Publications by authors named "J Peter Donnelly"

1,427 Publications

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Human arrival and landscape dynamics in the northern Bahamas.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Department of Oceanography, Texas A&M University, College Station, TX 77550.

The first Caribbean settlers were Amerindians from South America. Great Abaco and Grand Bahama, the final islands colonized in the northernmost Bahamas, were inhabited by the Lucayans when Europeans arrived. The timing of Lucayan arrival in the northern Bahamas has been uncertain because direct archaeological evidence is limited. We document Lucayan arrival on Great Abaco Island through a detailed record of vegetation, fire, and landscape dynamics based on proxy data from Blackwood Sinkhole. From about 3,000 to 1,000 y ago, forests dominated by hardwoods and palms were resilient to the effects of hurricanes and cooling sea surface temperatures. The arrival of Lucayans by about 830 CE (2σ range: 720 to 920 CE) is demarcated by increased burning and followed by landscape disturbance and a time-transgressive shift from hardwoods and palms to the modern pine forest. Considering that Lucayan settlements in the southern Bahamian archipelago are dated to about 750 CE (2σ range: 600 to 900 CE), these results demonstrate that Lucayans spread rapidly through the archipelago in less than 100 y. Although precontact landscapes would have been influenced by storms and climatic trends, the most pronounced changes follow more directly from landscape burning and ecosystem shifts after Lucayan arrival. The pine forests of Abaco declined substantially between 1500 and 1670 CE, a period of increased regional hurricane activity, coupled with fires on an already human-impacted landscape. Any future intensification of hurricane activity in the tropical North Atlantic Ocean threatens the sustainability of modern pine forests in the northern Bahamas.
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http://dx.doi.org/10.1073/pnas.2015764118DOI Listing
March 2021

Harnessing the polyamine transport system to treat BRAF inhibitor-resistant melanoma.

Cancer Biol Ther 2021 Feb 18:1-13. Epub 2021 Feb 18.

Lankenau Institute for Medical Research , Wynnewood, PA, USA.

BRAF mutations are present in over half of all melanoma tumors. Although BRAF inhibitors significantly improve survival of patients with metastatic melanoma, recurrences occur within several months. We previously reported that BRAF mutant melanoma cells are more sensitive to a novel arylmethyl-polyamine ( ) compound that exploits their increased polyamine uptake compared to that of BRAF wildtype cells. Using an animal model of BRAF inhibitor-resistant melanoma, we show that co-treatment with the BRAF inhibitor, PLX4720, and significantly delays the recurrence of PLX4720-resistant melanoma tumors and decreases tumor-promoting macrophages. Development of BRAF inhibitor-resistance enriches for metastatic cancer stem cells (CSC) and increases tumor-promoting macrophages. studies demonstrated that CD304, CXCR4 spheroid cultures of BRAF mutant melanoma cells are resistant to PLX4720 but are more sensitive to compared to monolayer cultures of the same cells. significantly inhibited YUMM1.7 melanoma cell invasiveness across a Matrigel-coated filter using the CXCR4 ligand, SDF-1α, as the chemoattractant. also blocked the chemotactic effect of SDF-1α on CXCR4 macrophages and inhibited M2 polarization of macrophages. In melanoma-macrophage co-cultures, prevented the PLX4720-induced release of pro-tumorigenic growth factors, such as VEGF, from macrophages and prevented the macrophage rescue of BRAF mutant melanoma cells treated with PLX4720. Our study offers a novel therapy ( ) to treat chemo-resistant melanoma. is unique because it targets the polyamine transport system in BRAF inhibitor-resistant CSCs and also blocks CXCR4 signaling in invasive melanoma cells and pro-tumorigenic macrophages.
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http://dx.doi.org/10.1080/15384047.2021.1883185DOI Listing
February 2021

Influence of the mode of heating on cerebral blood flow, non-invasive intracranial pressure and thermal tolerance in humans.

J Physiol 2021 Feb 14. Epub 2021 Feb 14.

University of Otago, 55/47 Union St. W, Dunedin, Otago, 9016, New Zealand.

Key Points: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognition, orthostatic tolerance, work capacity and eventually, brain death. The brain's limitation in the heat is often ascribed to inadequate cerebral blood flow (CBF), but elevated intracranial pressure is commonly observed in mammalian models of heat stroke and can on its own cause functional impairment. The CBF response to incremental heat strain was dependent on the mode of heating, decreasing by 30% when exposed passively to hot, humid air (sauna), while remaining unchanged or increasing with passive hot-water immersion (spa) and exercising in a hot environment. Non-invasive intracranial pressure estimates (nICP) were increased universally by 18% at volitional thermal tolerance across all modes of heat stress, and therefore may play a contributing role in eliciting thermal tolerance. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under mild to severe heating due to lower blood flow but similarly increased nICP.

Abstract: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognitive function, orthostatic tolerance, work capacity, and eventually, brain death. This vulnerability is often ascribed to inadequate cerebral blood flow (CBF); however, elevated intracranial pressure (ICP) is also observed in mammalian models of heat stroke. We investigated the changes in CBF with incremental heat strain under three fundamentally different modes of heating, and assessed whether heating per se increased ICP. Fourteen fit participants (seven female) were heated to thermal tolerance or 40°C core temperature (T ; oesophageal) via passive hot-water immersion (spa), passive hot, humid air exposure (sauna), cycling exercise, and cycling exercise with CO inhalation to prevent heat-induced hypocapnia. CBF was measured with duplex ultrasound at each 0.5°C increment in T and ICP was estimated non-invasively (nICP) from optic nerve sheath diameter at thermal tolerance. At thermal tolerance, CBF was decreased by 30% in the sauna (P < 0.001), but was unchanged in the spa or with exercise (P ≥ 0.140). CBF increased by 17% when end-tidal was clamped at eupnoeic pressure (P < 0.001). On the contrary, nICP increased universally by 18% with all modes of heating (P < 0.001). The maximum T was achieved with passive heating, and preventing hypocapnia during exercise did not improve exercise or thermal tolerance (P ≥ 0.146). Therefore, the regulation of CBF is dramatically different depending on the mode and dose of heating, whereas nICP responses are not. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under equivalent heat strain.
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http://dx.doi.org/10.1113/JP280970DOI Listing
February 2021

Common Cause and Common Purpose: Strategies to Increase Engagement in Faculty Development Activities.

