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The mutualistic association between Wolbachia endosymbionts and their filarial nematode hosts has been exploited as a validated drug target delivering macrofilaricidal outcomes. Limitations of existing antibiotics to scale-up have driven the search for new drugs, which are effective in shorter regimens of 7 days or less. Here, we review the last 14 years of anti-Wolbachia drug discovery by the anti-Wolbachia (A·WOL) consortium, which has screened more than two million compounds, delivering thousands of hit compounds. Refined screening models integrated with robust pharmacokinetic/pharmacodynamic (PK/PD) driven optimisation and selection strategies have delivered the first two drug candidates specifically designed to target Wolbachia. AWZ1066S and ABBV-4083 are currently progressing through clinical trials with the aim of delivering safe and effective macrofilaricides to support the elimination of onchocerciasis and lymphatic filariasis.

Background In adults, the gold standard for surgical repair of an inguinal hernia is a mesh repair, whereas, in children, the standard is high ligation of the hernia sac. However, adolescents represent a “gray zone” between children and adults, and there is no consensus on the most appropriate operation for inguinal hernias in these patients. We aimed to describe the outcomes in adolescents undergoing high ligation for inguinal hernia repair and determine what factors may portend an increased risk of recurrence in this population. Methods A retrospective cohort study was performed of all children that underwent open high ligation for an inguinal hernia at our tertiary children's hospital from January 2000 to January 2018, who were 12 to 18 years old at the time of surgery. We compared the patient demographic data, medical history, and repair characteristics for the cohort of hernias that developed a recurrence to the cohort that did not. Results During our study period, 256 adolescent patients underwent repair with 11 of those patients having both sides repaired for a total of 267 hernias repaired. The median age at surgery was 14.7 years, and 83.9% of the hernias were in male patients. There was a 6.0% recurrence rate, and all patients that developed recurrence underwent a reoperation. The median time from surgery to reoperation for recurrence was 3.1 years. Patients with recurrence were more likely to have cardiac (25.0% vs. 5.8%, p = 0.02) and gastrointestinal comorbidities (25% vs. 7.1%, p = 0.01). There were no other significant differences between the two cohorts. Conclusion High ligation of the hernia sac in adolescents is effective and has an acceptable risk of recurrence while avoiding any additional morbidity that may come from the use of mesh. Patients with cardiac and gastrointestinal comorbidities should be counseled on the higher risk of recurrence.

Purpose Almost 30% of pediatric trauma transfers to our facility have previously been shown to be potentially preventable transfers (PT). However, we sought to evaluate what care from support services these PT received during admission. Methods Traumatically injured children transferred between January 2014 and June 2019 were retrospectively analyzed. A PT was defined as a child who was discharged within 36 h of arrival without surgical intervention or advanced imaging studies. PT that received support services were compared to those that did not to determine which patients may benefit from these services were their transfers prevented. Results There were 3212 transfers, and 927 (29%) were PT. When compared to non-PT, PT were younger, closer to our hospital, and had a lower ISS, extremity or C-spine injury, or assault/non-accidental trauma mechanism. PT were less likely to have a chest injury or a CT at the referring hospital. Of the PT, 30% had a support service consulted. PT with higher ISS or a head injury was more likely to receive a consultation with a support service. Conclusions A significant proportion of these “preventable” transfers still receive important care from support services during their admission. Type of study Retrospective study. Level of evidence III

Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.

Background/Purpose the timing of endorectal pull-through for Hirschsprung disease (HD) is controversial. Neonatal primary endorectal pull-through theoretically prevents preoperative enterocolitis. Delayed primary endorectal pull-through offers the surgeon the benefit of more robust perineal anatomy and allows primary caregivers the time to emotionally process the diagnosis and to gain experience with rectal irrigations. We hypothesized that delayed primary endorectal pull-through would be associated with equivalent perioperative morbidity compared to the neonatal repair and would lead to improved long-term functional outcomes. Methods we analyzed all patients in the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) registry who had a primary endorectal pull-through for HD and at least three-and-one-half years of follow up in a specialty colorectal clinic. We evaluated patient demographics, operative outcomes, perioperative episodes of enterocolitis, and long-term functional outcomes for the neonatal ( Results eighty-two patients were identified of whom 49 were operated upon in the neonatal period and 33 in a delayed fashion. The median age at operation was 11 days [IQR 7 – 19 days] for the neonatal cohort and 98 days [IQR 61 – 188 days] for the delayed cohort. Thirty-four (69.4%) of the neonatal and 22 (66.7%) of the delayed cohort patients had rectosigmoid transition zones. Four of 49 patients (8.1%) in the neonatal cohort were diagnosed with enterocolitis preoperatively compared to two of 33 (6.0%) in the delayed cohort (p = 0.89). Eighteen of 49 patients (36.7%) in the neonatal cohort and 16 of 33 (48.5%) in the delayed cohort had at least one postoperative episode of enterocolitis (p = 0.38). Fifteen of 49 patients (30.6%) in the neonatal cohort were receiving bowel management for fecal incontinence at most recent follow up compared to five of 33 (15.2%) in the delayed cohort (p = 0.13). Conclusion delayed primary endorectal pull-through offers a safe alternative to operation in the neonatal period and appears to have, at least, equivalent functional outcomes. Level of evidence : Level III, retrospective comparative study

Background HARC is a soft and flexible hyaluronic acid filler containing lidocaine, manufactured using XpresHAnrntechnology, restoring natural-looking volume and soft contours. Objectives To evaluate safety and effectiveness of HARCnfor cheek augmentation and correction of midface contour deficiencies compared to a control product HAJV (hereafter referred to as Control). Primary objective was to demonstrate non-inferiority of HARCncompared to the Control, by blinded evaluation of change from baseline in midface fullness 12 weeks after last injection, using a 4 grade midface volume scale (MMVS). Materials and methods Subjects over the age of 21 with loss of fullness in the midface area (MMVS score 2, 3, or 4) were randomized 2:1 to treatment with HARC(n=142) or Control (n=68). Optional touch-up was allowed after 4 weeks. Study assessments included MMVS, aesthetic improvement, subject satisfaction, and safety. Subjects were followed for 48 weeks. Results Overall, most subjects were female (89%) and mean age was 53 years (range 24-80). Total mean volume injected was 4.3 mL for HARCnand 4.9 mL for Control. Primary objective was met; mean change from baseline in MMVS score at week 12: -1.4 (HARC), -1.3 (Control), 95% CI: -0.22, 0.06. HARCneffectiveness was supported by a high degree of aesthetic improvement and subject satisfaction throughout 48 weeks. Related adverse events were generally mild and transient. Conclusions nHARCnwas well tolerated and non-inferior to Control for correction of midface fullness at 12 weeks after last injection. Aesthetic improvement and subject satisfaction were high and lasted through week 48. nJ Drugs Dermatol. 2021;20(9):949-956. doi:10.36849/JDD.6191.

