, weakness measured by handgrip strength was associated with increased risk of COPD exacerbations (IRR 1.46, 95% CI 1.09– 1.97). The frailty phenotype was not associated with all-cause hospitalizations but was associated with increased risk of non-COPD-related hospitalizations.Conclusion: This longitudinal cohort study shows that a high proportion of patients with COPD are pre-frail or frail. The frailty phenotype was associated with an increased risk of non-COPD hospitalizations but not with all-cause hospitalizations or COPD exacerbations. Among the individual frailty components, low handgrip strength was associated with increased risk of COPD exacerbations over a 2-year period. Measuring handgrip strength may identify COPD patients who could benefit from programs to reduce COPD exacerbations.Keywords: chronic obstructive pulmonary disease, frailty, weakness, handgrip strength

Abstract The nutritional characteristics of food resources play an important role in the foraging behavior of animals and can provide information valuable to their conservation and management. We examined the nutritional ecology of wild water buffalo (Bubalus arnee; hereafter “buffalo”) in the Koshi Tappu Wildlife Reserve of Nepal during autumn using a multidimensional nutritional niche framework. We identified 54 plant species as being foraged by buffalo. We found that buffalo consumed graminoids and forbs 2–3 times more frequently than browse items. Proximate analyses of the 16 most frequently foraged plants indicated that buffalo diets were highest in carbohydrate (40.41% ± 1.82%) followed by crude protein (10.52% ± 0.93%) and crude fat (1.68% ± 0.23%). The estimated macronutrient balance (i.e., realized nutrient niche) of the buffalo diet (20.5% protein: 72.8% carbohydrate: 6.7% lipid) was not significantly different than the average balance of all analyzed food items based on 95% confidence regions. Our study suggests that buffalo are likely macronutrient specialists, yet may be generalists in the sense that they feed on a wide range of food items to achieve a nutrient balance similar to that available in forage items. However, the four most frequently consumed items tended to be higher in protein energy than less frequently consumed foods, suggesting some preference for higher protein forage relative to relatively abundant carbohydrates. Although limited in scope, our study provides important information on the nutritional ecology of buffalo, which may be useful for the conservation and management of this endangered species.

Fibroblast growth factor receptor 4 (FGFR4) aberrant expression and activity have been linked to the pathogenesis of a variety of cancers including rhabdomyosarcomas (RMS). We found that treatment of alveolar rhabdomyosarcoma (aRMS) cells with Guadecitabine (SGI-110), a next-generation DNA methyltransferase inhibitor (DNMTi), resulted in a significant reduction of FGFR4 protein levels, 5 days post treatment. Chromatin immunoprecipitation-sequencing (ChIP-seq) in aRMS cells revealed attenuation of the H3K4 mono-methylation across the FGFR4 super enhancer without changes in tri-methylation of either H3K4 or H3K27. These changes were associated with a significant reduction in FGFR4 transcript levels in treated cells. These decreases in H3K4me1 in the FGFR4 super enhancer were also associated with a 240-fold increase in KDM5B (JARID1B) mRNA levels. Immunoblot and immunofluorescent studies also revealed a significant increase in the KDM5B protein levels after treatment in these cells. KDM5B is the only member of KDM5 (JARID1) family of histone lysine demethylases that catalyzes demethylation of H3K4me1. These data together suggest a pleiotropic effect of DNMTi therapy in aRMS cells, converging to significantly lower FGFR4 protein levels in these cells.

Sung Woo Joo,1 Woon Yoon,2 Young Tak Jo,2 Harin Kim,2 Yangsik Kim,2 Jungsun Lee2 1Medical Corps, Republic of Korea Navy 1st Fleet, Donghae, Republic of Korea; 2Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaCorrespondence: Jungsun LeeDepartment of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Republic of KoreaTel +82-2-3010-3422Fax +82-2-485-8381Email js_lee@amc.seoul.krPurpose: Despite a large number of resting-state functional MRI (rsfMRI) studies in schizophrenia, current evidence on the abnormalities of functional connectivity (FC) of resting-state networks shows high variability, and the findings on recent-onset schizophrenia are insufficient compared to those on chronic schizophrenia.Patients and Methods: We performed a rsfMRI in 46 patients with recent-onset schizophrenia and 22 healthy controls. Group independent component brainmap and dual regression were performed for voxel-wise comparisons between the groups. Correlation of the symptom severity, cognitive function, duration of illness, and a total antipsychotics dose with FC was evaluated with Spearman’s rho correlation.Results: The patient group had areas with a significantly decreased FC compared to that of the control group in which it existed in the left supplementary motor cortex and supramarginal gyrus (the executive control network) and the right postcentral gyrus (the auditory network). The patient group had a significant correlation of the total antipsychotics dose with the FC of the cluster in the left supplementary motor cortex in the executive control network.Conclusion: Patients with recent-onset schizophrenia have decreased FC of the executive control and auditory networks compared to healthy controls.Keywords: schizophrenia, resting-state fMRI, executive control network, auditory network

