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Fieldwork is a core element of health professional and education student training that is often a professional registration and practice requirement. There are many personal, social, and professional factors that impact on students’ fieldwork performance. The impact of professionalism, resilience, and reflective thinking on fieldwork performance is not well described in the literature.

To investigate if first-year occupational therapy students who have had no on-campus, face-to-face learning experiences differed from second-, third- and fourth-year students in their perceptions and experiences of online learning during the Covid-19 pandemic.

Nerve injuries after total hip arthroplasty are relatively uncommon, but a higher prevalence has been reported in revision arthroplasties, in women and in patients with dysplastic hips. We report a case of a patient who had a painful neuritis of the sciatic nerve after primary arthroplasty, without any objective evidence of motor or sensory deficit and had complete relief of pain after the limb lengths were matched to the contra-lateral side after revision arthroplasty. [ABSTRACT FROM AUTHOR]

Abstract Background Understanding the evolution of cultivated barley is important for two reasons. First, the evolutionary relationships between different landraces might provide information on the spread and subsequent development of barley cultivation, including the adaptation of the crop to new environments and its response to human selection. Second, evolutionary information would enable landraces with similar traits but different genetic backgrounds to be identified, providing alternative strategies for the introduction of these traits into modern germplasm. Results The evolutionary relationships between 651 barley landraces were inferred from the genotypes for 24 microsatellites. The landraces could be divided into nine populations, each with a different geographical distribution. Comparisons with ear row number, caryopsis structure, seasonal growth habit and flowering time revealed a degree of association between population structure and phenotype, and analysis of climate variables indicated that the landraces are adapted, at least to some extent, to their environment. Human selection and/or environmental adaptation may therefore have played a role in the origin and/or maintenance of one or more of the barley landrace populations. There was also evidence that at least some of the population structure derived from geographical partitioning set up during the initial spread of barley cultivation into Europe, or reflected the later introduction of novel varieties. In particular, three closely-related populations were made up almost entirely of plants with the daylength nonresponsive version of the photoperiod response gene PPD-H1, conferring adaptation to the long annual growth season of northern Europe. These three populations probably originated in the eastern Fertile Crescent and entered Europe after the initial spread of agriculture. Conclusions The discovery of population structure, combined with knowledge of associated phenotypes and environmental adaptations, enables a rational approach to identification of landraces that might be used as sources of germplasm for breeding programs. The population structure also enables hypotheses concerning the prehistoric spread and development of agriculture to be addressed.

Abstract Background There is a long history of certain medical conditions being associated with stigma, stereotypes, and negative attitudes. Research has shown that such attitudes can have a detrimental effect on patients presenting with stigmatised medical conditions and can even flow on to impact their family. The objective of this study was to measure the attitudes of undergraduate students enrolled in six different health-related courses at Monash University toward patients with intellectual disability, substance abuse, and acute mental illness. Methods A convenience sample of undergraduate students enrolled in six health-related courses in first, second and third years at Monash University were surveyed. The Medical Condition Regard Scale - a valid and reliable, self-report measure of attitudes - was administered to students along with a brief demographic form. Mean scores, t-tests, and ANOVA were used to analyse student attitudes. Ethics approval was granted. Results 548 students participated. Statistically significant differences were found between the courses (p = 0.05), year of the course (p = 0.09), and gender (p = 0.04) for the medical condition of intellectual disability. There was no statistically significant difference between the courses, year of the course, gender, and age group for substance abuse or acute mental illness conditions. Conclusion The findings suggest that students in undergraduate health-related courses, as a group, have a strong regard for patients with intellectual disability and some regard for patients with acute mental illness, but not for patients presenting with substance abuse problems.

Abstract Background Visualising the evolutionary history of a set of sequences is a challenge for molecular phylogenetics. One approach is to use undirected graphs, such as median networks, to visualise phylogenies where reticulate relationships such as recombination or homoplasy are displayed as cycles. Median networks contain binary representations of sequences as nodes, with edges connecting those sequences differing at one character; hypothetical ancestral nodes are invoked to generate a connected network which contains all most parsimonious trees. Quasi-median networks are a generalisation of median networks which are not restricted to binary data, although phylogenetic information contained within the multistate positions can be lost during the preprocessing of data. Where the history of a set of samples contain frequent homoplasies or recombination events quasi-median networks will have a complex topology. Graph reduction or pruning methods have been used to reduce network complexity but some of these methods are inapplicable to datasets in which recombination has occurred and others are procedurally complex and/or result in disconnected networks. Results We address the problems inherent in construction and reduction of quasi-median networks. We describe a novel method of generating quasi-median networks that uses all characters, both binary and multistate, without imposing an arbitrary ordering of the multistate partitions. We also describe a pruning mechanism which maintains at least one shortest path between observed sequences, displaying the underlying relations between all pairs of sequences while maintaining a connected graph. Conclusion Application of this approach to 5S rDNA sequence data from sea beet produced a pruned network within which genetic isolation between populations by distance was evident, demonstrating the value of this approach for exploration of evolutionary relationships.