Background Fluid therapy-the administration of fluids to maintain adequate organ tissue perfusion and oxygenation-is essential in patients admitted to the intensive care unit (ICU) with traumatic brain injury. We aimed to quantify the variability in fluid management policies in patients with traumatic brain injury and to study the effect of this variability on patients' outcomes.Methods We did a prospective, multicentre, comparative effectiveness study of two observational cohorts: CENTER-TBI in Europe and OzENTER-TBI in Australia. Patients from 55 hospitals in 18 countries, aged 16 years or older with traumatic brain injury requiring a head CT, and admitted to the ICU were included in this analysis. We extracted data on demographics, injury, and clinical and treatment characteristics, and calculated the mean daily fluid balance (difference between fluid input and loss) and mean daily fluid input during ICU stay per patient. We analysed the association of fluid balance and input with ICU mortality and functional outcome at 6 months, measured by the Glasgow Outcome Scale Extended (GOSE). Patient-level analyses relied on adjustment for key characteristics per patient, whereas centre-level analyses used the centre as the instrumental variable.Findings 2125 patients enrolled in CENTER-TBI and OzENTER-TBI between Dec 19, 2014, and Dec 17, 2017, were eligible for inclusion in this analysis. The median age was 50 years (IQR 31 to 66) and 1566 (74%) of patients were male. The median of the mean daily fluid input ranged from 1middot48 L (IQR 1middot12 to 2middot09) to 4middot23 L (3middot78 to 4middot94) across centres. The median of the mean daily fluid balance ranged from -0middot85 L (IQR -1middot51 to -0middot49) to 1middot13 L (0middot99 to 1middot37) across centres. In patient-level analyses, a mean positive daily fluid balance was associated with higher ICU mortality (odds ratio [OR] 1middot10 [95% CI 1middot07 to 1middot12] per 0middot1 L increase) and worse functional outcome (1middot04 [1middot02 to 1middot05] per 0middot1 L increase); higher mean daily fluid input was also associated with higher ICU mortality (1middot05 [1middot03 to 1middot06] per 0middot1 L increase) and worse functional outcome (1middot04 [1middot03 to 1middot04] per 1-point decrease of the GOSE per 0middot1 L increase). Centre-level analyses showed similar associations of higher fluid balance with ICU mortality (OR 1middot17 [95% CI 1middot05 to 1middot29]) and worse functional outcome (1middot07 [1middot02 to 1middot13]), but higher fluid input was not associated with ICU mortality (OR 0middot95 [0middot90 to 1middot00]) or worse functional outcome (1middot01 [0middot98 to 1middot03]).Interpretation In critically ill patients with traumatic brain injury, there is significant variability in fluid management, with more positive fluid balances being associated with worse outcomes. These results, when added to previous evidence, suggest that aiming for neutral fluid balances, indicating a state of normovolaemia, contributes to improved outcome. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Gemcitabine and nab-paclitaxel (Abraxane®) is a standard of care chemotherapy combination used in the treatment of patients with advanced pancreatic cancer. While the combination has shown a survival benefit when compared to gemcitabine monotherapy, it is associated with significant off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the site-specific deposition of drug-payloads. However, loading a single microbubble formulation with two drug payloads can be challenging and often involves several manipulations post-microbubble preparation that can be cumbersome and generally results in low / inconsistent drug loadings. In this manuscript, we report the one-pot synthesis of a gemcitabine functionalised phospholipid and use it to successfully generate stable microbubble formulations loaded with gemcitabine (Lipid-Gem MB) or a combination of gemcitabine and paclitaxel (Lipid-Gem-PTX MB). Efficacy of the Lipid-Gem MB and Lipid-Gem-PTX MB formulations, following ultrasound (US) stimulation, was evaluated in a three-dimensional (3D) PANC-1 spheroid model of pancreatic cancer and a mouse model bearing ectopic BxPC-3 tumours. The results demonstrated a significant reduction in the cell viability in spheroids for both formulations reducing from 90 ± 10% to 62 ± 5% for Lipid-Gem MB and 84 ± 10% to 30 ± 6% Lipid-Gem-PTX MB following US irradiation. When compared with a clinically relevant dose of free gemcitabine and paclitaxel (i.e. non-particle bound) in a BxPC-3 murine pancreatic tumour model, both formulations also improved tumour growth delay with tumours 40 ± 20% and 40 ± 30% smaller than the respective free drug formulation when treated with Lipid-Gem MB and Lipid-Gem-PTX MB respectively, at the conclusion of the experiment. These results highlight the potential of UTMD mediated Gem / PTX as a treatment for pancreatic cancer and the facile preparation of Lipid-Gem-PTX MBs using a gemcitabine functionalised lipid should expedite clinical translation of this technology.

In this article, we analyse the legal components of disclosing confidential patient information under the UK’s common law duty of confidentiality (CLDoC) and processing personal (health) data under the UK’s General Data Protection Regulation (GDPR) and Data Protection Act 2018. We describe the ostensible divide between the CLDoC and data protection law when it comes to the requirements of a valid signal of consent by a patient to use and disclose patient information, obtained by a health professional in the context of direct care, for health care and health research purposes. Ultimately, our analysis suggests that we are saddled, at least in the medium term, with two regimes operating with different standards of a valid consent—while putatively protecting similar interests. There is, however, opportunity for progress. It is possible to improve professional guidance on the interaction between the regimes and to achieve significant normative alignment without aligning the signalling standard for consent; this would promote consistent protection of reasonable expectations of patients across both regimes. Further coherence would require aligning not only the standard, but also the role played by consent under each regime. Here we argue that, in relation to direct care, any such shift should be away from consent as the normal justification. In relation to health research, on the contrary, it should be toward consent as the normal justification for use and disclosure of patient information under both the CLDoC and data protection law.

The present study involved performing an experiment to clarify whether vibration measurement values on the tool handle, in accordance with ISO 5349-1, can assess risk from workplace environments. The study investigated the relationship between the vibration magnitude of a hand-held electric drill with different operating postures. The experiment included the determination of the participant’s temporary threshold shift (TTS) of vibrotactile perception threshold (VPT) at the tip of the index finger. The experimental hypothesis was that the vibration measurement values on the tool handle, in accordance with the ISO 5349-1 standard, include the effect of posture on the vibration measurements obtained despite the variation in posture and test participants. The hand-transmitted vibration (HTV) was applied using a hand-held electric drill applied to a pre-cast concrete paving slab substrate (600 × 600 × 50 mm, 55 MPa) using a 10 mm diameter masonry drill bit (without hammer action). The tool was operated using the right hand on twelve male subjects with three working postures (n = 36). Vibration was measured in three orthogonal directions according to the international standard ISO 5349-1 procedure. Vibration magnitudes were expressed as root-mean-square (r.m.s.) acceleration, frequency-weighted using the Wh frequency weighting. Clause 4.3 states that the characterisation of the vibration exposure is assessed from the acceleration of the surface in contact with the hand as the primary quantity. The experimental results indicate that the TTS following vibration exposure is not related to the measured vibration magnitude on the tool handle. Therefore, the automatic inclusion of posture and test participant variation is not proven. The results suggest that the vibration measurement values on the tool handle do not predict the TTS after hand-transmitted vibration in varying posture across the test participants. The research concludes that tool handle vibration measurement, in accordance with ISO 5349-1, does not properly assess the potential hazard from authentic workplace tool usage conditions of varying postures.

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.Author summaryAround a billion people are infected by the soil transmitted helminths Ascaris, hookworm and whipworm. In the case of whipworm, the benzimidazole drugs, which are distributed to school children in affected areas, have low cure rates. This means that finding an improved treatment for whipworm is a priority. We previously identified five DHB compounds in a screen for new compounds active against whipworm. Here we systematically dissect these molecules, making 47 modified versions of the compounds. This allowed us to define the features of these compounds that are important for activity against whipworm. We also demonstrate activity of DHB compounds against other parasitic nematodes, and against Schistosoma mansoni, a trematode parasite. These results show the potential for further development of DHB compounds as broad-spectrum anthelmintics.

Objective Nodding syndrome is a poorly understood epileptic encephalopathy characterized by a unique seizure type—head nodding—and associated with Onchocerca volvulus infection. We hypothesized that altered immune activation in the cerebrospinal fluid (CSF) and plasma of children with nodding syndrome may yield insights into the pathophysiology and progression of this seizure disorder. Method We conducted a case‐control study of 154 children (8 years or older) with long‐standing nodding syndrome and 154 healthy age‐matched community controls in 3 districts of northern Uganda affected by nodding syndrome. Control CSF samples were obtained from Ugandan children in remission from hematological malignancy during routine follow‐up. Markers of immune activation and inflammation (cytokines and chemokines) and complement activation (C5a) were measured in plasma and CSF using ELISA or Multiplex Luminex assays. O volvulus infection was assessed by serology for anti–OV‐16 IgG levels. Results The mean (SD) age of the population was 15.1 (SD: 1.9) years, and the mean duration of nodding syndrome from diagnosis to enrollment was 8.3 (SD: 2.7) years. The majority with nodding syndrome had been exposed to O volvulus (147/154 (95.4%)) compared with community children (86/154 (55.8%)), with an OR of 17.04 (95% CI: 7.33, 45.58), P < .001. C5a was elevated in CSF of children with nodding syndrome compared to controls (P < .0001). The levels of other CSF markers tested were comparable between cases and controls after adjusting for multiple comparisons. Children with nodding syndrome had lower plasma levels of IL‐10, APRIL, CCL5 (RANTES), CCL2, CXCL13, and MMP‐9 compared with community controls (P < .05 for all; multiple comparisons). Plasma CRP was elevated in children with nodding syndrome compared to community children and correlated with disease severity. Significance Nodding syndrome is associated with exposure to O. volvulus. Compared to controls, children with long‐standing symptoms of nodding syndrome show evidence of complement activation in CSF and altered immune activation in plasma.