Am J Med 2021 Feb 8. Epub 2021 Feb 8.

Chair of Medicine, University of California, Irvine, 101 The City Drive South, Building 26, Room 1000, Orange, CA 92868. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.01.002DOI Listing
February 2021

Negligible influence of moderate to severe hyperthermia on blood-brain barrier permeability and neuronal-parenchymal integrity in healthy men.

J Appl Physiol (1985) 2021 Jan 14. Epub 2021 Jan 14.

Department of Kinesiology, University of Windsor, Canada.

With growing use for hyperthermia as a cardiovascular therapeutic, there is surprisingly little information regarding the acute effects it may have on the integrity of the neurovascular unit (NVU). Indeed, relying on animal data would suggest hyperthermia comparable to levels attained in thermal therapy will disrupt the blood-brain barrier (BBB) and damage the cerebral parenchymal cells. We sought to address the hypothesis that controlled passive hyperthermia is not sufficient to damage the NVU in healthy humans. Young men (n=11) underwent acute passive heating until +2°C or absolute esophageal temperature of 39.5°C. The presence of BBB opening was determined by trans-cerebral exchange kinetics (radial-arterial and jugular venous cannulation) of S100B. Neuronal parenchymal damage was determined by the trans-cerebral exchange of tau protein, neuron specific enolase (NSE) and neurofilament-light protein (NF-L). Cerebral blood flow to calculate exchange kinetics was measured by duplex ultrasound of the right internal carotid and left vertebral artery. Passive heating was performed via warm-water perfused suit. In hyperthermia, there was no increase in the cerebral exchange of S100B (p=0.327), tau protein (p=0.626), NF-L (p=0.0.447) or NSE (p=0.908) suggesting +2°C core temperature is not sufficient to acutely stress the NVU in healthy men. However, there was a significant condition effect (p=0.028) of NSE, corresponding to a significant increase in arterial (p=0.023) but not venous (p=0.173) concentrations in hyperthermia, potentially indicating extra-cerebral release of NSE. Collectively, results from the present study support the notion that in young men there is little concern for NVU damage with acute hyperthermia of +2°C.
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http://dx.doi.org/10.1152/japplphysiol.00645.2020DOI Listing
January 2021

The impact of anti-mould prophylaxis on Aspergillus PCR blood testing for the diagnosis of invasive aspergillosis.

J Antimicrob Chemother 2021 Feb;76(3):635-638

Cardiff University School of Medicine, Cardiff, UK.

Background: The performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined.

Objectives: To determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA).

Methods: As part of the systematic review and meta-analysis of 22 cohort studies investigating Aspergillus PCR blood testing in 2912 patients at risk of IA, subgroup analysis was performed to determine the impact of AMP on the accuracy of Aspergillus PCR. The incidence of IA was calculated in patients receiving and not receiving AMP. The impact of two different positivity thresholds (requiring either a single PCR positive test result or ≥2 consecutive PCR positive test results) on accuracy was evaluated. Meta-analytical pooling of sensitivity and specificity was performed by logistic mixed-model regression.

Results: In total, 1661 (57%) patients received prophylaxis. The incidence of IA was 14.2%, significantly lower in the prophylaxis group (11%-12%) compared with the non-prophylaxis group (18%-19%) (P < 0.001). The use of AMP did not affect sensitivity, but significantly decreased specificity [single PCR positive result threshold: 26% reduction (P = 0.005); ≥2 consecutive PCR positive results threshold: 12% reduction (P = 0.019)].

Conclusions: Contrary to its influence on GM-EIA, AMP significantly decreases Aspergillus PCR specificity, without affecting sensitivity, possibly as a consequence of AMP limiting the clinical progression of IA and/or leading to false-negative GM-EIA results, preventing the classification of probable IA using the EORTC/MSGERC definitions.
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http://dx.doi.org/10.1093/jac/dkaa498DOI Listing
February 2021

Evaluating a Widely Implemented Proprietary Deterioration Index Model among Hospitalized COVID-19 Patients.

Ann Am Thorac Soc 2020 Dec 24. Epub 2020 Dec 24.

University of Michigan Medical School, 12266, Ann Arbor, Michigan, United States.

Rationale: The Epic Deterioration Index (EDI) is a proprietary prediction model implemented in over 100 U.S. hospitals that was widely used to support medical decision-making during the COVID-19 pandemic. The EDI has not been independently evaluated, and other proprietary models have been shown to be biased against vulnerable populations.

Objective: To independently evaluate the EDI in hospitalized COVID-19 patients overall and in disproportionately affected subgroups.

Methods: We studied adult patients admitted with COVID-19 to non-ICU care at a large academic medical center from March 9 through May 20, 2020. We used the EDI, calculated at 15-minute intervals, to predict a composite outcome of ICU-level care, mechanical ventilation, or in-hospital death. In a subset of patients hospitalized for at least 48 hours, we also evaluated the ability of the EDI to identify patients at low risk of experiencing this composite outcome during their remaining hospitalization.