The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement in rodent models of cocaine use disorder. The output from the mPFC is potently modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets. We previously showed that treatment with chondroitinase ABC (ABC) reduced the consolidation and reconsolidation of a cocaine conditioned place preference memory. However, self-administration memories are more difficult to disrupt. Here we report in male rats that ABC treatment in the mPFC attenuated the consolidation and blocked the reconsolidation of a cocaine self-administration memory. However, reconsolidation was blocked when rats were given a novel, but not familiar, type of retrieval session. Furthermore, ABC treatment prior to, but not after, memory retrieval blocked reconsolidation. This same treatment did not alter a sucrose memory, indicating specificity for cocaine-induced memory. In naive rats, ABC treatment in the mPFC altered levels of PV intensity and cell firing properties. In vivo recordings from the mPFC and dorsal hippocampus (dHIP) during the novel retrieval session revealed that ABC prevented reward-associated increases in high-frequency oscillations and synchrony of these oscillations between the dHIP and mPFC. Together, this is the first study to show that ABC treatment disrupts reconsolidation of the original memory when combined with a novel retrieval session that elicits coupling between the dHIP and mPFC. This coupling after ABC treatment may serve as a fundamental signature for how to disrupt reconsolidation of cocaine memories and reduce relapse., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

In situ abdominal normothermic regional perfusion (A-NRP) has been used for liver transplantation (LT) with donation after circulatory death (DCD) liver grafts in Europe with excellent results; however, adoption of A-NRP in the United States has been lacking. The current report describes the implementation and results of a portable, self-reliant A-NRP program in the United States. Isolated abdominal in situ perfusion with an extracorporeal circuit was achieved through cannulation in the abdomen or femoral vessels and inflation of a supraceliac aortic balloon and cross-clamp. The Quantum Transport System by Spectrum was used. The decision to use livers for LT was made through an assessment of perfusate lactate (q15min). From May to November 2022, 14 A-NRP donation after circulatory death procurements were performed by our abdominal transplant team (N = 11 LT, N = 20 kidney transplants, and 1 kidney-pancreas transplant). The median A-NRP run time was 68 minutes. None of the LT recipients had post-reperfusion syndrome, nor were there any cases of primary nonfunction. All livers were functioning well at the time of maximal follow-up with zero cases of ischemic cholangiopathy. The current report describes the feasibility of a portable A-NRP program that can be used in the United States. Excellent short-term post-transplant results were achieved with both livers and kidneys procured from A-NRP., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: The utilization of extracorporeal life support (ECLS) for intraoperative support during lung transplantation has increased over the past decade. Although veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has recently emerged as the preferred modality over cardiopulmonary bypass (CPB), many centers continue to use both forms of ECLS during lung transplantation. Our novel hybrid VA-ECMO/CPB circuit allows for seamless transition from VA-ECMO to CPB at a significant cost savings compared to a standalone VA-ECMO circuit. This study describes our initial experience and outcomes in the first 100 bilateral lung transplantations using this novel hybrid VA-ECMO/CPB circuit., Methods: Medical records from September 2017 to May 2021 of the first 100 consecutive patients undergoing bilateral lung transplantation with intraoperative hybrid VA-ECMO support were examined retrospectively. We excluded patients with single lung transplants, retransplantations, preoperative ECLS bridging, and veno-venous (VV) ECMO and those supported with CPB only. Perioperative recipient, anesthetic, perfusion variables, and outcomes were assessed., Results: Of the 100 patients supported with VA-ECMO, 19 were converted intraoperatively to CPB. Right ventricular dysfunction was seen in 37% of patients, and the median mean pulmonary artery pressure was 28 mm Hg. No oxygenator clotting was observed with a median heparin dose of 13,000 units in the VA-ECMO group. Primary graft dysfunction grade 3 at 72 hours was observed in 10.1% of all patients and observed 1-year mortality was 4%., Conclusions: The use of a hybrid VA-ECMO/CPB circuit in our institution allows for rapid conversion to CPB with acceptable outcomes across a diverse recipient group at a significantly reduced cost compared to standalone VA-ECMO circuits., Competing Interests: A.K.M. serves as a consultant and scientific advisory board member for Attgeno AB, with all compensation to the Mayo Clinic. T.N. serves on an advisory board for Lung Bioengineering, with all compensation to the Mayo Clinic. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