Autism spectrum disorder is associated with sensory processing alterations, such as sensory hyper- and hypo-responsiveness. Twin studies are scarce in this field, but they are necessary in order to disentangle the genetic and environmental contributions to this association. Furthermore, it is unclear how different neurodevelopmental/psychiatric conditions contribute to altering sensory processing. We investigated the association between autistic traits/autism spectrum disorder diagnosis and sensory processing alterations in twins ( N = 269), using the adult/adolescent sensory profile, which differentiates four sub-domains: Low Registration, Sensation Seeking, Sensory Sensitivity, and Sensation Avoiding. While the associations between autistic traits and Low Registration and Sensation Avoiding persisted within monozygotic (genetically identical) twins, Sensory Sensitivity was only associated with autistic traits within dizygotic twins. In multivariate analyses with different neurodevelopmental/psychiatric diagnoses as predictor variables, autism spectrum disorder and attention deficit hyperactivity disorder were the strongest predictors for two adult/adolescent sensory profile sub-domains each. The results suggest that the association between autistic traits and Sensory Sensitivity is influenced by genetics while non-shared environmental factors influence the associations between autistic traits and Low Registration and Sensation Avoiding. They further indicate that altered sensory processing is not specific to autism spectrum disorder, while autism spectrum disorder is a strong predictor of certain sensory processing alterations, even when controlling for other (comorbid) neurodevelopmental/psychiatric conditions. Lay abstract Individuals diagnosed with autism often describe that they process sensory information differently from others, and many experience sensory issues as problematic. For instance, an increased sensitivity to smells or sounds can make participating in social settings challenging. While sensory issues are now part of the diagnostic criteria for autism, they also co-occur with other psychiatric diagnoses such as attention deficit hyperactivity disorder and anxiety disorders. It is unclear to what extent the relationship between autism and alterations in sensory processing are due to genetics or environment. In addition, more research is needed on how autism, as compared to other diagnoses, is associated with sensory issues. Using a twin study, we found that genetic factors influenced self-reported reactivity to sensory stimuli in autism while environmental factors influenced other sensory issues (e.g. difficulties in detecting or differentiating sensory input). Hence, sensory hyper-reactivity might be an early onset core feature of autism, while other domains of alterations in sensory processing might develop later, influenced by the environment. Moreover, autism was more strongly associated with sensory issues related to increased sensitivity/reactivity as compared to other psychiatric diagnoses. However, attention deficit hyperactivity disorder was more strongly related to deficits in detecting/differentiating sensory stimuli and with an increased drive to seek sensory input. Our results indicate that sensory issues are not specific to autism, but that some aspects of altered sensory processing are more relevant for autism than for other diagnoses.

Background Previous research from our center has shown that 27% of the pediatric trauma transfers from referring facilities are potentially preventable. Our hospital is the only level 1 pediatric trauma center (PTC) in our state, and we are developing a pediatric trauma telehealth network to help keep certain injured children closer to home. We instituted a pediatric trauma telehealth program with a partnering community-based hospital in our state and aim to report our experience over the first year. Methods All pediatric trauma patients that presented to our partnering hospital from January 2019 to February 2020 were reviewed. Disposition was: a) telehealth consultation, b) admission to the children's unit without a telehealth consultation per our head trauma protocol, or c) transfer without telehealth consultation. Data on demographics, hospital course, and disposition were collected via chart review. Results Eight patients underwent telehealth consults and another 8 patients were admitted to the partnering hospital's children's unit based on the head trauma protocol without a telehealth consult. Patient's ages ranged from 7 months to 15 years. Of the patients that underwent telehealth consult, 7 presented with a head injury and 1 presented with a rib fracture/small pneumothorax. The patient with a pneumothorax was observed for 6 h and discharged home after a repeat chest x-ray was stable. All 15 patients with head injuries were observed and discharged from either the emergency department or children's unit after passing concussion testing. No patients required transfer to our PTC after observation, and none were readmitted. Fifty-six patients were transferred without telehealth consultation, and 3 of these patients could potentially have avoided transfer with a telehealth consultation. Conclusions Telehealth in pediatric trauma can be a safe mechanism for preventing the transfer of patients that can be safely observed at a partnering hospital. From a facility that transfers an average of 30 trauma patients per year to our hospital, this program prevented 16 such transfers. Development of a head trauma protocol in collaboration with a pediatric neurosurgeon leads to an unexpected number of patients being admitted to the partnering hospital for observation without utilization of a telehealth consultation. Type of study Retrospective study. Level of evidence III

Immune cell infiltration has been identified as a prognostic biomarker in several cancers. However, no immune based biomarker has yet been validated for use in pancreatic ductal adenocarcinoma (PDAC). We undertook a systematic review and meta‐analysis of immune cell infiltration, measured by immunohistochemistry (IHC), as a prognostic biomarker in PDAC. All other IHC prognostic biomarkers in PDAC were also summarised. MEDLINE, EMBASE and Web of Science were searched between 1998 and 2018. Studies investigating IHC biomarkers and prognosis in PDAC were included. REMARK score and Newcastle–Ottawa scale were used for qualitative analysis. Random‐effects meta‐analyses were used to pool results, where possible. Twenty‐six articles studied immune cell infiltration IHC biomarkers and PDAC prognosis. Meta‐analysis found high infiltration with CD4 (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.51–0.83.) and CD8 (HR = 0.68, 95% CI = 0.55–0.84.) T‐lymphocytes associated with better disease‐free survival. Reduced overall survival was associated with high CD163 (HR = 1.62, 95% CI = 1.03–2.56). Infiltration of CD3, CD20, FoxP3 and CD68 cells, and PD‐L1 expression was not prognostic. In total, 708 prognostic biomarkers were identified in 1101 studies. In summary, high CD4 and CD8 infiltration are associated with better disease‐free survival in PDAC. Increased CD163 is adversely prognostic. Despite the publication of 708 IHC prognostic biomarkers in PDAC, none has been validated for clinical use. Further research should focus on reproducibility of prognostic biomarkers in PDAC in order to achieve this.

The AATCC TM22-2014 spray test (similarly BS EN ISO 4920:2012) is widely used to determine the water repellency of textiles. Given the ongoing move towards non-fluorinated chemistries to provide water repellent finishes on textiles, modifications to the spray test are suggested to discriminate between those which initially demonstrate similar repellency and aid in assessment of performance within laboratory textile testing. An extended shower duration of 60 minutes or 120 minutes is recommended, with additional calculations to objectively quantify surface wetting. This increased test period demonstrated differences in performance between repellent finishes with a 1.37 g mass difference between fluorinated and non-fluorinated chemistries after 120 minutes. Further quantification of repellent performance, as set out in this study, would determine the performance of non-fluorinated durable water repellent (DWR) chemistries and suitability for end use.