Results: Among 392 COVID-19 hospitalizations meeting inclusion criteria, 103 (26%) met the composite outcome. Median age of the cohort was 64 (IQR 53-75) with 168 (43%) Black patients and 169 (43%) women. Area under the receiver-operating-characteristic curve (AUC) of the EDI was 0.79 (95% CI 0.74-0.84). EDI predictions did not differ by race or sex. When exploring clinically-relevant thresholds of the EDI, we found patients who met or exceeded an EDI of 68.8 made up 14% of the study cohort and had a 74% probability of experiencing the composite outcome during their hospitalization with a sensitivity of 39% and a median lead time of 24 hours from when this threshold was first exceeded. Among the 286 patients hospitalized for at least 48 hours who had not experienced the composite outcome, 14 (13%) never exceeded an EDI of 37.9, with a negative predictive value of 90% and a sensitivity above this threshold of 91%.

Conclusions: We found the EDI identifies small subsets of high- and low-risk COVID-19 patients with good discrimination although its clinical utility as an early warning system is limited by low sensitivity. These findings highlight the importance of independent evaluation of proprietary models before widespread operational use among COVID-19 patients.
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http://dx.doi.org/10.1513/AnnalsATS.202006-698OCDOI Listing
December 2020

Psychological Determinants of Physical Activity and Development in Early Childhood Among Children With Developmental Delays: The Role of Parent Beliefs Regarding the Benefits of Physical Activity.

Front Sports Act Living 2020 18;2:104. Epub 2020 Aug 18.

Department of Pediatrics, School of Medicine, University of California, Irvine, Irvine, CA, United States.

Among the various psychological determinants of physical activity (PA) in early childhood, relatively little attention has been paid to the role of parent beliefs in the benefits of PA for their child. Believing that PA is beneficial may impact parent behavior, resulting in more opportunities for PA in early childhood, particularly among children with neurodevelopmental disabilities (NDs) who may face more barriers to PA. Greater opportunity for PA may promote the development of motor skills and healthy body composition. This study examined the association between parental beliefs about PA and children's weight status in a sample of 147 children (32 ± 4 months old) with NDs. The proportion of parents with below average (mean - 1SD) perceptions of the benefits of PA whose children were overweight or obese was approximately was 2.5 times (proportion ratio, 2.35; 95% CI, 1.05-5.27) larger than it was for parents with above average (mean + 1SD) perceptions (after adjusting for the confounding effects of ethnicity, marital status, and mothers' self-reported depressive symptoms). Mothers' self-reported depressive symptoms was the only other covariate that was significantly associated with the weight status of these children, though, these data also signal possible ( = 0.07) differences in proportions between Hispanic/Latinx and White children in the sample who were classified as overweight and obese. Our study demonstrates the importance of considering parental or caregiver beliefs in the value of PA as another risk factor that may predict risk for overweight and obesity. Future studies should include parental beliefs in the benefits of PA as a potential psychological determinant of PA and associated health outcomes.
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http://dx.doi.org/10.3389/fspor.2020.00104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739724PMC
August 2020

Cu(III)-bis-thiolato complex forms an unusual mono-thiolato Cu(III)-peroxido adduct.

Chem Commun (Camb) 2021 Jan;57(1):69-72

School of Engineering, University of Warwick, Gibbet Hill Road, Coventry CV4 7Al, UK.

The stable complex [bis(toluene-3,4-dithiolato)copper(iii)][NEt3H] has been synthesised and characterised as a square-planar Cu(iii) complex by X-ray photoelectron spectroscopy, cyclic voltammetry and DFT calculations. Intriguingly, when fragmented in FTICR-MS, an unusual [(toluene-3,4-dithiolate)Cu(iii)(peroxide)]- complex is formed by reaction with oxygen. Natural 1,2-dithiolenes known to bind molybdenum might stabilise Cu(iii) in vivo.
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http://dx.doi.org/10.1039/d0cc06921cDOI Listing
January 2021

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study.

PLoS One 2020 14;15(12):e0243427. Epub 2020 Dec 14.

Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden.

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243427PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735618PMC
January 2021

Readmission and Death After Initial Hospital Discharge Among Patients With COVID-19 in a Large Multihospital System.

JAMA 2021 01;325(3):304-306

VA Center for Clinical Management Research, HSR&D Center of Innovation, Ann Arbor, Michigan.

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http://dx.doi.org/10.1001/jama.2020.21465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737131PMC
January 2021

Intermittent and continuous energy restriction result in similar weight loss, weight loss maintenance, and body composition changes in a 6 month randomized pilot study.

Clin Obes 2021 Apr 10;11(2):e12430. Epub 2020 Dec 10.

Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, Kansas, USA.

Poor adherence is a barrier to successful weight control. Intermittent energy restriction (IER) provides an alternative approach to those for whom daily energy restriction is not ideal. This study assessed changes in weight, body composition, and macronutrient intake for an IER and a continuous energy restriction (CONT) approach within a multicomponent weight management intervention. We randomized 35 adults with overweight/obesity (BMI = 31.2 ± 2.4 kg/m ) to CONT or IER for 24 weeks (12-week weight loss intervention and 12 weeks of weight loss maintenance). Diets were delivered within a multimodal weight management program including weekly group meetings with a registered dietitian, increased physical activity, and a comprehensive lifestyle change program. Retention and adherence were similar for CONT and IER. Weight, BMI, fat mass, percentage body fat, waist circumference, hip circumference, blood pressure, and heart rate all decreased after 24 weeks (all, P < .01), but there were no main effects of group (all, P > .27). Weight loss was clinically relevant in both CONT (11.38 ± 7.9%) and IER (9.37 ± 9.7%), and the proportion of each group achieving 5% weight loss was 82 and 61% (P = .16), respectively. Participant satisfaction was high in both groups. The results from this study (a) support the feasibility of IER as an alternative for weight loss and weight loss maintenance, (b) indicate that IER is an effective alternative to CONT for weight control and improvements in body composition, and (c) emphasize the importance of intensive lifestyle interventions with ongoing support for effective behaviour modification.
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http://dx.doi.org/10.1111/cob.12430DOI Listing
April 2021

Nanoliposomal Irinotecan and Metronomic Temozolomide for Patients With Recurrent Glioblastoma: BrUOG329, A Phase I Brown University Oncology Research Group Trial.