Hydrogels are extensively used as tunable, biomimetic three-dimensional cell culture matrices, but optically deep, high-resolution images are often difficult to obtain, limiting nanoscale quantification of cell-matrix interactions and outside-in signalling. Here we present photopolymerized hydrogels for expansion microscopy that enable optical clearance and tunable ×4.6-6.7 homogeneous expansion of not only monolayer cell cultures and tissue sections, but cells embedded within hydrogels. The photopolymerized hydrogels for expansion microscopy formulation relies on a rapid photoinitiated thiol/acrylate mixed-mode polymerization that is not inhibited by oxygen and decouples monomer diffusion from polymerization, which is particularly beneficial when expanding cells embedded within hydrogels. Using this technology, we visualize human mesenchymal stem cells and their interactions with nascently deposited proteins at <120 nm resolution when cultured in proteolytically degradable synthetic polyethylene glycol hydrogels. Results support the notion that focal adhesion maturation requires cellular fibronectin deposition; nuclear deformation precedes cellular spreading; and human mesenchymal stem cells display cell-surface metalloproteinases for matrix remodelling., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Malnutrition and sarcopenia are prevalent in patients with head and neck squamous cell carcinoma (HNSCC). Pre-treatment sarcopenia and adverse oncological outcomes in this population are well described. The impact of myosteatosis and post-treatment sarcopenia is less well known. Patients with HNSCC ( n = 125) undergoing chemoradiotherapy, radiotherapy alone and/or surgery were assessed for sarcopenia and myosteatosis, using cross-sectional computed tomography (CT) imaging at the third lumbar (L3) vertebra, at baseline and 3 months post-treatment. Outcomes were overall survival (OS) at 12 months and 5 years post-treatment. One hundred and one participants had a CT scan evaluable at one or two time points, of which sixty-seven (66 %) participants were sarcopenic on at least one time point. Reduced muscle attenuation affected 93 % ( n = 92) pre-treatment compared with 97 % ( n = 90) post-treatment. Five-year OS favoured those without post-treatment sarcopenia (hazard ratio, HR 0·37, 95 % CI 0·16, 0·88, P = 0·06) and those without both post-treatment myosteatosis and sarcopenia (HR 0·33, 95 % CI 0·13, 0·83, P = 0·06). Overall, rates of myosteatosis were high at both pre- and post-treatment time points. Post-treatment sarcopenia was associated with worse 5-year OS, as was post-treatment sarcopenia in those who had myosteatosis. Post-treatment sarcopenia should be evaluated as an independent risk factor for decreased long-term survival post-treatment containing radiotherapy (RT) for HNSCC.

Background: Enteral nutrition (EN) is often required in patients with head and neck cancer (HNSCC); however, initiation criteria is limited or inconsistent. This study aimed to describe the relationship of treatment toxicities and requirement for EN and investigate toxicity and baseline characteristics association with EN duration., Methods: Acute toxicities and baseline characteristics were collected from patients with HNSCC (n = 110) undergoing H-IMRT. Percentage EN contributing to estimated requirements and EN duration were measured., Results: The threshold for patients needing ≥50% of estimated requirements via EN increased from week 3 to 4 for grade ≥2 oral/pharyngeal mucositis, dysgeusia, thick saliva and nausea, and for grade 3 dysphagia. Patients with grade 2-3 dysphagia had a reduced risk of ceasing EN compared to those with grade 0-1 dysphagia., Conclusions: Using acute toxicities in clinical practice may be a useful tool to inform prompt initiation of EN prior to decline in nutritional status and anticipate EN duration., (© 2022 Wiley Periodicals LLC.)