Young Eun Mok,1 Jong-ha Lee,2 Moon-soo Lee1 1Division of Child and Adolescent Psychiatry, Department of Psychiatry, Korea University Guro Hospital, Guro-gu, Seoul, Republic of Korea; 2Department of Psychiatry, Korea University Ansan Hospital, Ansan, Gyeonggi Province, Republic of KoreaCorrespondence: Moon-soo LeeDivision of Child and Adolescent Psychiatry, Department of Psychiatry, Korea University Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul 08308, Republic of KoreaTel +82 2 2626 3163Fax +82 2 852 1937Email npboard@korea.ac.krPurpose: Adolescent depression can have a chronic course; hence, the importance of adherence to antidepressant medication for successful treatment outcomes is emphasized. This study aimed to examine different adherence measures and identify clinical factors that influence adherence in adolescent depression.Patients and Methods: A prospective study was conducted for patients diagnosed with depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition from outpatient psychiatric settings at Korea University Medical Center, Guro Hospital. Patient demographics were obtained from a questionnaire, interview, and review of chart records. Adherence was assessed by four methods (Medication Event Monitoring System [MEMS], pill count, clinical rating scale, and patient’s self-report). The Toronto Side Effect Scale was used to evaluate side effects, and specific depressive symptoms were assessed using the Hamilton Rating Scale for Depression and Childhood Depression Inventory–Korean version. The Multidimensional Scale of Perceived Social Support was administered to analyze social support, and the Parenting Stress Index-Short Form was used to evaluate parental stress levels. We used concordance correlation analysis to evaluate the relationship among the four adherence measures and the relationship between adherence level and clinical factors.Results: Overall, the study enrolled 48 outpatients (mean age 16.33± 1.93 years). The mean duration of illness was 1.27± 2.17 years. Adherence rates for MEMS, clinician rating scale, pill count, and self-report after conversion to dichotomous measures were 67.5%, 48.9%, 60.0%, and 56.3%, respectively. Only the duration of illness remained significantly correlated with MEMS (r = 0.510, p =0.001).Conclusion: Pill count exhibited a higher degree of agreement with MEMS adherence than the other two adherence measures, possibly indicating that pill count may be a considerably reliable measure of adherence. Furthermore, MEMS adherence was positively correlated with disease duration, suggesting that the longer the duration of illness, the higher the adherence.Keywords: medication event monitoring system, pill count, duration of illness, self-report, clinician rating scale, symptom severity, parental stress

The causes of the Upper Pleistocene megafauna extinction in Australia and New Guinea are debated, but fossil data are lacking for much of this region. Here, Hocknull and colleagues report a new, diverse megafauna assemblage from north-eastern Australia that persisted until ~40,000 years ago.

Amyloid light chain (AL) amyloidosis is a disease of misfolded, fibrous proteins, either kappa or lambda subtype, that can be deposited into one or more organs, caused by a proliferation of plasma cells. The liver is uncommonly the main organ system affected and rarely the only organ affected by amyloid deposition. With hepatic involvement, the most common presenting findings are hepatomegaly and elevation of serum alkaline phosphatase. We report a case of a 50-year-old male who presented to our gastroenterology clinic with marked hepatomegaly secondary to hepatic amyloidosis, in concert with bone marrow involvement and nephrotic syndrome. Biopsies in conjunction with Congo red staining demonstrated 95% replacement of hepatic structure and 80% replacement of bone marrow with amyloid deposition. Despite these findings, liver chemistries, renal function, and blood count were normal. Our case presents not only the rare finding of primary hepatic amyloidosis but also an atypical presentation of this disorder. Although rare, AL amyloidosis should be in a differential diagnosis of any patient who presents with unexplained hepatomegaly, nephrotic-range proteinuria, heart failure with preserved ejection fraction, fatigue, weight loss or a history of monoclonal gammopathy of undetermined significance.

It has been commonly believed that the driving force at the donor-acceptor heterojunction is vital to efficient charge separation in organic solar cells. Here Zhong et al. show that the driving force can be as small as 0.05 eV without compromising the charge transfer rate and efficiency.

A pharmaceutical industry viewpoint on how the fundamental laws of photochemistry are used to identify the parameters required to implement photochemistry from lab to scale. Parameters such as photon stoichiometry and light intensity are highlighted within to inform future publications.