Am J Clin Oncol 2021 02;44(2):49-52

Brown University Oncology Research Group, Providence, RI.

Background: Liposomal formulations may improve the solubility and bioavailability of drugs potentially increasing their ability to cross the blood-brain barrier. We performed a phase I study to determine the maximum tolerated dose and preliminary efficacy of pegylated nanoliposomal irinotecan (nal-IRI)+metronomic temozolomide (TMZ) in patients with recurrent glioblastoma.

Patients And Methods: Patients with glioblastoma who progressed after at least 1 line of therapy were eligible. All patients received TMZ 50 mg/m2/d until disease progression. Three dose levels of nal-IRI were planned, 50, 70, and 80 mg/m2, intravenously every 2 weeks. Patients were accrued in a 3+3 design. The study included a preliminary assessment after the first 13 evaluable patients. The trial would be terminated early if 0 or 1 responses were observed in these patients.

Results: Twelve patients were treated over 2 dose levels (nal-IRI 50 and 70 mg/m2). At dose level 2, nal-IRI 70 mg/m2, 2 of 3 patients developed dose-limiting toxicities including 1 patient who developed grade 4 neutropenia and grade 3 diarrhea and anorexia and 1 patient with grade 3 diarrhea, hypokalemia fatigue, and anorexia. Accrual to dose level 1 was expanded to 9 patients. The Drug Safety Monitoring Board (DSMB) reviewed the data of the initial 12 patients-there were 0/12 responses (0%) and the median progression-free survival was 2 months and accrual was halted.

Conclusions: The maximum tolerated dose of nal-IRI was 50 mg/m2 every 2 weeks with TMZ 50 mg/m2/d. The dose-limiting toxicities were diarrhea and neutropenia. No activity was seen at interim analysis and the study was terminated.
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http://dx.doi.org/10.1097/COC.0000000000000780DOI Listing
February 2021

Autonomic Nervous System Activity during Refractory Rise in Intracranial Pressure.

J Neurotrauma 2021 Jan 12. Epub 2021 Jan 12.

Brain Division of Neurosurgery, Department of Clinical Neurosciences, Physics Laboratory, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

Refractory intracranial hypertension (RIH) is a dramatic increase in intracranial pressure (ICP) that cannot be controlled by treatment. Recent reports suggest that the autonomic nervous system (ANS) activity may be altered during changes in ICP. Our study aimed to assess ANS activity during RIH and the causal relationship between rising in ICP and autonomic activity. We reviewed retrospectively 24 multicenter (Cambridge, Tromso, Berlin) patients in whom RIH developed as a pre-terminal event after acute brain injury (ABI). They were monitored with ICP, arterial blood pressure (ABP), and electrocardiography (ECG) using ICM+ software. Parameters reflecting autonomic activity were computed in time and frequency domain through the measurement of heart rate variability (HRV) and baroreflex sensitivity (BRS). Our results demonstrated that a rise in ICP was associated to a significant rise in HRV and BRS with a higher significance level in the high-frequency HRV ( < 0.001). This increase was followed by a significant decrease in HRV and BRS above the upper-breakpoint of ICP where ICP pulse-amplitude starts to decrease whereas the mean ICP continues to rise. Temporality measured with a Granger test suggests a causal relationship from ICP to ANS. The above results suggest that a rise in ICP interacts with ANS activity, mainly interfacing with the parasympathetic-system. The ANS seems to react to the rise in ICP with a response possibly focused on maintaining the cerebrovascular homeostasis. This happens until the critical threshold of ICP is reached above which the ANS variables collapse, probably because of low perfusion of the brain and the central autonomic network.
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http://dx.doi.org/10.1089/neu.2020.7091DOI Listing
January 2021

Sexual dimorphism and the placenta - results from the ROLO kids study.

J Matern Fetal Neonatal Med 2020 Nov 22:1-7. Epub 2020 Nov 22.

UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland.

Background/aims: To assess the association between placental morphology and neonatal and infant anthropometry, including analysis by sex.

Study Design: Data from the ROLO Kids [Randomized COntrol Trial of LOw Glycaemic Index in Pregnancy] study were analyzed including placental weight and morphology. Placental, anthropometric and skinfold measurements were recorded as markers of adiposity in 196 neonates and 215 infants at 6 months of age. Ratios including subscapular-to-triceps skinfold ratio and waist-to-height ratio were used as markers of central adiposity, while the sum of all skinfolds and subscapular plus triceps skinfolds were used as markers of general adiposity. Analysis was performed for total groups and by sex.

Results: On simple linear regression placental weight was associated with neonatal and infant anthropometric measurements. On multiple regression, the placental weight was associated with birth weight. In the neonatal period placental weight was associated with general adiposity in males only (sum of skinfolds ( 0.007,  < .001) and subscapular + triceps skinfolds a marker of general adiposity ( 0.004  < .001)). At 6 months of age placental length was positively associated with central adiposity in the total group ( 0.006, .036) and maximum cord diameter was inversely associated with infant central adiposity ( - 0.309 .043) in males only.

Conclusion: The placental phenotype is associated with anthropometry at birth and this association persists to early infancy with a stronger relationship noted in this cohort amongst males. This suggests sexual dimorphism may play a role in the impact of the placenta on infant anthropometry.
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http://dx.doi.org/10.1080/14767058.2020.1849097DOI Listing
November 2020

Visualising the pressure-time burden of elevated intracranial pressure after severe traumatic brain injury: a retrospective confirmatory study.