Overindulgence, excessive consumption, and a pattern of compulsive use of natural rewards, such as certain foods or drugs of abuse, may result in the development of obesity or substance use disorder, respectively. Natural rewards and drugs of abuse can trigger similar changes in the neurobiological substrates that drive food- and drug-seeking behaviors. This review examines the impact natural rewards and drugs of abuse have on perineuronal nets (PNNs). PNNs are specialized extracellular matrix structures that ensheathe certain neurons during development over the critical period to provide synaptic stabilization and a protective microenvironment for the cells they surround. This review also analyzes how natural rewards and drugs of abuse impact the density and maturation of PNNs within reward-associated circuitry of the brain, which may contribute to maladaptive food- and drug-seeking behaviors. Finally, we evaluate the relatively few studies that have degraded PNNs to perturb reward-seeking behaviors. Taken together, this review sheds light on the complex way PNNs are regulated by natural rewards and drugs and highlights a need for future studies to delineate the molecular mechanisms that underlie the modification and maintenance of PNNs following exposure to rewarding stimuli., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Sex differences in motivation for food rewards, gambling, and drugs of abuse are modulated by multiple factors, including sensory stimuli, gonadal hormones, and cognitive bias. Cues, drugs of abuse, and a high-fat diet can significantly impact neural signaling in the reward system and functioning of neural systems that regulate executive functions differentially in males and females. Additionally, sex differences in risky decision-making, cognitive bias, and motivation for food and drugs of abuse are mediated by gonadal hormones in both sexes. As neuroscientists analyze data from both sexes, it is becoming apparent that these differences are not simply mediated by hormones in females, but involve sex differences in the specific neural responses to stimuli, including both external stimuli and internal hormonal signals. Understanding sex differences in the mechanisms underlying reward-seeking behaviors and the development of substance use disorders will help uncover potential therapies and treatments that will benefit both men and women. Based on these observations, it is essential that females are included in neuroscience research., (Copyright © 2022 the authors.)

Fatty acid composition across functional brain regions was determined in bovine brains collected from cattle that were provided supplements of calcium salts containing either palm or fish oil. The Angus cattle were divided into two groups, with one group offered the supplement of calcium salts of palm oil and the other offered the calcium salts of fish oil (n = 5 females and n = 5 males/supplement) for 220 days. These supplements to the basal forage diet were provided ad libitum as a suspension in dried molasses. The fish oil exclusively provided eicosapentaenoic acid (EPA, C20:5 n-3) and docosahexaenoic acid (DHA, C22:6 n-3). The functional regions were dissected from the entire brains following commercial harvest. While the cattle provided diets supplemented with the calcium salts of palm oil had increased (p < 0.01) liver concentrations of C18:1 n-9, C18:2 n-6, and arachidonic acid, the fish-oil-supplemented cattle had greater (p < 0.01) concentrations of liver EPA, DHA, and C18:3 n-3. In the brain, DHA was the most abundant polyunsaturated fatty acid. In the amygdala, pons, frontal lobe, internal capsule, and sensory cortex, DHA concentrations were greater (p < 0.05) in the brains of the cattle fed fish oil. Differences among the supplements were small, indicating that brain DHA content is resistant to dietary change. Arachidonic acid and C22:4 n-6 concentrations were greater across the regions for the palm-oil-supplemented cattle. EPA and C22:5 n-3 concentrations were low, but they were greater across the regions for the cattle fed fish oil. The effects of sex were inconsistent. The fatty acid profiles of the brain regions differed by diet, but they were similar to the contents reported for other species.