Introduction Enhanced recovery protocols include multimodal perioperative pain control and frequently include use of NSAIDs. There is conflicting evidence that ketorolac use in inflammatory bowel disease (IBD) may precipitate disease flares and postoperative complications. The outcomes of children who receive ketorolac in this setting are not well known. We sought to evaluate ketorolac utilization in children following colectomy for ulcerative colitis. Methods All patients undergoing colectomy for ulcerative colitis between 2007 and 2017 at a tertiary children's hospital were reviewed. We collected patient age, duration of symptoms, operative details, medication utilization, length of stay, and postoperative complications. We performed a cohort comparison of these variables across patients who did vs. did not receive postoperative ketorolac. Results Sixty children were identified with median age at diagnosis of 12.6 years (IQR: 9.9–14.5). At colectomy, patients had a median PUCAI score of 60 (45–70), ESR 34 mm/h (15–50), hemoglobin 10.9 g/dL (9.3–12.9), and albumin 3.1 g/dL (2.4–3.8). Postoperatively, 45% (n = 27) received ketorolac. Patients in both cohorts had a similar length of stay, duration of opioid exposure, total morphine equivalents utilized, readmission rate, and unexpected return to the operating room. There were no documented cases of postoperative bleeding, acute kidney injury, or disease related flares among children receiving ketorolac. Conclusions Administration of ketorolac after colectomy in IBD was not associated with an increase in any postoperative complications, though the study was underpowered to detect these differences. However, ketorolac administration did not lead to a decreased utilization of opioid analgesia. Further prospective research is necessary to understand whether ketorolac in this population is safe and offers benefit. Type of study Retrospective study. Level of evidence III

Contains fulltext : 229365.pdf (Publisher’s version ) (Open Access) Associations between adult attention-deficit/hyperactivity disorder (ADHD) symptoms and dietary habits have not been well established and the underlying mechanisms remain unclear. We explored these associations using a Swedish population-based twin study with 17,999 individuals aged 20-47 years. We estimated correlations between inattention and hyperactivity/impulsivity with dietary habits and fitted twin models to determine the genetic and environmental contributions. Dietary habits were defined as (a) consumption of food groups, (b) consumption of food items rich in particular macronutrients, and (c) healthy and unhealthy dietary patterns. At the phenotypic level, inattention was positively correlated with seafood, high-fat, high-sugar, high-protein food consumptions, and unhealthy dietary pattern, with correlation coefficients ranging from 0.03 (95%CI: 0.01, 0.05) to 0.13 (95% CI: 0.11, 0.15). Inattention was negatively correlated with fruits, vegetables consumptions and healthy dietary pattern, with correlation coefficients ranging from -0.06 (95%CI: -0.08, -0.04) to -0.07 (95%CI: -0.09, -0.05). Hyperactivity/impulsivity and dietary habits showed similar but weaker patterns compared to inattention. All associations remained stable across age, sex and socioeconomic status. Nonshared environmental effects contributed substantially to the correlations of inattention (56-60%) and hyperactivity/impulsivity (63-80%) with dietary habits. The highest and lowest genetic correlations were between inattention and high-sugar food (r(A) = .16, 95% CI: 0.07, 0.25), and between hyperactivity/impulsivity and unhealthy dietary pattern (r(A) = .05, 95% CI: -0.05, 0.14), respectively. We found phenotypic and etiological overlap between ADHD and dietary habits, although these associations were weak. Our findings contribute to a better understanding of common etiological pathways between ADHD symptoms and various dietary habits.

BackgroundAlthough rehabilitation is beneficial for individuals with traumatic brain injury (TBI), a significant proportion of them do not receive adequate rehabilitation after acute care.ObjectiveTherefore, the goal of this prospective and multicenter study was to investigate predictors of access to rehabilitation in the year following injury in patients with TBI.MethodsData from a large European study (CENTER-TBI), including TBIs of all severities between December 2014 and December 2017 were used (N = 4498 patients). Participants were dichotomized into those who had and those who did not have access to rehabilitation in the year following TBI. Potential predictors included sociodemographic factors, psychoactive substance use, preinjury medical history, injury-related factors, and factors related to medical care, complications, and discharge.ResultsIn the year following traumatic injury, 31.4% of patients received rehabilitation services. Access to rehabilitation was positively and significantly predicted by female sex (odds ratio [OR] = 1.50), increased number of years of education completed (OR = 1.05), living in Northern (OR = 1.62; reference: Western Europe) or Southern Europe (OR = 1.74), lower prehospital Glasgow Coma Scale score (OR = 1.03), higher Injury Severity Score (OR = 1.01), intracranial (OR = 1.33) and extracranial (OR = 1.99) surgery, and extracranial complication (OR = 1.75). On contrast, significant negative predictors were lack of preinjury employment (OR = 0.80), living in Central and Eastern Europe (OR = 0.42), and admission to hospital ward (OR = 0.47; reference: admission to intensive care unit) or direct discharge from emergency room (OR = 0.24).ConclusionsBased on these findings, there is an urgent need to implement national and international guidelines and strategies for access to rehabilitation after TBI.

Background:. Acute thrombosis of the superior mesenteric vein (SMV) is a rare but potentially catastrophic condition. Clinically separate from portal venous thrombosis due to a higher proportion of associated thrombophilic disorders and intestinal infarction, SMV thrombosis warrants a distinct approach to management. The aim of this review is to report the evidence for current practice. Methods:. A systematic review was carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four clinical trials databases and 4 trial registries were searched. This search was not limited by language or study type, but was limited to an adult population (18 years and above). The search period was between January 1, 2000 and February 28, 2019. The review was registered in the PROSPERO database: CRD42018116825. Bias was assessed using the ROBINS-I tool. Results:. A total of 7989 studies were identified, resulting in 19 observational studies being analyzed. Eighteen studies reported on anti-coagulation, 1 reported on anti-coagulation plus endovascular thrombectomy, 9 reported on thrombolysis, and 10 reported on the role of surgery. Bias assessment showed that confounding was a significant area of potential bias. This review has reported that the management of SMV thrombosis is centered around a patients’ perceived hemodynamic stability. If there is evidence of perforation or peritonism then surgical intervention is advocated. Otherwise, anti-coagulation or thrombolysis is preferred. Conclusions:. The data reported were compared with, and added to, that presented by the European Society for Vascular Surgery 2017 guidelines. Overall the source data were heterogenous, with multiple sources of bias and statistical comparison was not achievable.

Background The United States Environmental Protection Agency (EPA) recently lowered residential floor and windowsill dust lead hazard standards, but maintained previous post-abatement clearance standards. We examined whether the discrepancy in these regulations places children at higher risk of lead poisoning. Methods In 250 children from Cincinnati, Ohio (2004-2008) living in homes built before 1978, we measured residential floor and windowsill dust lead loadings and blood lead concentrations at ages 1 and 2 years. Using linear regression with generalized estimating equations, we estimated covariate-adjusted associations of dust lead levels with blood lead concentrations and risk of lead poisoning. Results An increase in floor dust lead from 10 (revised dust lead hazard standard) to 40 μg/ft2 (post-abatement clearance standard) was associated with 26% higher (95% confidence interval (CI):15, 38) blood lead concentrations and 2.1 times the risk of blood lead concentrations ≥5 μg/dL (95% CI: 1.44, 3.06). Extrapolating our findings to US children age 1-5 years, we estimated that 6.9% (95% CI: 1.5, 17.2) of cases of blood lead concentrations ≥5 μg/dL are attributable to floor dust lead loadings between 10 and ≤40 μg/ft2. Conclusions The EPA's residential dust lead regulations place children at increased risk of lead poisoning. We recommend adopting more protective dust lead standards. Impact We determined whether children are at increased risk of lead poisoning with the 2019 EPA residential post-abatement lead clearance standards being higher than dust lead hazard standards.In this observational study, 2019 EPA dust lead clearance standards were associated with increased risk of lead poisoning compared to the revised dust lead hazard standard. Both EPA standards were associated with increased risk of lead poisoning compared to more stringent standards employed in our study.Extrapolating our findings to US children, the 2019 EPA dust lead clearance standards could place up to 36,700 children at risk of lead poisoning.