Abstract DNA damage is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, relationships between DNA damage accumulation, DNA damage response (DDR), and upper and lower motor neuron vulnerability in human ALS are unclear; furthermore, it is unknown whether epigenetic silencing of DNA repair pathways contributes to ALS pathogenesis. We tested the hypotheses that DNA damage accumulates in ALS motor neurons along with diminished DDR, and that DNA repair genes undergo hypermethylation. Human postmortem CNS tissue was obtained from ALS cases (N = 34) and age-matched controls without neurologic disease (N = 15). Compared to age-matched controls, abasic sites accumulated in genomic DNA of ALS motor cortex and laser capture microdissection-acquired spinal motor neurons but not in motor neuron mitochondrial DNA. By immunohistochemistry, DNA damage accumulated significantly in upper and lower motor neurons in ALS cases as single-stranded DNA and 8-hydroxy-deoxyguanosine (OHdG) compared to age-matched controls. Significant DDR was engaged in ALS motor neurons as evidenced by accumulation of c-Abl, nuclear BRCA1, and ATM activation. DNA damage and DDR were present in motor neurons at pre-attritional stages and throughout the somatodendritic attritional stages of neurodegeneration. Motor neurons with DNA damage were also positive for activated p53 and cleaved caspase-3. Gene-specific promoter DNA methylation pyrosequencing identified the DNA repair genes Ogg1, Apex1, Pnkp and Aptx as hypomethylated in ALS. In human induced-pluripotent stem cell (iPSC)-derived motor neurons with familial ALS SOD1 mutations, DNA repair capacity was similar to isogenic control motor neurons. Our results show that vulnerable neurons in human ALS accumulate DNA damage, and contrary to our hypothesis, strongly activate and mobilize response effectors and DNA repair genes. This DDR in ALS motor neurons involves recruitment of c-Abl and BRCA1 to the nucleus in vivo, and repair of DNA double-strand breaks in human ALS motor neurons with SOD1 mutations in cell culture.

An understanding of the seasonality of infections informs public health strategies and assists clinicians in their management of patients with undifferentiated illness. The seasonality of infections is driven by a variety of environmental and human factors; however, the role of individual climatic factors has garnered much attention. This study utilises Poisson regression models to assess the seasonality of six important infections in tropical Australia and their association with climatic factors and severe weather events over a 21-year period. Melioidosis and leptospirosis showed marked wet season predominance, while more cases of rickettsial disease and cryptococcosis were seen in cooler, drier months. Staphylococcus aureus infections were not seasonal, while influenza demonstrated inter-seasonality. The climate did not significantly change during the 21 years of the study period, but the incidence of melioidosis and rickettsial disease increased considerably, highlighting the primacy of other factors-including societal inequality, and the impact of urban expansion-in the incidence of these infections. While anthropogenic climate change poses a threat to the region-and may influence the burden of these infections in the future-this study highlights the fact that, even for seasonal diseases, other factors presently have a greater effect on disease incidence. Public health strategies must also target these broader drivers of infection if they are to be effective.

Amanzi Springs is a series of inactive thermal springs located near Kariega in the Eastern Cape of South Africa. Excavations in the 1960s exposed rare, stratified Acheulian-bearing deposits that were not further investigated over the next 50 years. Reanalysis of the site and its legacy collection has led to a redefined stratigraphic context for the archaeology, a confirmed direct association between Acheulian artefacts and wood, as well as the first reliable age estimates for the site. Thermally transferred optically stimulated luminescence and post-infrared infrared stimulated luminescence dating indicates that the Acheulian deposits from the Amanzi Springs Area 1 spring eye formed during Marine Isotope Stage (MIS) 11 at ~ 404–390 ka. At this time, higher sea levels of ~13-14m would have placed Amanzi Springs around 7 km from a ria that would have formed along what is today the Swartkops River, and which likely led to spring reactivation. This makes the Amanzi Springs Area 1 assemblage an unusual occurrence of a verified late occurring, seaward, open-air Acheulian occupation. The Acheulian levels do not contain any Middle Stone Age (MSA) elements such as blades and points that have been documented in the interior of South Africa at this time. However, a small number of stone tools from the upper layers of the artefact zone, and originally thought of as intrusive, have been dated to ~190 ka, at the transition between MIS 7 to 6, and represent the first potential MSA identified at the site.