Br J Anaesth 2021 01 9;126(1):e15-e17. Epub 2020 Nov 9.

University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1016/j.bja.2020.09.018DOI Listing
January 2021

Topographic transcriptomics of the nucleus accumbens shell: Identification and validation of fatty acid binding protein 5 as target for cocaine addiction.

Neuropharmacology 2021 02 9;183:108398. Epub 2020 Nov 9.

Dept. of Pharmacology and Toxicology, Center for Addiction Research, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, 77555, USA. Electronic address:

Substance use disorders for cocaine are major public health concerns with few effective treatment options. Therefore, identification of novel pharmacotherapeutic targets is critical for future therapeutic development. Evolution has ensured that genes are expressed largely only where they are needed. Therefore, examining the gene expression landscape of the nucleus accumbens shell (NAcSh), a brain region important for reward related behaviors, may lead to the identification of novel targets for cocaine use disorder. In this study, we conducted a novel two-step topographic transcriptomic analysis using five seed transcripts with enhanced expression in the NAcSh to identify transcripts with similarly enhanced expression utilizing the correlation feature to search the more than 20,000 in situ hybridization experiments of the Allen Mouse Brain Atlas. Transcripts that correlated with at least three seed transcripts were analyzed with Ingenuity Pathway Analysis (IPA). We identified 7-fold more NAcSh-enhanced transcripts than our previous analysis using single voxels in the NAcSh as the seed. Analysis of the resulting transcripts with IPA identified many previously identified signaling pathways such as retinoic acid signaling as well as novel pathways. Manipulation of the retinoic acid pathway specifically in the NAcSh of male rats via viral vector-mediated RNA interference targeting fatty acid binding protein 5 (FABP5) decreased cocaine self-administration and modulates excitability of medium spiny neurons in the NAcSh. These results not only validate the prospective strategy of conducting a topographic transcriptomic analysis, but also further validate retinoic acid signaling as a promising pathway for pharmacotherapeutic development against cocaine use disorder.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755097PMC
February 2021

Historically unprecedented Northern Gulf of Mexico hurricane activity from 650 to 1250 CE.

Sci Rep 2020 11 5;10(1):19092. Epub 2020 Nov 5.

Geology and Geophysics, Woods Hole Oceanographic Institution, Woods Hole, MA, USA.

Hurricane Michael (2018) was the first Category 5 storm on record to make landfall on the Florida panhandle since at least 1851 CE (Common Era), and it resulted in the loss of 59 lives and $25 billion in damages across the southeastern U.S. This event placed a spotlight on recent intense (exceeding Category 4 or 5 on the Saffir-Simpson Hurricane Wind Scale) hurricane landfalls, prompting questions about the natural range in variability of hurricane activity that the instrumental record is too short to address. Of particular interest is determining whether the frequency of recent intense hurricane landfalls in the northern Gulf of Mexico (GOM) is within or outside the natural range of intense hurricane activity prior to 1851 CE. In this study, we identify intense hurricane landfalls in northwest Florida during the past 2000 years based on coarse anomaly event detection from two coastal lacustrine sediment archives. We identified a historically unprecedented period of heightened storm activity common to four Florida panhandle localities from 650 to 1250 CE and a shift to a relatively quiescent storm climate in the GOM spanning the past six centuries. Our study provides long-term context for events like Hurricane Michael and suggests that the observational period 1851 CE to present may underrepresent the natural range in landfalling hurricane activity.
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http://dx.doi.org/10.1038/s41598-020-75874-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645782PMC
November 2020

Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19.

JAMA Intern Med 2021 01;181(1):41-51

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness.

Objective: To test whether tocilizumab decreases mortality in this population.

Design, Setting, And Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding.

Exposures: Treatment with tocilizumab in the first 2 days of ICU admission.

Main Outcomes And Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences.

Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%).

Conclusions And Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.
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http://dx.doi.org/10.1001/jamainternmed.2020.6252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577201PMC
January 2021

Revising evidence of hurricane strikes on Abaco Island (The Bahamas) over the last 700 years.

Sci Rep 2020 10 6;10(1):16556. Epub 2020 Oct 6.

National Museum of The Bahamas, PO Box EE-15082, Nassau, Bahamas.

The northern Bahamas have experienced more frequent intense-hurricane impacts than almost anywhere else in the Atlantic since 1850 CE. In 2019, category 5 (Saffir-Simpson scale) Hurricane Dorian demonstrated the destructive potential of these natural hazards. Problematically, determining whether high hurricane activity levels remained constant through time is difficult given the short observational record (< 170 years). We present a 700-year long, near-annually resolved stratigraphic record of hurricane passage near Thatchpoint Blue Hole (TPBH) on Abaco Island, The Bahamas. Using longer sediment cores (888 cm) and more reliable age-control, this study revises and temporally expands a previous study from TPBH that underestimated the sedimentation rate. TPBH records at least 13 ≥ category 2 hurricanes per century between 1500 to 1670 CE, which exceeds the 9 ≥ category 2 hurricanes per century within 50 km of TPBH since 1850 CE. The eastern United States also experienced frequent hurricanes from 1500 to 1670 CE, but frequency was depressed elsewhere in the Atlantic Ocean. This suggests that spatial heterogeneity in Atlantic hurricane activity since 1850 CE could have persisted throughout the last millennium. This heterogeneity is impacted by climatic and stochastic forcing, but additional high-resolution paleo-hurricane reconstructions are required to assess the mechanisms that impact regional variability.
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http://dx.doi.org/10.1038/s41598-020-73132-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538955PMC
October 2020

The Relative Utility of Concurrent Sources of Information for Diagnosis of Autism Spectrum Disorder in Early Childhood.