Introduction Sebaceous hyperplasia (SH) is a common skin presentation in adults. Due to their unwanted yellow papular appearance, patients may desire their removal. Although several treatment modalities have been reported, the full range and efficacy of options are unclear. Objective To determine the efficacy of laser modalities in the treatment of SH. The authors will also specifically assess the efficacy, recurrence rate and side effect profile of SH treatment with Er:YAG wavelength using a variable long pulsed (VLP) Er:YAG laser (SP Dynamis Fotona laser, Ljubljana, Slovenia) Methods a Materials: A comprehensive literature search was performed through PubMed, EMBASE, and Web of Science, using the search terms [(sebaceous hyperplasia)] and [(laser[s], Er:Yag, Er:Glass, Fraxel, CO2, PDL, Pulse dye laser, Diode, Xe-Cl, Excimer, Argon, KTP, Ruby, Alexandrite or Nd:YAG)]. The search yielded a total of 119 results and 8 were identified as relevant to this reviewResults: Pulse dye laser (PDL) provides a wide range of treatment results from complete reduction to flattening of the SH without significant adverse events; recurrence rates were unreported. Short PDL showed faster treatment response than long PDL. CO2 laser can produce considerable positive cosmetic outcomes with marked clinical improvement without any recurrence, but significant adverse effects have been reported. The 1450-nm diode laser has been described to produce good (75%) clinical improvement and lesion shrinkage ranging from 50% to greater than 75% without lasting adverse effects. In our clinic, Er:YAG has provided very significant cosmetic outcomes with a low recurrence rate and minimal adverse effects. Conclusions Laser modalities can provide satisfactory results for removing SH. It is crucial that the laser is being used by an expert who is familiar with the device as well as understand the laser tissue interaction to minimize patient adverse effects while providing the best cosmetic outcome. In our experience, Er:YAG laser can provide a safe and highly effective solution for SH. J Drugs Dermatol. 2020;19(5) n doi:10.36849/JDD.2020.3971.

Introduction: Neurocognitive problems associated with posttraumatic stress disorder (PTSD) can interact with impairment resulting from traumatic brain injury (TBI). Research question: We aimed to identify neurocognitive problems associated with probable PTSD following TBI in a civilian sample. Material and methods: The study is part of the CENTER-TBI project (Collaborative European Neurotrauma Effectiveness Research) that aims to better characterize TBI. For this cross-sectional study, we included patients of all severities aged over 15, and a Glasgow Outcome Score Extended (GOSE) above 3. Participants were assessed at six months post-injury on the PTSD Checklist-5 (PCL-5), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test (RAVLT) and the Cambridge Neuropsychological Test Automated Battery (CANTAB). Primary analysis was a complete case analysis. Regression analyses were performed to investigate the association between the PCL-5 and cognition. Results: Of the 1134 participants included in the complete case analysis, 13.5% screened positive for PTSD. Probable PTSD was significantly associated with higher TMT-(B-A) (OR ​= ​1.35, 95% CI: 1.14–1.60, p ​< ​.001) and lower RAVLT-delayed recall scores (OR ​= ​0.74, 95% CI: 0.61–0.91, p ​= ​.004) after controlling for age, sex, psychiatric history, baseline Glasgow Coma Scale and education. Discussion and conclusion: Poorer performance on cognitive tests assessing task switching and, to a lesser extent, delayed verbal recall is associated with probable PTSD in civilians who have suffered TBI.

Despite improved outcomes at pediatric trauma centers (PTC), 90% of injured children are not treated at PTCs. Telemedicine may play a role in ensuring patients are transferred to the appropriate level of care. We aimed to determine the level of interest in trauma telemedicine with our PTC among referring facilities. A survey was conducted with the trauma program directors of 45 hospitals in Utah, which consisted of four multiple choice questions designed to determine interest in pediatric trauma telemedicine support, projected frequency of use, anticipated uses of telemedicine, and perceived barriers to implementation. Forty-one directors (91%) responded. 88% of directors were interested in developing a pediatric trauma telemedicine network. 20% estimated their center would use telemedicine more than once a week, 17% once a week, 24% once a month, and 37% a few times a year. The most frequently cited uses of a telemedicine program were triage/transfer decisions and provider support. Inadequate volume and insufficient funding were the most common perceived barriers. These data show there is a strong interest amongst hospitals in our state in pediatric trauma telemedicine. Inadequate volume to warrant a program and insufficient facility funding remain concerns for development of a program.

Aims: There has been a paradigm shift in diagnosis of cardiac transthyretin amyloidosis (ATTR) with non-invasive techniques including technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphy. We evaluated structural and functional biventricular alterations by transthoracic echocardiography (TTE) and determined the correlation with 99mTc-DPD tracer uptake in ATTR.Materials and Methods: ATTR patients (wild-type, hereditary or asymptomatic transthyretin [TTR] variant carriers) with 99mTc-DPD and TTE were selected; 99mTc-DPD uptake was analyzed quantitatively. TTE assessment of left ventricle (LV) and right ventricle (RV) parameters was performed.Results: Forty ATTR patients (wild-type n = 17; hereditary ATTR and TTR variant carriers n = 23; median age 68.8 ± 22 years) were included. TTE parameters displaying good correlation with 99mTc-DPD tracer uptake included LV average wall thickness (r = 0.837), LV indexed mass (LVMI; r = 0.802), RV wall thickness (r = 0.610), average e' (r = −0.830), E/e' ratio (r = 0.786), LV global longitudinal strain (GLS; r = 0.714) and RV GLS (r = 0.632; p < 0.001 for all). Hereditary ATTR and TTR variant carriers without cardiac tracer uptake had normal echocardiographic parameters. Receiver operating characteristic curves demonstrated strong diagnostic accuracies for structural (LV wall thickness, LVMI and RV wall thickness; area under the curve (AUC) of 0.96 for all) and functional (LV and RV GLS; AUC of 0.86 and 0.88, respectively) parameters.Conclusion: Good correlations between TTE biventricular structural and functional parameters were demonstrated with quantitative 99mTc-DPD uptake. Echocardiography may potentially assume a significant role in longitudinal follow-up for monitoring disease progression and for evaluating treatment response.

Lymphedema is a life-long sequelae to several neglected tropical diseases (NTD). In Bangladesh the main cause is lymphatic filariasis (LF) and Ethiopia is endemic for both LF and podoconiosis. The World Health Organization (WHO) recommends daily self-care including meticulous washing and drying of affected skin and attention to entry lesions, limb exercises and elevation. Adherence to this regime reduces secondary infections which cause disabling episodes of acute dermato-lymphangitis (ADL). Self-care practices must be integrated into family life, supported by community and monitored by health staff; however, little is known about the influence of personal and socio-demographic factors on adherence. People affected by lymphedema (n=272), adult caregivers (n=272), and health workers (n=68) in Bangladesh and Ethiopia were trained in lymphedema management according to WHO recommendations. Surveys on the causes and management of lymphedema were collected at baseline and 24-weeks, and patients completed a daily journal of self-care activities and symptoms. At baseline knowledge on causes and management of lymphedema was greater among health workers (>70%) than patients and caregivers (

Background Current treatment options for onchocerciasis are sub-optimal, prompting research and development of a safe cure (macrofilaricide). Onchocerca ochengi, a parasite of cattle, is used as a close surrogate for the human parasite O. volvulus in a murine model for pre-clinical screening of macrofilaricides. Skin from naturally infected cattle have been used in previous studies as a reliable source of parasite material. However, there is limited knowledge on how source-related factors such as the microfilaridermia status of the cattle, the nodule load and nodular worm viability may affect survival of male O. ochengi worms implanted in the rodent hosts. Such relationships were investigated in this study. Methods Dermal tissue and nodules were obtained from Gudali cattle, dissected and cultured to obtain migrating microfilariae (mf) and male worms. Emerged male worms were implanted into SCID mice and Gerbils (Meriones unguiculatus) and recovery rates were determined upon 42 days post implantation. Finally, nodules were processed for histology and embryogram analyses to assess the nodular worm viability and fertility, respectively. Results Of the 69 cattle sampled, 24 (34.8%) were mf+ and 45 (65.2%) were mf–. The mean nodule loads were 180.5 ± 117.7 (mf+) and 110.6 ± 102.7 (mf-) (p = 0.0186). The mean male worm harvest from nodules were 76.8 ± 120.3 and 47.2 ± 33.4 (p = 0.2488) for mf+ and mf– cattle, respectively. The number of male worms per 100 nodules were 57/100 and 46/100 nodules for mf+ and mf– cows, respectively. Female worms from nodules of mf– cows had higher counts of both normal and abnormal embryos with higher proportions of dead nodular worms evinced by histology compared to those from mf+ cows. A total of 651 worms were implanted into mice and gerbils, out of which 129 (19.81%) were recovered. Logistic regression analysis indicated that the microfilaridermia status of the cattle (presence of mf) (OR = 4.3319; P = 0.001) is the single most important predictor of the success of male worm recovery after implantation into rodents. Conclusion Microfilaridermic cattle provide a promising source of adult O. ochengi. Male worms from this group of cattle have a better success rate of survival in a murine implant model. Nevertheless, in the programmatic point of view, amicrofilaridermic Gudali cattle would still constitute an important source of O. ochengi male worms with relatively good viability after implantation into rodents., Graphical abstract Image 1, Highlights • There is a need of developing safe macrofilaricide for human onchocerciasis using cattle Onchocerca ochengi. • Skin from naturally infected cattle have been used as a reliable parasite source for development of murine pre-clinical screening models. • The role of source-related factors on O. ochengi production and the success of pre-clinical screening models is assessed. • Worms from positive microfilaridermic cattle are successfully recovered after their implantation into rodents.