Objective: To examine the quality of life experienced by women with symptomatic uterine fibroids who had been treated with UAE in comparison to myomectomy. We report the four-year follow-up of the FEMME randomised trial. Two-year follow-up data has been previously reported. Study Design: Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolization were recruited from 29 UK hospitals. Women were excluded if they had significant adenomyosis, any malignancy, pelvic inflammatory disease or had had a previous open myomectomy or uterine artery embolization.Participants were randomised to myomectomy or embolization in a 1:1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic, according to clinician preference. Embolization of the uterine arteries was performed according to local practice, under fluoroscopic guidance.The primary outcome measure was the Uterine Fibroid Symptom Quality of Life questionnaire, adjusted for baseline score and reported here at four years post-randomisation. Subsequent procedures for fibroids, pregnancy and outcome were amongst secondary outcomes.Trial registration ISRCTN70772394 https://doi.org/10.1186/ISRCTN70772394 Results: 254 women were randomized, 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolization (98 underwent embolization). At four years, 67 (53%) and 81 (64%) completed UFS-QoL quality of life scores. Mean difference in the UFS-QoL at 4 years was 5.0 points (95% CI −1.4 to 11.5; p = 0.13) in favour of myomectomy. There were 15 pregnancies in the UAE group and 7 in the myomectomy group, with a cumulative pregnancy rate to four years of 15% and 6% respectively (hazard ratio: 0.48; 95% CI 0.18–1.28). The cumulative repeat procedure rate to four years was 24% in the UAE group and 13% in the myomectomy group (hazard ratio: 0.53; 95% CI 0.27–1.05). Conclusions: Myomectomy resulted in greater improvement in quality of life compared with uterine artery embolization, although by four years, this difference was not statistically significant. Missing data may limit the generalisability of this result. The numbers of women becoming pregnant were too small draw a conclusion on the effect of the procedures on fertility.

More refined knowledge of how tropical forests respond to changes in the abiotic environment is necessary to mitigate climate change, maintain biodiversity, and preserve ecosystem services. To evaluate the unique response of diverse Afrotropical forest communities to disturbances in the abiotic environment, we employ country-wide tree species inventories, remotely sensed climate data, and future climate predictions collected from 104 1-ha plots in the central African country of Gabon. We predict a 3–8% decrease in Afrotropical forest species richness by the end of the century, in contrast to the 30–50% loss of plant diversity predicted to occur with equivalent warming in the Neotropics. This work reveals that forecasts of community species composition are not generalizable across regions, and more representative studies are needed in understudied diverse biomes. This study serves as an important counterpoint to work done in the Neotropics by providing contrasting predictions for Afrotropical forests with substantially different ecological, evolutionary, and anthropogenic histories.

Abstract Species responses to disturbance influence their extinction risks. Greater sage‐grouse (Centrocercus urophasianus) are bioindicators of sagebrush ecosystem health and the loss of sagebrush (Artemisia spp.) due to wildfire, can cause long‐term declines in sage‐grouse populations and other sagebrush obligate species. We examined the demographic response of a greater sage‐grouse population following a mega‐wildfire using stochastic age‐structured female‐based matrix models over 6 years (2013–2018). Notably, chick survival (range = 0.18–0.38) and female survival (yearling range: 0.20–0.68; adult range: 0.27–0.75) were low compared to values reported for greater sage‐grouse in other parts of their distribution. Greater sage‐grouse displayed variation in demographic tactics after the fire; however, adult female survival explained most of the variation in λ during each year, which reflected a declining population in 3 of 6 years with more uncertainty observed in 2015 when populations may have been increasing, and 2017 and 2018, when populations may have been declining. The continued annual population decline observed since 2016 suggested there were additional strong environmental impacts that may have been compounded by the fire effects, prolonging recovery of greater sage‐grouse. Our results support others that reported negative effects to greater sage‐grouse demographics from broad‐scale fire and provide a baseline for understanding how this species responds to loss of sagebrush cover based on their life history strategy.

Multiple factors have been proposed to explain the disappearance of Neandertals between ca. 50 and 40 kyr BP. Central to these discussions has been the identification of new techno-cultural complexes that overlap with the period of Neandertal demise in Europe. One such complex is the Châtelperronian, which extends from the Paris Basin to the Northern Iberian Peninsula between 43,760-39,220 BP. In this study we present the first open-air Châtelperronian site in the Northern Iberian Peninsula, Aranbaltza II. The technological features of its stone tool assemblage show no links with previous Middle Paleolithic technology in the region, and chronological modeling reveals a gap between the latest Middle Paleolithic and the Châtelperronian in this area. We interpret this as evidence of local Neandertal extinction and replacement by other Neandertal groups coming from southern France, illustrating how local extinction episodes could have played a role in the process of disappearance of Neandertals.

The very proton-rich 71Kr isotope was produced through the in-flight fragmentation of 78Kr on a beryllium target at RIKEN – Nishina Center in order to study its β-decay properties. A stack of double-sided silicon strip detectors, called WAS3ABi, was used as the decay station, where the detection of ion implants, β-decays and β-delayed protons took place. Beta-delayed γ-rays were measured using a system of 84 HPGe detectors, called EURICA, surrounding the decay station. The main goal of the present study was the precise measurement of the half-life of 71Kr, as in the literature there is an almost 10 σ difference between the most precise independent results. Implant–β time correlations, implant–proton time correlations and implant–β–γ time correlations were all used to derive the half-life value, followed by a thorough investigation of systematic uncertainties for each method. As these values were found to be consistent, the weighted average t1/2 = 94.40+19ms is reported as a new half-life value in this work. Furthermore a total of 26 previously unreported γ following the β-decay of 71Kr were also identified in the analysis.