Front Pediatr 2020 28;8:486. Epub 2020 Aug 28.

Center for Autism and Neurodevelopmental Disorders, School of Medicine, University of California, Irvine, Irvine, CA, United States.

The development of effective screening methods for Autism Spectrum Disorder (ASD) in early childhood remains a public health priority for communities around the world. Little is known regarding the concurrence between parent concerns about ASD and formal ASD diagnostic methods. This study aimed to examine the relationships among parental ASD concern, ADOS classification, and a physician specialist's diagnosis. One hundred and thirty-four toddlers (74% male; mean age = 31.8 months, SD 4.4) received an evaluation at a university center specializing in ASD and neurodevelopmental disorders. Correspondence between parental ASD suspicion and physician diagnosis of ASD was 61% ( = 0.028). Correspondence between parental suspicion of ASD and ADOS ASD classification was 57% ( = 0.483). Correspondence between ADOS classification and physician diagnosis of ASD was 88% ( = 0.001). Our results have implications for evaluations in low resource regions of the world where access to physician specialists may be limited; the high correspondence between ADOS classification and a physician specialist's diagnosis supports the use of trained ADOS evaluators, such as field health workers or early childhood educators, in a tiered screening process designed to identify those most in need of a specialist's evaluation. Our results also have implications for public health efforts to provide parent education to enable parents to monitor their child's development and share concerns with their providers. Parent awareness and expression of concern coupled with timely responses from providers may lead toward earlier identification of ASD, and other neurodevelopmental disorders, and hence, generate opportunities for earlier and more personalized intervention approaches, which in turn may help improve long-term outcomes. Empowering parents and community members to screen for ASD may be especially important in regions of the world where access to formal diagnosis is limited.
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http://dx.doi.org/10.3389/fped.2020.00486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493686PMC
August 2020

Breastfeeding and maternal eating behaviours are associated with child eating behaviours: findings from the ROLO Kids Study.

Eur J Clin Nutr 2020 Sep 30. Epub 2020 Sep 30.

UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland.

Background: Child eating behaviours can negatively contribute to the development of childhood obesity. This study investigated associations between breastfeeding habits, maternal eating behaviours and child eating behaviours, in 5-year-old children.

Methods: Secundigravida women were recruited to the ROLO dietary randomised controlled trial (Dublin, Ireland) and were followed up with their children to 5 years of age. Breastfeeding exposure and duration were obtained at postnatal and infant follow-up at 2 and 6 months and 2 and 5 years. At 5 years, maternal and child eating behaviours were measured using the Three Factor Eating Questionnaire and the Child Eating Behaviour Questionnaire, respectively. Regression determined associations between breastfeeding habits and maternal eating behaviours with child eating behaviours, controlling for RCT group, maternal education level, maternal BMI at 5 years, childcare exposure and child BMI centile at 5-year follow-up.

Results: There were 230 mother and child pairs analysed. One hundred and fifty-eight mothers had initiated breastfeeding. Median breastfeeding duration was 22 (IQR 33) weeks. Children who were never breastfed were more likely to express a desire to drink (B = -1.01, p = 0.022). Longer breastfeeding duration was associated with lower food responsiveness (B = -1.71, p = 0.003). Maternal uncontrolled eating was positively associated with child food responsiveness, emotional overeating and emotional undereating (B = 0.21, p < 0.001; B = 0.14, p = 0.005; B = 0.14, p = 0.005, respectively). Maternal emotional eating was associated with child emotional overeating and undereating (B = 0.27, p < 0.001, B = 0.29, p = 0.004, respectively).

Conclusion: Not breastfeeding and short breastfeeding duration may contribute to the development of obesogenic eating behaviours in children, alongside maternal eating behaviours including uncontrolled and emotional eating. These 'food approach' eating behaviours may increase risk of overweight/obesity as they are associated with increased energy intake, hence the importance of research surrounding eating behaviours.
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http://dx.doi.org/10.1038/s41430-020-00764-7DOI Listing
September 2020

Dry needling curricula in entry-level education programs in the United States for physical therapists.

J Man Manip Ther 2020 Sep 30:1-9. Epub 2020 Sep 30.

Department of Physical Therapy, University of Saint Augustine for Health Sciences , Miami, FL, USA.

 The objective of this paper was to determine the extent to which dry needling is instructed in entry-level education programs for physical therapists.  Program directors from 226 entry-level education programs recognized by the Commission on Accreditation in Physical Therapy Education were recruited via e-mail to participate in an anonymous 35-item electronic survey during the 2017-2018 academic year.  The survey evaluated dry needling curricula, faculty qualifications, attitudes and experience, and programs' future plans for teaching dry needling.  A total of 75 programs responded to the survey (response rate = 33.1%).  Forty (53.3%) had integrated dry needling theory and psychomotor training into their programs and 8 (10.6%) planned to include such content in their curriculum in the future.  Of the 40 respondents, 28 indicated that dry needling education was integrated into a required course, 4 indicated that dry needling was an elective course, and 8 did not specify how dry needling education was integrated. Faculty teaching dry needling appear to be well qualified, with the majority having 5-10 years of experience using dry needling in clinical practice. The primary reason for programs not teaching dry needling is that it was not considered an entry-level skill. There appeared to be variability in how dry needling was integrated into the curricula, as well as in the depth and breadth of instruction.  Our research may serve as a baseline for faculty to assess existing dry needling curricula and as a guide for developing curricula in new or existing physical therapy programs.
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http://dx.doi.org/10.1080/10669817.2020.1813471DOI Listing
September 2020

A dyadic approach for a remote physical activity intervention in adults with Alzheimer's disease and their caregivers: Rationale and design for an 18-month randomized trial.