Although highly heritable, environment also contributes to the etiology of autism spectrum disorder (ASD), with several specific environmental factors previously suggested. A registry-linked population-based twin cohort of 15,701 pairs (586 individuals with an ASD diagnosis), was established within the Child and Adolescent Twin Study in Sweden. Participants were evaluated for autistic symptoms at age 9 using the Autism-Tics, ADHD and other Comorbidities parental interview. A series of binary cut-offs indicated whether participants scored over various ASD symptom percentiles. Three early medical factors previously associated with ASD, beyond familial confounding (low birth weight, congenital malformations and perinatal hypoxia), were summed up creating an individual cumulative exposure load. A series of unconditional logistic regressions between all individuals and conditional regressions within twin pairs were performed for each outcome and exposure level. Between all individuals increasing cumulative early exposure loads were associated with increasing risk of ASD diagnosis (OR 3.33 (95%CI 1.79–6.20) for three exposures) and autistic symptoms (ranging from OR 2.12 (1.57–2.86) for three exposures at the 55th symptom percentile cut-off to OR 3.39 (2.2–5.24) at the 95th). Within twin pairs, the association between three exposures and an ASD diagnosis remained similar, but not statistically significant (OR 2.39 (0.62–9.24)). Having a higher load of early cumulative exposure was consistently associated with autistic symptoms after adjusting for familial confounding and sex (OR 3.45 (1.66–7.15) to OR 7.36 (1.99–27.18)). This study gives support to the cumulative stress hypothesis of ASD, and the dimensional model regarding environmental exposures, after adjustment for familial confounding.

Background\ud \ud Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations.\ud Methods\ud \ud Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp) and genetic associations (rg), as well as the contribution of genetic influences to rp.\ud Results\ud \ud The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg = 0.73; 95% CI = 0.66–0.79). Moderate genetic correlations were estimated for anxiety disorders (rg = 0.47; 95% CI = 0.33–0.61), depression (rg = 0.52; 95% CI = 0.37–0.66), and intentional self-harm (rg = 0.54; 95% CI = 0.36–0.71).\ud Conclusions\ud \ud ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.

Acquired unilateral alacrima as a presenting sign of an intracranial tumor is exceptionally rare, and only described once previously in a case of nasopharyngeal carcinoma. The authors present a 32-year-old female patient who presents with a year-long history of alacrima and arhinorrhea. She was subsequently diagnosed with a petroclival chondrosarcoma extending into Meckel's cave and the cavernous sinus and underwent surgical debulking. To the authors' knowledge, this is the first reported case of acquired unilateral alacrima as a presenting feature of a skull base chondrosarcoma. This case serves to remind general ophthalmologists and oculoplastic surgeons alike that acquired alacrima may be the presenting feature of serious intracranial disease.

The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16−18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10–14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days., Graphical abstract Image 1, Highlights • CBR417 and CBR490 provide long-term effects in 2 chronic filaria jird models. • CBR417 and CBR490 deplete >99% Wolbachia in B. pahangi and L. sigmodontis filariae. • CBR417 and CBR490 clear L. sigmodontis microfilariae after 10–14 weeks. • CBR417 and CBR490 inhibit filarial embryogenesis in both models. • Suboptimal doses do not maintain reduction of microfilariae and Wolbachia.

BackgroundAccumulating evidence suggests that many psychiatric disorders etiologically represent the extreme end of dimensionally distributed features rather than distinct entities. The extent to which this applies to eating disorders (EDs) is unknown.MethodsWe investigated if there is similar etiology in (a) the continuous distribution of the Eating Disorder Inventory-2 (EDI-2), (b) the extremes of EDI-2 score, and (c) registered ED diagnoses, in 1481 female twin pairs at age 18 years (born 1992–1999). EDI-2 scores were self-reported at age 18. ED diagnoses were identified through the Swedish National Patient Register, parent-reported treatment and/or self-reported purging behavior of a frequency and duration consistent with DSM-IV criteria. We differentiated between anorexia nervosa (AN) and other EDs.ResultsThe heritability of the EDI-2 score was 0.65 (95% CI 0.61–0.68). The group heritabilities in DeFries–Fulker extremes analyses were consistent over different percentile-based extreme groups [0.59 (95% CI 0.37–0.81) to 0.65 (95% CI 0.55–0.75)]. Similarly, the heritabilities in liability threshold models were consistent over different levels of severity. In joint categorical-continuous models, the twin-based genetic correlation was 0.52 (95% CI 0.39–0.65) between EDI-2 score and diagnoses of other EDs, and 0.26 (95% CI 0.08–0.42) between EDI-2 score and diagnoses of AN. The non-shared environmental correlations were 0.52 (95% CI 0.32–0.70) and 0.60 (95% CI 0.38–0.79), respectively.ConclusionsOur findings suggest that some EDs can partly be conceptualized as the extreme manifestation of continuously distributed ED features. AN, however, might be more distinctly genetically demarcated from ED features in the general population than other EDs.

Background: The burden of traumatic brain injury (TBI) poses a large public health and societal problem, but the characteristics of patients and their care pathways in Europe are poorly understood. We aimed to characterise patient case-mix, care pathways, and outcomes of TBI. Methods: CENTER-TBI is a Europe-based, observational cohort study, consisting of a core study and a registry. Inclusion criteria for the core study were a clinical diagnosis of TBI, presentation fewer than 24 h after injury, and an indication for CT. Patients were differentiated by care pathway and assigned to the emergency room (ER) stratum (patients who were discharged from an emergency room), admission stratum (patients who were admitted to a hospital ward), or intensive care unit (ICU) stratum (patients who were admitted to the ICU). Neuroimages and biospecimens were stored in repositories and outcome was assessed at 6 months after injury. We used the IMPACT core model for estimating the expected mortality and proportion with unfavourable Glasgow Outcome Scale Extended (GOSE) outcomes in patients with moderate or severe TBI (Glasgow Coma Scale [GCS] score ≤12). The core study was registered with ClinicalTrials.gov, number NCT02210221, and with Resource Identification Portal (RRID: SCR_015582). Findings: Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study and from 22 782 patients in the registry. In the core study, 848 (19%) patients were in the ER stratum, 1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum. In the ICU stratum, 720 (36%) patients had mild TBI (GCS score 13–15). Compared with the core cohort, the registry had a higher proportion of patients in the ER (9839 [43%]) and admission (8571 [38%]) strata, with more than 95% of patients classified as having mild TBI. Patients in the core study were older than those in previous studies (median age 50 years [IQR 30–66], 1254 [28%] aged >65 years), 462 (11%) had serious comorbidities, 772 (18%) were taking anticoagulant or antiplatelet medication, and alcohol was contributory in 1054 (25%) TBIs. MRI and blood biomarker measurement enhanced characterisation of injury severity and type. Substantial inter-country differences existed in care pathways and practice. Incomplete recovery at 6 months (GOSE

Contrary to previous assumptions that most mutations are deleterious, there is increasing evidence for persistence of large-effect mutations in natural populations. A possible explanation for these observations is that mutant phenotypes and fitness may depend upon the specific environmental conditions to which a mutant is exposed. Here, we tested this hypothesis by growing large-effect flowering time mutants of Arabidopsis thaliana in multiple field sites and seasons to quantify their fitness effects in realistic natural conditions. By constructing environment-specific fitness landscapes based on flowering time and branching architecture, we observed that a subset of mutations increased fitness, but only in specific environments. These mutations increased fitness via different paths: through shifting flowering time, branching, or both. Branching was under stronger selection, but flowering time was more genetically variable, pointing to the importance of indirect selection on mutations through their pleiotropic effects on multiple phenotypes. Finally, mutations in hub genes with greater connectedness in their regulatory networks had greater effects on both phenotypes and fitness. Together, these findings indicate that large-effect mutations may persist in populations because they influence traits that are adaptive only under specific environmental conditions. Understanding their evolutionary dynamics therefore requires measuring their effects in multiple natural environments.