We compare systems with single giant planets to systems with multiple giant planets using a catalog of planets from a high-precision radial velocity survey of FGKM stars. Our comparison focuses on orbital properties, planet masses, and host-star properties. We use hierarchical methods to model the orbital eccentricity distributions of giant singles and giant multiples, and find that the distributions are distinct. The multiple giant planets typically have moderate eccentricities and their eccentricity distribution extends to e = 0.47 (90th percentile), while the single giant planets have a pileup of nearly circular orbits and a long tail that extends to e = 0.77. We determine that the stellar hosts of multiple giants are distinctly more metal rich than the hosts of solitary giants, with respective mean metallicities of 0.228 ± 0.027 versus 0.129 ± 0.019 dex. We measure the distinct occurrence distributions of single and multiple giants with respect to orbital separation, and find that single gas giants have a ∼2.3 σ significant hot Jupiter ( a < 0.06) pileup not seen among multigiant systems. We find that the median mass ( $M\sin i$ ) of giants in multiples is nearly double that of single giants (1.71 M _J versus 0.92 M _J ). We find that giant planets in the same system have correlated masses, analogous to the “peas in a pod” effect seen among less-massive planets.

With JWST’s successful deployment and unexpectedly high fuel reserves, measuring the masses of sub-Neptunes transiting bright, nearby stars will soon become the bottleneck for characterizing the atmospheres of small exoplanets via transmission spectroscopy. Using a carefully curated target list and observations from more than 2 yr of APF-Levy and Keck-HIRES Doppler monitoring, the TESS-Keck Survey is working toward alleviating this pressure. Here we present mass measurements for 11 transiting planets in eight systems that are particularly suited to atmospheric follow-up with JWST. We also report the discovery and confirmation of a temperate super-Jovian-mass planet on a moderately eccentric orbit. The sample of eight host stars, which includes one subgiant, spans early-K to late-F spectral types ( T _eff = 5200–6200 K). We homogeneously derive planet parameters using a joint photometry and radial velocity modeling framework, discuss the planets’ possible bulk compositions, and comment on their prospects for atmospheric characterization.

We present the stellar and planetary properties for 85 TESS Objects of Interest (TOIs) hosting 108 planet candidates that compose the TESS-Keck Survey (TKS) sample. We combine photometry, high-resolution spectroscopy, and Gaia parallaxes to measure precise and accurate stellar properties. We then use these parameters as inputs to a light-curve processing pipeline to recover planetary signals and homogeneously fit their transit properties. Among these transit fits, we detect significant transit-timing variations among at least three multiplanet systems (TOI-1136, TOI-1246, TOI-1339) and at least one single-planet system (TOI-1279). We also reduce the uncertainties on planet-to-star radius ratios R _p / R _⋆ across our sample, from a median fractional uncertainty of 8.8% among the original TOI Catalog values to 3.0% among our updated results. With this improvement, we are able to recover the Radius Gap among small TKS planets and find that the topology of the Radius Gap among our sample is broadly consistent with that measured among Kepler planets. The stellar and planetary properties presented here will facilitate follow-up investigations of both individual TOIs and broader trends in planet properties, system dynamics, and the evolution of planetary systems.

We present the Distant Giants Survey, a three-year radial velocity campaign to measure P(DG∣CS), the conditional occurrence of distant giant planets (DG; M _p ∼ 0.3–13 M _J , P > 1 yr) in systems hosting a close-in small planet (CS; R _p < 10 R _⊕ ). For the past two years, we have monitored 47 Sun-like stars hosting small transiting planets detected by TESS. We present the selection criteria used to assemble our sample and report the discovery of two distant giant planets, TOI-1669 b and TOI-1694 c. For TOI-1669 b we find that $M\sin i=0.573\pm 0.074\,\,{M}_{{\rm{J}}}$ , P = 502 ± 16 days, and e < 0.27, while for TOI-1694 c, $M\sin i=1.05\pm 0.05\,\,{M}_{{\rm{J}}}$ , P = 389.2 ± 3.9 days, and e = 0.18 ± 0.05. We also confirmed the 3.8 days transiting planet TOI-1694 b by measuring a true mass of M = 26.1 ± 2.2 M _⊕ . At the end of the Distant Giants Survey, we will incorporate TOI-1669 b and TOI-1694 c into our calculation of P(DG∣CS), a crucial statistic for understanding the relationship between outer giants and small inner companions.