Contemp Clin Trials 2020 Nov 23;98:106158. Epub 2020 Sep 23.

Department of Internal Medicine, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. Electronic address:

Adults with Alzheimer's disease and related dementia (ADRD) and their caregivers represent a sizeable and underserved segment of the population with low levels of moderate physical activity (MPA). Options for increasing MPA in community dwelling adults with ADRD and their caregivers are limited. A home-based physical activity intervention delivered remotely via video conferencing to groups of adults with ADRD and their caregivers (RGV), represents a potentially effective approach for increasing MPA in this group. We will conduct an 18-month randomized trial (6 mos. Active intervention, 6 mos. Maintenance, 6 mos. no contact) to compare the effectiveness of the RGV approach with usual care, enhanced with caregiver support (EUC), for increasing MPA in 100 community dwelling adults with ADRD and their caregiver. The primary aim is to compare MPA (min/wk.), assessed by accelerometer, across the 6-mo. active intervention in adults with ADRD randomized to RGV or EUC. Secondarily, we will compare adults with ADRD and their caregivers randomized to RGV or ECU on the following outcomes across 18 mos.: MPA (min/wk.), sedentary time (min/wk.), percentage meeting 150 min/wk. MPA goal, functional fitness, activities of daily living, quality of life, residential transitions, cognitive function, and caregiver burden. Additionally, we will evaluate the influence of age, sex, BMI, attendance (exercise/support sessions), use of recorded sessions, self-monitoring, peer interactions during group sessions, caregiver support, type and quality of dyadic relationship, and number of caregivers on changes in MPA in adults with ADRD and their caregiver across 18 mos.
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http://dx.doi.org/10.1016/j.cct.2020.106158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686020PMC
November 2020

Effects of Age and Sex on Optic Nerve Sheath Diameter in Healthy Volunteers and Patients With Traumatic Brain Injury.

Front Neurol 2020 7;11:764. Epub 2020 Aug 7.

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

The measurement of optic nerve sheath diameter (ONSD) has been reported as a non-invasive marker for intracranial pressure (ICP). Nevertheless, it is uncertain whether possible ONSD differences occur with age and sex in healthy and brain-injured populations. The aim of this study was to investigate the effects of sex and age on ONSD in healthy volunteers and patients with traumatic brain injury. We prospectively included 122 healthy adult volunteers (Galliera Hospital, Genova, Italy), and compared age/sex dependence of ONSD to 95 adult patients (Addenbrooke's Hospital, Cambridge, UK) with severe traumatic brain injury (TBI) requiring intubation and invasive ICP monitoring. The two groups were stratified for sex and age. Age was divided into 3 subgroups: (1) young adults: 18-44 years; (2) middle-aged adults: 45-64 years; (3) old adults: >65 years. In healthy volunteers, ONSD was significantly different between males and females [median (interquartile range): 4.2 (3.9-4.6) mm vs. 4.1 (3.6-4.2) mm ( = 0.01), respectively] and was correlated with age (R = 0.50, < 0.0001). ONSD was significantly increased in group 3 compared to groups 2 and 1, indicating that ONSD values are higher in elderly subjects. In TBI patients, no differences in ONSD were found for sex and the correlation between ONSD and age was non-significant (R = 0.13, = 0.20). ONSD increases with age and is significantly larger for males in healthy volunteers but not in TBI patients. Different ONSD cut-off values need not be age- or sex-adjusted for the assessment of increased ICP in TBI patients.
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http://dx.doi.org/10.3389/fneur.2020.00764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426488PMC
August 2020

Digoxin Use in Cardiac Amyloidosis.

Am J Cardiol 2020 10 24;133:134-138. Epub 2020 Jul 24.

Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address:

Despite limited options for rate control of atrial fibrillation and for low-output heart failure seen in cardiac amyloidosis (CA), digoxin use is discouraged due to a reported increased risk of sensitivity and toxicity. We present our experience with digoxin use in patients with CA and report the event rate of suspected digoxin-related arrhythmias and toxicity. This is a retrospective study of patients with CA seen at our institution between November 1995 and October 2018. Patients were screened for a history of ≥7 days of continuous digoxin use and stratified based on amyloid precursor protein-transthyretin (ATTR) and immunoglobulin light chain (AL). Medical records were used to identify suspected digoxin-related arrhythmias and toxicity events. Digoxin was used in 69 patients (42 ATTR, 27 AL) for a median duration of 6 months (IQR, 1 to 16). Indication for use was rate control in 64% of patients and symptomatic heart failure management in 36%. Suspected digoxin-related arrhythmias and toxicity events occurred in 12% of patients. No deaths were attributed to digoxin use or toxicity, but 11 patients died while on digoxin-most due to progressive heart failure in the setting of CA. In conclusion, digoxin may be a therapeutic option for rate and symptom control for some patients with AL-CA and ATTR-CA. Rigorous patient selection is recommended, and patients should be closely monitored during digoxin administration.
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http://dx.doi.org/10.1016/j.amjcard.2020.07.034DOI Listing
October 2020

Weight management for adults with mobility related disabilities: Rationale and design for an 18-month randomized trial.

Contemp Clin Trials 2020 09 6;96:106098. Epub 2020 Aug 6.