American Society of Breast Surgeons (ASBrS) guidelines state that it is the responsibility of the surgeon to discuss the risks/benefits of and give a recommendation regarding contralateral prophylactic mastectomy (CPM). We conducted a survey of ASBrS members to evaluate the factors that affect this recommendation, confidence in this recommendation, and awareness/adoption of the guidelines. A survey was sent to the ASBrS membership. Vignettes with the following variables about breast cancer patient were randomly included: age, disease stage, receptor status, family history (FH) of breast cancer, and patient preference for CPM. Respondents were asked to estimate the patient’s chance of developing contralateral cancer, whether they would recommend CPM, and their confidence in this recommendation, and about their familiarity with and use of the guidelines. 536 members (21.9%) responded. The odds of recommending CPM and confidence in recommendation were higher in a younger patient, higher-stage disease, triple-negative and human epidermal growth factor receptor (HER)2+ relative to estrogen receptor (ER)+, and in women with FH. Of surgeons, 51% were familiar or very familiar with the guidelines and 38% used the guidelines most or all of the time. Surgeons who used the guidelines were not less likely to recommend CPM. While surgeons generally agree on the factors that are important in making a recommendation on CPM, there is variability in how strongly the different factors influence the recommendation and their confidence in that recommendation. In addition, while most surgeons were at least a little familiar with the ASBrS guidelines, the vast majority do not routinely use them.

Mandrakes (Mandragora spp., Solanaceae) are known to contain tropane alkaloids and have been used since antiquity in traditional medicine. Tropane alkaloids such as scopolamine and hyoscyamine are used in modern medicine to treat pain, motion sickness, as eye pupil dilators and antidotes against organo-phosphate poisoning. Hyoscyamine is converted to 6β-hydroxyhyoscyamine (anisodamine) and scopolamine by hyoscyamine 6β-hydroxylase (H6H), a 2-oxoglutarate dependent dioxygenase. We describe here a marked chemo-diversity in the tropane alkaloid content in Mandragora spp. M. officinarum and M. turcomanica lack anisodamine and scopolamine but display up to 10 fold higher hyoscyamine levels as compared with M. autumnalis. Transcriptomic analyses revealed that H6H is highly conserved among scopolamine-producing Solanaceae. MoH6H present in M. officinarum differs in several amino acid residues including a homozygotic mutation in the substrate binding region of the protein and its prevalence among accessions was confirmed by Cleaved-Amplified-Polymorphic-Sequence analyses. Functional expression revealed that MaH6H, a gene isolated from M. autumnalis encodes an active H6H enzyme while the MoH6H sequence isolated from M. officinarum was functionally inactive. A single G to T mutation in nucleotide 663 of MoH6H is associated with the lack of anisodamine and scopolamine in M. officinalis.

The Anti- Wolbachia (A·WOL) consortium at the Liverpool School of Tropical Medicine (LSTM) has partnered with the Global High-Throughput Screening (HTS) Centre at AstraZeneca to create the first anthelmintic HTS for neglected tropical diseases (NTDs). The A·WOL consortium aims to identify novel macrofilaricidal drugs targeting the essential bacterial symbiont ( Wolbachia) of the filarial nematodes causing onchocerciasis and lymphatic filariasis. Working in collaboration, we have validated a robust high-throughput assay capable of identifying compounds that selectively kill Wolbachia over the host insect cell. We describe the development and validation process of this complex, phenotypic high-throughput assay and provide an overview of the primary outputs from screening the AstraZeneca library of 1.3 million compounds.

Alterations in social cognition are hypothesized to underlie social communication challenges in autism spectrum disorder. However, the etiologic underpinnings driving this association, as well as the impact of other psychiatric conditions on the association, remain unclear. Using a co-twin control design, we examined n = 308 twins (mean age = 16.63; 46% females) with autism spectrum disorder, attention-deficit/hyperactivity disorder, affective disorders, or typical development using the Reading the Mind in the Eyes Test to operationalize social cognition ability. Clinical diagnosis of autism spectrum disorder, as well as the extent of quantitative autistic traits, as measured by parental reports using the Social Responsiveness Scale-2, predicted fewer expected responses on the Reading the Mind in the Eyes Test across the pairs. The association remained when adjusting for other diagnoses and IQ. In addition, male sex, lower age, and lower IQ predicted poorer performance on the Reading the Mind in the Eyes Test. The associations between autism and social cognition ability were lost within pairs in both the full sample and the monozygotic subsample. We conclude that the association between autism and social cognition across the sample highlights the importance of social cognition alterations in autism spectrum disorder when compared with other conditions. The attenuation of the association in the within-pair models indicate familial confounding, such as genes and shared environment, influencing both autism and social cognition.

Objectives Measure the sound levels produced by various lasers commonly used during routine outpatient cosmetic surgery to determine whether or not their use exceeds exposure levels set forth by the US National Institute for Occupational Safety and Health (NIOSH) and the US Occupational Safety and Health Administration (OSHA). Materials and methods Using two different meters, the sound levels of lasers commonly used in cosmetic surgery were recorded during various procedures for several indications: tattoo removal, treatment of lentigines and pigmented lesions, facial erythema and vascular lesions, hair removal and resurfacing of acne scars, and photoaging. Results All but five lasers had a maximum sound level below 85 dBA, the limit proposed by NIOSH. The loudest laser examined was a fully ablative 2,940 nm Er:YAG during facial resurfacing, with an average maximum sound level of 101.5 decibels (dBA). Two other lasers used for resurfacing exceeded 85 dBA including a fractional ablative 1064 Nd:YAG with an average maximum of 97.8 and a different fully ablative 2,940 nm Er:YAG which had an average maximum of 96.3 nm. The two other lasers that exceeded 85 dBA were picosecond lasers used to treat black tattoos, including a 1,064 nm Nd:YAG with an average maximum of 93.7 dBA and a 755 nm alexandrite with an average maximum of 93.6 dBA. Conclusion Although some lasers in cosmetic surgery may be perceived as being quite loud, they remain safe. Even the loudest laser studied would have to be used for nearly 2 hours before exceeding the OSHA recommended exposure limit. Even physicians who spend a large amount of time using lasers in clinical practice should be reassured that these devices are not likely to produce noise-induced hearing loss (NIHL) hearing loss. Lasers Surg. Med. 51:491-494, 2019. © 2019 Wiley Periodicals, Inc.

Purpose: Interferon-α favors a Th1 shift in immunity, and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects, leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-α (HDI) showed promising efficacy, supporting this hypothesis. Patients and Methods: E3611 followed a 2-by-2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipilimumab doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression-free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. Results: For eligible and treated patients (N = 81) at a median follow-up time of 29.8 months, median PFS was 4.4 months [95% confidence interval (CI), 2.7–8.2] when ipilimumab was used alone and 7.5 months (95% CI, 5.1–11.0) when HDI was added. Median PFS was 3.8 months (95% CI, 2.6–7.5) with 3 mg/kg ipilimumab and 6.5 months (95% CI, 5.1–13.5) with 10 mg/kg. By study arm, median PFS was 8.0 months (95% CI, 2.8–20.2) in arm A, 6.2 months (95% CI, 2.7–25.7) in B, 5.7 months (95% CI, 1.5–11.1) in C, and 2.8 months (95% CI, 2.6–5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. Conclusions: Although PFS was increased, the differences resulting from adding interferon-α or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

Background: Broken Hill is home to Australia's oldest silver–zinc–lead mine. However, the precise source of childhood blood lead (PbB) exposures has been subject to considerable debate. Lead sources include natural soil Pb enrichment, legacy deposition, contemporary mining emissions, and Pb-based paint. Objective: To test whether contemporary mining emissions independently affect childhood PbB in Broken Hill. Methods: Children's (