The detection of satellites around extrasolar planets, so called exomoons, remains a largely unexplored territory. In this work, we study the potential of detecting these elusive objects from radial velocity monitoring of self-luminous, directly imaged planets. This technique is now possible thanks to the development of dedicated instruments combining the power of high-resolution spectroscopy and high-contrast imaging. First, we demonstrate a sensitivity to satellites with a mass ratio of 1%–4% at separations similar to the Galilean moons from observations of a brown-dwarf companion (HR 7672 B; K _mag = 13; 0.″7 separation) with the Keck Planet Imager and Characterizer ( R ∼ 35,000 in the K band) at the W. M. Keck Observatory. Current instrumentation is therefore already sensitive to large unresolved satellites that could be forming from gravitational instability akin to binary star formation. Using end-to-end simulations, we then estimate that future instruments such as the Multi-Object Diffraction-limited High-resolution Infrared Spectrograph, planned for the Thirty Meter Telescope, should be sensitive to satellites with mass ratios of ∼10 ^−4 . Such small moons would likely form in a circumplanetary disk similar to the Jovian satellites in the solar system. Looking for the Rossiter–McLaughlin effect could also be an interesting pathway to detecting the smallest moons on short orbital periods. Future exomoon discoveries will allow precise mass measurements of the substellar companions that they orbit and provide key insight into the formation of exoplanets. They would also help constrain the population of habitable Earth-sized moons orbiting gas giants in the habitable zone of their stars.

Ji-Eun Lee,1 Se Young Kim,2 Jae-Ho Yoo,3 Il Tae Hwang,4 Jung Sub Lim,5 Kyung Hee Yi,6 Young-Jun Rhie,7 Gyung Min Lee,8 Hyo-Kyoung Nam,9 Hyun Wook Chae,10 Eun Young Kim,11 Chong Kun Cheon,12 Jieun Lee,13 Young Suk Shim,14 YuJin Lee,15 Eun Young Kim,15 Jin Soon Hwang16 1Department of Pediatrics, Inha University Hospital, Inha University Graduate School of Medicine, Incheon, Republic of Korea; 2Department of Pediatrics & Adolescent Medicine, Bundang Jeseang General Hospital, Daejin Medical Center, Seongnam, Republic of Korea; 3Department of Pediatrics, Dong-a University Hospital, Dong-a University College of Medicine, Busan, Republic of Korea; 4Department of Pediatrics, Kangdong Sacred Heart Hospital, Hallym University, College of Medicine, Seoul, Republic of Korea; 5Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Republic of Korea; 6Department of Pediatrics, Wonkwang University Sanbon Medical Center, Gunpo, Republic of Korea; 7Department of Pediatrics, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea; 8Department of Pediatrics, Konyang University Hospital, Daejeon, Republic of Korea; 9Department of Pediatrics, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 10Department of Pediatrics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 11Department of Pediatrics, Chosun University Hospital, Chosun University School of Medicine, Gwangju, Republic of Korea; 12Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea; 13Department of Pediatrics, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea; 14Department of Pediatrics & Adolescent Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Republic of Korea; 15Life Sciences, LG Chem, Ltd., Seoul, Republic of Korea; 16Department of Pediatrics & Adolescent Medicine, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of KoreaCorrespondence: Jin Soon HwangDepartment of Pediatrics & Adolescent Medicine, Ajou University Hospital, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do 16499, Republic of KoreaTel +82 31 219 5166Fax +82 31 219 5169Email pedhwang@ajou.ac.krPurpose: To assess the usability and safety of the disposable pen compared to those of reusable devices in patients receiving recombinant human growth hormone (rhGH) treatment.Patients and methods: This study was a multicenter, single-arm, open-label, switch-over, prospective, Phase IV trial. After screening, eligible patients who were previously treated with rhGH using a reusable device were enrolled to receive treatment with the disposable pen for 8 weeks. The ease of use, preference, and tolerability of the disposable pen compared to those of the reusable device were assessed by the subjects and/or their caregivers using a questionnaire. Adverse events were evaluated by the investigators.Results: Of 116 subjects enrolled in this study, 115 received treatment with the disposable pen and 109 completed the study. The mean age of the subjects was 9.4 years. Compared to the previous reusable device, the disposable pen was assessed as significantly easier to use (mean value 7.88, 95% confidence interval (CI) [7.45–8.30] on a numerical scale ranging from 0 (far less easy) to 10 (far easier)). Furthermore, the percentage of subjects who preferred the disposable pen to the previously used reusable device was 75.7% (95% CI [67.6%–83.8%]). The percentages of subjects who rated pain and discomfort at the injection site as “not at all” were higher after using the disposable pen compared to the reusable device. No specific safety concerns were identified.Conclusion: The disposable pen is easier to use than the reusable devices and is preferred by approximately 75% of patients receiving rhGH treatment. Moreover, the disposable pen is safe and acceptable. Therefore, it could be a good alternative to reusable devices. The disposable pen is expected to provide benefits to patients receiving rhGH treatment.Clinicaltrials.gov identifier: NCT03015909.Keywords: growth hormone, disposable equipment, patient preference, usability, safety