Parvalbumin (PV)-positive cells are GABAergic fast-spiking interneurons that modulate the activity of pyramidal neurons in the medial prefrontal cortex (mPFC) and their output to brain areas associated with learning and memory. The majority of PV cells within the mPFC are surrounded by a specialized extracellular matrix structure called the perineuronal net (PNN). We have shown that removal of PNNs with the enzyme chondroitinase-ABC (Ch-ABC) in the mPFC prevents the consolidation and reconsolidation of cocaine-associated conditioned place preference (CPP) memories. Here we examined the extent to which retrieval of a CPP memory during cocaine-primed reinstatement altered the levels and function of PV neurons and their surrounding PNNs during the reconsolidation period. We further determined the extent to which PNN removal prior to reinstatement altered PV intensity levels and PV cell function. Male Sprague-Dawley rats were trained for cocaine-induced conditioned place preference (CPP) followed by extinction training, microinjection of Ch-ABC in the prelimbic PFC, and cocaine-induced reinstatement. Rats were sacrificed immediately prior to reinstatement or at 2 h, 6 h, or 48 h after reinstatement for immunohistochemistry or 2 h later for electrophysiology. Our findings indicate that PNN removal only partially diminished reinstatement. Cocaine-primed reinstatement produced only minor changes in PNN or PV intensity in vehicle controls. However, after PNN removal, the intensity of remaining PNN-surrounded PV cells was decreased at all times except at 2 h post-reinstatement, at which time cocaine increased PV intensity. Consistent with this, in vehicle controls, PV neurons naturally devoid of PNNs showed a similar pattern to Ch-ABC-treated rats prior to and after cocaine reinstatement, suggesting a protective effect of PNNs on cocaine-induced changes in PV intensity. Using whole-cell patch-clamp, cocaine-primed reinstatement in Ch-ABC-treated rats decreased the number of elicited action potentials but increased excitatory synaptic transmission, which may have been compensatory. These findings suggest that without PNNs, cocaine-induced reinstatement produces rapid changes in PV intensity and PV cell excitability, which may in turn regulate output of the mPFC post-memory retrieval and diminish the maintenance of cocaine memory during reconsolidation., Competing Interests: JH is the CEO of Rewire Neuro. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gonzalez, Jorgensen, Ramos, Harkness, Aadland, Brown and Sorg.)

Persistent/chronic inflammatory pain involves multiple pathophysiological mechanisms and is far more complex than acute/momentary pain. Current therapeutics for chronic inflammatory pain are often not effective because the etiology responsible for the pain is not addressed by traditional pharmacological treatments. Cathepsin K is a cysteine protease that has mostly been studied in the context of bone and joint disorders. Previous work by others has shown that inhibition of cathepsin K activity reduces osteoarthritis-associated nociception in joints. However, the role of cathepsin K in cutaneous inflammation is understudied. We assessed the effectiveness of genetic deletion or pharmacological inhibition of cathepsin K in male mice on the expression of nocifensive behaviors after formalin injection or mechanical and thermal hypersensitivity after injection of complete Freund's adjuvant (CFA) into the mouse hind paw. Our data demonstrate that cathepsin K knockout mice (Ctsk -/- ) have a reduction in nocifensive behaviors in the formalin test. In addition, Ctsk -/- do not develop mechanical hypersensitivity after CFA injection for up to 7 days. Moreover, we found that inhibition of cathepsin K reduced mechanical hypersensitivity after CFA injection and mRNA levels, protein levels, and cathepsin K activity levels were elevated after CFA injection. Based upon our data, cathepsin K is indicated to play a role in the expression of chemically-induced cutaneous hypersensitivity, as Ctsk -/- mice do not develop mechanical hypersensitivity and show a reduction in nocifensive behaviors. Further research is needed to determine whether attenuating cathepsin K activity may generate a clinically relevant therapeutic., (© 2022. The Author(s).)

Objective: Food-seeking behaviors can be driven by food-associated cues, and palatable food seeking in response to food cues is a risk factor for obesity development. Cue-induced food seeking increases following a period of abstinence, a behavioral phenomenon known as "incubation of craving," which may contribute to an individual's difficulty abstaining from palatable foods. Pharmacological and environmental manipulations have been employed to try and reduce incubation of craving, albeit primarily in drug abuse paradigms. The goal of this study was to determine whether forced exercise can attenuate incubation of high-fat food craving., Methods: Male Sprague Dawley rats learned to self-administer high-fat pellets (60%) in combination with a compound cue (light + tone). The influence of high-intensity interval exercise on the time-dependent increase in cue-induced lever responding was investigated 30 days after the first cue test., Results: Rats exposed to exercise during abstinence did not express incubation of craving., Conclusions: The results suggest that high-intensity exercise can prevent the establishment of incubation of craving for foods high in fat and may reduce cue-induced maladaptive food-seeking behaviors that contribute to overeating and obesity., (© 2022 The Obesity Society.)

Epithelial organoids are stem cell–derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational research. By definition, they self-organize, but the structures formed are often heterogeneous and irreproducible, which limits their use in the lab and clinic. We describe methodologies for spatially and temporally controlling organoid formation, thereby rendering a stochastic process more deterministic. Bioengineered stem cell microenvironments are used to specify the initial geometry of intestinal organoids, which in turn controls their patterning and crypt formation. We leveraged the reproducibility and predictability of the culture to identify the underlying mechanisms of epithelial patterning, which may contribute to reinforcing intestinal regionalization in vivo. By controlling organoid culture, we demonstrate how these structures can be used to answer questions not readily addressable with the standard, more variable, organoid models.