Department of Internal Medicine, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. Electronic address:

Adults with mobility related disabilities (MRDs) represent an underserved group with a high prevalence of overweight/obesity and limited options for weight management. We previously demonstrated clinically meaningful 12-month weight loss in adults with MRDs (-6.2%, 36% ≥5% of baseline weight) using an enhanced Stop Light Diet (eSLD) delivered using at home face-to-face behavioral sessions and optional physical activity. However, the costs/logistics associated with intervention delivery by individual home visits limits the potential for scaling and implementation of this approach. Thus, we will conduct a two-arm randomized trial in 128 overweight/obese adults with MRDs to compare weight loss (6 mos.) and maintenance (12 mos.) between interventions utilizing the eSLD, behavioral counseling, and increased physical activity delivered to individual participants in their homes or delivered to groups of participants in their homes remotely via video conferencing. The primary aim will compare weight loss between interventions arms across 6 months. Secondarily, we will compare weight loss (0-18 mos.), the proportion of participants who achieve clinically meaningful weight loss (≥5%) from 0 to 6 and 0 to18 months, and changes in quality of life from 0 to 6 and 0 to 18 months between interventions arms. We will also conduct cost, cost-effectiveness and contingent valuation comparisons and explore the influence of behavioral session attendance, compliance with the recommendations for diet and physical activity, self-monitoring of diet and physical activity, barriers to physical activity, sleep quality, and medications on weight change across 6 and 18 months. NCT REGISTRATION: NCT04046471.
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http://dx.doi.org/10.1016/j.cct.2020.106098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494524PMC
September 2020

Polyamine Blocking Therapy Decreases Survival of Tumor-Infiltrating Immunosuppressive Myeloid Cells and Enhances the Antitumor Efficacy of PD-1 Blockade.

Mol Cancer Ther 2020 10 3;19(10):2012-2022. Epub 2020 Aug 3.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.

Despite unprecedented advances in the treatment of cancer through the use of immune checkpoint blockade (ICB), responses are not universal and alternative strategies are needed to enhance responses to ICB. We have shown previously that a novel polyamine blocking therapy (PBT), consisting of cotreatment with α-difluoromethylornithine (DFMO) to block polyamine biosynthesis and a Trimer polyamine transport inhibitor, decreases myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages (TAM). Both MDSCs and TAMs promote tumor progression, inhibit antitumor immunity, and limit the efficacy of ICB. In this study, we investigated the use of PBT to heighten therapeutic responses to PD-1 blockade in mice bearing 4T1 mammary carcinoma and B16F10 melanoma tumors. Whereas PBT inhibited primary tumor growth in both tumor models, 4T1 lung metastases were also dramatically decreased in mice treated with PBT. Reductions in MDSC and TAM subpopulations in 4T1 tumors from PBT-treated mice were accompanied by reduced cytoprotective autophagy only in tumor-infiltrating MDSC and macrophage subpopulations but not in the lung or spleen. PBT treatment blunted M2-like alternative activation of bone marrow-derived macrophages and reduced STAT3 activation in MDSC cultures while increasing the differentiation of CD80, CD11c macrophages. PBT significantly enhanced the antitumor efficacy of PD-1 blockade in both 4T1 and B16F10 tumors resistant to anti-PD-1 monotherapy, increasing tumor-specific cytotoxic T cells and survival of tumor-bearing animals beyond that with PBT or PD-1 blockade alone. Our results suggest that cotreatment with DFMO and the Trimer polyamine transport inhibitor may improve the therapeutic efficacy of immunotherapies in patients with cancer with resistant tumors.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-1116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541445PMC
October 2020

RCT of a Comprehensive Outpatient Treatment for Children with Autism Spectrum Disorder.

J Clin Child Adolesc Psychol 2020 Jul 22:1-15. Epub 2020 Jul 22.

Institute for Autism Research, Canisius College.

Objective: This study tested the efficacy of an intensive outpatient psychosocial treatment for children with autism spectrum disorder (ASD) without intellectual disability (ID).

Method: Eighty-eight children (ages 7-12 years) were randomly assigned to the treatment or control (waitlist) condition. The 18-week cognitive-behavioral treatment (two 90-min sessions per week) included small-group instruction and therapeutic activities targeting social/social-communication skills, face-emotion recognition, nonliteral language skills, and interest expansion. A behavioral system was used to increase skills development and reduce ASD symptoms. Efficacy was tested immediately following treatment (posttest), with maintenance assessed 4-6 weeks later (follow-up). Measures included parent ratings of the children's social/social-communication skills, ASD symptoms, broad social skills, and behavior symptoms, child tests of social-cognitive skills (emotion recognition and nonliteral language), and behavioral observations.

Results: Significant effects favoring the treatment group were found at posttest on the primary measures of ASD symptoms (Social Responsiveness Scale, Second Edition; Constantino & Gruber, 2012) and social/social-communication skills (Adapted Skillstreaming Checklist; Lopata, Thomeer, Volker, Nida & Lee, 2008), and secondary measures of nonliteral language skills, broad social skills, and behavior symptoms (measures of emotion-recognition skills and social behaviors during structured game sessions were non-significant). The significant treatment effects found at posttest were all maintained at follow-up.

Conclusions: The outpatient treatment improved several core areas of functioning for children with ASD without ID. Additional elements may be needed to expand the efficacy of the treatment so that the observed skills/symptom improvements generalize to social interactions during gameplay.
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http://dx.doi.org/10.1080/15374416.2020.1790380DOI Listing
July 2020

Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US.

JAMA Intern Med 2020 07 15. Epub 2020 Jul 15.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19.

Objectives: To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19.

Design, Setting, And Participants: This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020.

Exposures: Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds.

Main Outcomes And Measures: The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes.

Results: A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (≥80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (≥40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (Pao2:Fio2<100 vs ≥300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2 vs 0: OR, 2.61; 95% CI, 1.30-5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46-4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs ≥100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies.

Conclusions And Relevance: This study identified demographic, clinical, and hospital-level risk factors that may be associated with death in critically ill patients with COVID-19 and can facilitate the identification of medications and supportive therapies to improve outcomes.
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http://dx.doi.org/10.1001/jamainternmed.2020.3596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364338PMC
July 2020