Jiwoo Lee, Yun Kyung Cho, Hwi Seung Kim, Chang Hee Jung, Joong-Yeol Park, Woo Je Lee Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaCorrespondence: Woo Je LeeDepartment of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Republic of KoreaTel +82-2-3010-5882Fax +82-2-2045-4034Email lwjatlas@gmail.comPurpose: For patients with type 2 diabetes (T2DM) who remain above their glycemic target on insulin therapy, a combination of insulin and a glucagon-like peptide 1 receptor agonist has been recommended. However, few studies have been conducted to determine the clinical efficacy and parameters affecting the response to this combination in a real-world setting. This study aimed to investigate the clinical efficacy and parameters affecting the glycemic response to dulaglutide as an add-on to insulin therapy for T2DM in a real-world clinical setting.Patients and methods: A retrospective study was performed in 120 patients with T2DM who had initiated dulaglutide as an add-on to insulin therapy between January 2017 and December 2018. After 6 months of treatment, the change in glycated hemoglobin (HbA1c) was evaluated. Multiple linear regression analysis was used to determine the parameters affecting the therapeutic response to dulaglutide.Results: The mean age of the patients was 55.1 years and 57.5% were male. The mean baseline HbA1c, body mass index, and duration of diabetes were 9.1%, 27.5 kg/m2, and 17.2 years, respectively. The change in HbA1c between baseline and 6 months was −0.97% (95% confidence interval [CI]: −1.28 to −0.66%, P

By dispersing seeds long distances, large, fruit-eating animals influence plant population spread and community dynamics. After fruit consumption, animal gut passage time and movement determine seed dispersal patterns and distances. These, in turn, are influenced by extrinsic, environmental variables and intrinsic, individual-level variables. We simulated seed dispersal by forest elephants (Loxodonta cyclotis) by integrating gut passage data from wild elephants with movement data from 96 individuals. On average, elephants dispersed seeds 5.3 km, with 89% of seeds dispersed farther than 1 km. The longest simulated seed dispersal distance was 101 km, with an average maximum dispersal distance of 40.1 km. Seed dispersal distances varied among national parks, perhaps due to unmeasured environmental differences such as habitat heterogeneity and configuration, but not with human disturbance or habitat openness. On average, male elephants dispersed seeds farther than females. Elephant behavioral traits strongly influenced dispersal distances, with bold, exploratory elephants dispersing seeds 1.1 km farther than shy, idler elephants. Protection of forest elephants, particularly males and highly mobile, exploratory individuals, is critical to maintaining long distance seed dispersal services that shape plant communities and tropical forest habitat.

The charcoal–herb extract complex (CHC) is a product of activated charcoal sorption of herb extracts that contain phenolic acids and flavonoids. The effective dose of CHC to promote animal growth is about one tenth of effective dosage of activated charcoal. The purpose of this study was to evaluate potential cooperative interactions between activated charcoal and herb extracts. Two feeding experiments were conducted. In Experiment 1, a responsive dose of CHC to broiler growth was determined to be 250 mg/kg of the diet. In Experiment 2, CHC increased growth performance and improved meat quality, but decreased indices of oxidative stress and inflammation as compared with similar doses of activated charcoal or herb extracts. CHC also increased concentrations of serum cholesterol, bile acid in the gallbladder, and bile acid in feces. The herb extracts present in CHC were largely represented by phenolic acids (PAs, caffeic acid, and vanillin) and flavonoids (FVs, daidzein, and quercetin-D-glucoside) in the detoxification activity of CHC in a mouse rescue test when the mice were gavaged with T-2 mycotoxin. PAs and FVs significantly increased the expression of CYP7A1, PXR, CYP3A37, Slco1B3, and Bsep in chicken primary hepatocytes. In conclusion, CHC integrated the cooperative interactions of activated charcoal and herb extracts via the FXR/RXR-PXR pathway to detoxify mycotoxins.