Background Atrial flutter is the most common arrhythmia post cardiac transplantation. Observational studies in the non transplant population have shown prognostic benefit with catheter ablation, however there are no data in the heart transplant population. Objectives This study evaluated the experience of catheter ablation in atrial flutter post cardiac transplantation. Methods A retrospective review of experience of late onset atrial flutter at the Freeman Hospital, Newcastle-upon-Tyne, United Kingdom, between 1985 and January 2020. Results Sixty eight of the 722 patients who survived 6 months post cardiac transplantation developed late atrial flutter giving an incidence of 9.4%. Thirty two patients were managed with ablation with treatment largely determined by time of flutter onset. Kaplan Meier estimates for arrhythmia free survival post first ablation for organised atrial arrhythmias was 83.3% at 1 year. Kaplan-Meier estimates for median survival post onset of atrial arrhythmias treated with ablation was 11.34 years (95% CI 8.00-14.57), compared to 5.79 years in patients managed medically (95%CI 2.26-9.32) (p = 0.026). Conclusions Atrial flutter is an important late complication of cardiac transplantation. Patients treated with ablation in the modern era had increased survival compared to a historical cohort. This article is protected by copyright. All rights reserved.

The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) is the world's premier clinical outcomes registry for adult cardiac surgery and a driving force for quality improvement in cardiac surgery. Echocardiographic data provide a wealth of hemodynamic, structural, and functional data and have been part of STS ACSD data collection since its inception. An increasing body of evidence suggests that the use of echocardiography in patients undergoing cardiac surgery has a positive impact on postoperative outcomes. In this report, we describe and summarize the type and rate of reporting of echocardiography-related variables in the STS ACSD, including the Adult Cardiac Anesthesiology Module, from July 2017 to December 2019 for the most frequently performed cardiac surgical procedures. With this review, we aim to increase awareness of the importance of collecting accurate and consistent echocardiography data in the STS ACSD and to highlight opportunities for growth and improvement.

BACKGROUND The prevalence of diagnosed Autism Spectrum Disorder (ASD) has increased substantially across the world. Much - or even most - prevalence increase seems to reflect changes in diagnostic practice and ascertainment. A key part of ASD assessment is to document that the relevant symptoms are associated with clinical impairment. The aim of the present study is to capitalize on a nationwide longitudinal study spanning 15 consecutive birth year cohorts in order to investigate whether there has been a secular change in how parents perceive the impairment and suffering conferred by autism symptomatology in their children. METHODS Data came from the Child and Adolescent Twin Study in Sweden (27,240 individuals), where parents had reported on their child's ASD symptoms and impairment. Impairment due to ASD symptoms was regressed on an ASD symptom score across time. This was done for five 3-year birth cohorts (1995-1997, 1998-2000, 2001-2003, 2004-2006, and 2007-2009). RESULTS Reported impairment increased with consecutively later birth cohorts. This was evident across all levels of autism symptomatology. At clinically relevant levels of symptomatology, parents of those born 2007-2009 reported a 23% higher degree of impairment as compared with parents of those born in 1995-1997. The relative difference, however, was even greater at levels that previously would have been considered below the diagnostic threshold. DISCUSSION The results presented here contribute to the notion of a growing diffuseness in the conceptualization of the ASD diagnosis by adding the element of secular changes in the parental perception of the consequences of ASD symptom expression.

Lymphatic filariasis causes disfiguring and disabling lymphoedema, which is commonly and frequently exacerbated by acute dermatolymphangioadenitis (ADLA). Affected people require long-term care and monitoring but health workers lack objective assessment tools. We examine the use of an infrared thermal imaging camera as a novel non-invasive point-of-care tool for filarial lower-limb lymphoedema in 153 affected adults from a highly endemic area of Bangladesh. Temperature differences by lymphoedema stage (mild, moderate, severe) and ADLA history were visualised and quantified using descriptive statistics and regression models. Temperatures were found to increase by severity and captured subclinical differences between no lymphoedema and mild lymphoedema, and differences between moderate and severe stages. Toes and ankle temperatures detected significant differences between all stages other than between mild and moderate stages. Significantly higher temperatures, best captured by heel and calf measures, were found in participants with a history of ADLA, compared to participants who never had ADLA, regardless of the lymphoedema stage. This novel tool has great potential to be used by health workers to detect subclinical cases, predict progression of disease and ADLA status, and monitor pathological tissue changes and stage severity following enhanced care packages or other interventions in people affected by lymphoedema.

IntroductionPerfluoroalkyl and polyfluoroalkyl substances (PFAS) are a diverse group of compounds that have been used in hundreds of industrial applications and consumer products including aqueous film-forming foam (AFFF) for many years. Multiple national and international health and environmental agencies have accepted that PFAS exposures are associated with numerous adverse health effects. Australian firefighters have been shown to have elevated levels of PFAS in their blood, specifically perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS), due to the historical use of AFFF. While PFAS concentrations decline over time once the source of exposure has been removed, their potential adverse health effects are such that it would be prudent to develop an intervention to lower levels at a faster rate than occurs via natural elimination rates.Methods and analysisThis is a randomised controlled trial of current and former Australian firefighters in the Metropolitan Fire Brigade/Fire Rescue Victoria, and contractors, with previous occupational exposure to PFAS and baseline elevated PFOS levels. The study is investigating whether whole blood donation every 12 weeks or plasma donation every 6 weeks will significantly reduce PFAS levels, compared with a control group. We have used covariate-adaptive randomisation to balance participants’ sex and blood PFAS levels between the three groups and would consider a 25% reduction in serum PFOS and PFHxS levels to be potentially clinically significant after 12 months of whole blood or plasma donation. A secondary analysis of health biomarkers is being made of changes between screening and week 52 in all three groups.Ethics and disseminationThis trial has been approved by Macquarie University Human Research Ethics Committee (reference number: 3855), final protocol V.2 dated 12 June 2019. Study results will be disseminated via peer-reviewed publications and presentations at conferences.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12619000204145).

Introduction: Understanding the sport-specific immune response elicited during both training and competition is imperative to maximise athlete health and performance. Despite a growing population of professional enduro mountain bike athletes, little is known about the recovery of the immune system following enduro racing events. Methods: Nine international level elite enduro mountain bike athletes (age 24.3 ± 2.4 years, height 178.5 ± 8.7 cm, mass 76.5 ± 12.5 kg) completed a laboratory-based maximal exercise test (LAB) on a cycle ergometer and competed in an international mountain bike enduro race event (RACE). Blood samples were taken before, immediately after, and 1 h after LAB and before, 1 h after, and 17 h after RACE. Leukocyte subsets were enumerated using seven-colour flow cytometry. Lucia’s training impulse (LuTRIMP) and vibration exposure (VIB) were quantified during RACE. Results: Seven participants were included in the final analyses. There was a significant (p &lt, 0.05) increase in neutrophil count alongside a reduction of cytotoxic lymphocyte cell subsets of both the innate (CD3-/CD56+ NK-cells and CD3-/CD56dim NK-cells) and adaptive (CD8+/CD62L-/CD45RA- T-cells and CD8+/CD27+/CD28- T-cells) components of the immune system one hour after RACE. All cell counts returned to baseline values 17 h afterwards (p &gt, 0.05). Cell subset redistribution from pre- to post-one-hour time points (%Δpre-post1h) in cell subsets with potent effector functions (Neutrophils, CD3−/CD56+ NK-cells, CD8+/CD62L-/CD45RA- T-cells, CD8+/CD27+/CD28− T-cells, and CD3−/CD56dim/CD57− NK-cells) was significantly greater at RACE than LAB (p &lt, 0.05). VIB was shown to be a superior predictor of %Δpre-post1h CD4+ T-cells, CD4+ early T-cells, CD4+ naïve T-cells, and NK cells as compared with LuTRIMP on its own (ΔR2 = 0.63 − 0.89, p &lt, 0.05). Conclusions: The race event offers a greater challenge to the immune system than LAB, and potentially, whole body vibration is a key component of training load measurement in mountain bike applications.