Amyotrophic lateral sclerosis (ALS) is a fatal disease. Skeletal muscles and motor neurons (MNs) degenerate. ALS is a complex disease involving many genes in multiple tissues, the environment, cellular metabolism, and lifestyles. We hypothesized that epigenetic anomalies in DNA and RNA occur in ALS and examined this idea in: (1) mouse models of ALS, (2) human ALS, and (3) mouse ALS with therapeutic targeting of DNA methylation. Human superoxide dismutase-1 (hSOD1) transgenic (tg) mice were used. They expressed nonconditionally wildtype (WT) and the G93A and G37R mutant variants or skeletal muscle-restricted WT and G93A and G37R mutated forms. Age-matched non-tg mice were controls. hSOD1 mutant mice had increased DNA methyltransferase enzyme activity in spinal cord and skeletal muscle and increased 5-methylcytosine (5mC) levels. Genome-wide promoter CpG DNA methylation profiling in skeletal muscle of ALS mice identified hypermethylation notably in cytoskeletal genes. 5mC accumulated in spinal cord MNs and skeletal muscle satellite cells in mice. Significant increases in DNA methyltransferase-1 (DNMT1) and DNA methyltransferase-3A (DNMT3A) levels occurred in spinal cord nuclear and chromatin bound extracts of the different hSOD1 mouse lines. Mutant hSOD1 interacted with DNMT3A in skeletal muscle. 6-methyladenosine (6mA) RNA methylation was markedly increased or decreased in mouse spinal cord depending on hSOD1-G93A model, while fat mass and obesity associated protein was depleted and methyltransferase-like protein 3 was increased in spinal cord and skeletal muscle. Human ALS spinal cord had increased numbers of MNs and interneurons with nuclear 5mC, motor cortex had increased 5mC-positive neurons, while 6mA was severely depleted. Treatment of hSOD1-G93A mice with DNMT inhibitor improved motor function and extended lifespan by 25%. We conclude that DNA and RNA epigenetic anomalies are prominent in mouse and human ALS and are potentially targetable for disease-modifying therapeutics.

Clostridioides difficile infections (CDIs), and particularly recurrent infections, cause a significant burden on the health-care system. Bezlotoxumab is a new agent for the prevention of recurrent CDIs that has shown strong efficacy and high tolerability in clinical trials. The purpose of this review is to evaluate the published literature for bezlotoxumab, with a focus on literature published since the release of the 2021 focused update to the CDI treatment guidelines. A Medline/PubMed search for “bezlotoxumab” was conducted, resulting in 152 articles. Seventeen studies are included in this review, after excluding non-English-language papers, phase I and II trials, and review articles. Studies published since the 2021 focused update support the recommendations in those guidelines. Furthermore, real-world studies have shown similar results to larger clinical trials. Those with more risk factors for recurrent CDI appear to benefit most from bezlotoxumab. Currently, there are no data to support the use of bezlotoxumab outside current guideline recommendations, but future trials may build on the data seen in real-world studies to further elucidate the place in therapy for bezlotoxumab.

Microplastic pollution is of public concern for global environmental health, aquaculture, and fisheries. Toxicity studies have shown that microplastic ingestion may cause intestinal damage, microbiota dysbiosis, and disturb the lipid and energy metabolism in fish. To determine the impact of environmentally relevant, chronic, low dose microplastic fibers on fish health, medaka larvae, and juveniles were exposed to five concentrations of polyethylene (PE) fibers for 21 days through the feed. Fish growth and condition were assessed to determine the overall impact on fish health. To identify impaired energy intake, the gastrointestinal tract (GIT) integrity was evaluated at the molecular and cellular levels. Microbiota analysis was performed by comparing the top seven most abundant phyla present in both larval and juvenile fish exposed to 0, 1.5, and 3 PE fibers/fish/day. A shift in the phyla Proteobacteria and Bacteroidetes were observed. Larval samples demonstrated decreased proteobacteria abundance, while juvenile samples displayed an increase in abundance. Relative gene expression of key digestive genes from GIT tissue was quantified using real time-quantitative polymerase chain reaction. An effect on digestive gene expression potentially affecting nutrient absorption and antioxidant production was indicated via a significant decrease of solute carrier family 6 member 6 expression in larvae exposed to 6 fibers/fish/day. No significant molecular changes were observed in juvenile GIT tissue, although a non-monotonous dose-response was observed. GIT morphology was analyzed using histomorphological observations of the GIT mucus and cell types. No significant impairment of the GIT epithelial layers was observed in larvae or juveniles. To assess growth and condition, Fulton’s condition factor was measured. No differences were observed in larval or juvenile growth. Comparisons of different developmental stages allowed for identifying vulnerable developmental stages for microplastic exposure; larvae were more susceptible to molecular changes, while shifts in juvenile microbial communities were similar to changes reported post-polystyrene microplastic sphere exposure. This study is one of the first to provide toxicological data on the risk of PE fiber ingestion during fish development stages. Results indicate no imminent threat to fish condition at current measured environmental levels of microplastics; however, close monitoring of vital spawning grounds for commercially important fishes is recommended.

Summary: Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, we describe a progressive evolutionary downregulation of pathogen-sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs), acquisition of a unique caspase-1/-4 effector fusion protein that processes gasdermin D pore formation without inducing rapid lytic cell death, and the formation of a caspase-8 containing inflammasome that inefficiently processes interleukin-1β. Inflammasomes regulate gut immunity, but the carnivorous diet has antimicrobial properties that could compensate for the loss of these immune pathways. We speculate that the consequences of systemic inflammasome downregulation, however, can impair host sensing of specific pathogens such that they can reside undetected in the Carnivora.