Objective: Assess executive function (EF) improvement with SHP465 mixed amphetamine salts (MAS) extended-release in adults with attention-deficit/hyperactivity disorder (ADHD) using responder analyses of the Brown Attention-Deficit Disorder Scale (BADDS)., Methods: Post hoc analyses examined data from placebo-controlled SHP465 MAS dose-optimization (12.5-75 mg) and fixed-dose (25-75 mg) studies. Treatment response was assessed using two definitions (BADDS total score at endpoint <50 [no EF impairment] vs. ≥50 [impaired]; BADDS total score at endpoint relative to the in-treatment 90% CI range for baseline total score [below the range = improved])., Results: Response rates (SHP465 MAS vs. placebo) favored SHP465 MAS (all nominal p < .0001) in the dose-optimization (BADDS <50: 41.9% vs. 19.2%; below 90% CI range: 57.4% vs. 29.6%) and fixed-dose (BADDS <50: 51.9% vs. 16.7%; below 90% CI range: 70.6% vs. 32.3%) studies., Conclusion: Improvement in EF measured by BADDS response rates was approximately 2-fold greater with SHP465 MAS than placebo.

Nutrition care plays a critical role in optimising outcomes for patients receiving treatment for head and neck cancer (HNC), with carers playing an important role in supporting patients to maintain nutrition intake. This study explores patient and carer experience of nutrition care from diagnosis of HNC to 1 year post treatment completion to identify areas for improvement of service delivery. A longitudinal qualitative study design was used with a heterogeneous sample of 20 patients and 15 carers of patients undergoing curative intent treatment for HNC. Interviews conducted at four time points provided a total of 117 interview datasets that were analysed using reflexive thematic analysis based on Gadamerian hermeneutic inquiry. Patient and carer experiences were reflected in two primary themes: (1) the battle to maintain control and (2) navigating the road ahead. This research identifies the need to co-design strategies to improve nutrition care that is inclusive of patients and carers., (© 2021. Crown.)

Deep Brain Stimulation (DBS) is an important tool in the treatment of pharmacologically resistant neurological movement disorders such as essential tremor (ET) and Parkinson's disease (PD). However, the open-loop design of current systems may be holding back the true potential of invasive neuromodulation. In the last decade we have seen an explosion of activity in the use of feedback to "close the loop" on neuromodulation in the form of adaptive DBS (aDBS) systems that can respond to the patient's therapeutic needs. In this paper we summarize the accomplishments of a 5-year study at the University of Washington in the use of neural feedback from an electrocorticography strip placed over the sensorimotor cortex. We document our progress from an initial proof of hardware all the way to a fully implanted adaptive stimulation system that leverages machine-learning approaches to simplify the programming process. In certain cases, our systems out-performed current open-loop approaches in both power consumption and symptom suppression. Throughout this effort, we collaborated with neuroethicists to capture patient experiences and take them into account whilst developing ethical aDBS approaches. Based on our results we identify several key areas for future work. "Graded" aDBS will allow the system to smoothly tune the stimulation level to symptom severity, and frequent automatic calibration of the algorithm will allow aDBS to adapt to the time-varying dynamics of the disease without additional input from a clinician. Additionally, robust computational models of the pathophysiology of ET will allow stimulation to be optimized to the nuances of an individual patient's symptoms. We also outline the unique advantages of using cortical electrodes for control and the remaining hardware limitations that need to be overcome to facilitate further development in this field. Over the course of this study we have verified the potential of fully-implanted, cortically driven aDBS as a feasibly translatable treatment for pharmacologically resistant ET., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received hardware and funding from Medtronic. Medtronic was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2021 Fra̧czek, Ferleger, Brown, Thompson, Haddock, Houston, Ojemann, Ko, Herron and Chizeck.)

Background: The relationship between surgeon and hospital charges and reimbursements for revision total knee arthroplasty (TKA) has not been well examined. The objective of this study is to report trends and variations in hospital charges and payments compared to surgeons for stage 1 (S1) vs stage 2 (S2) septic revision TKA and aseptic revision (AR) TKA., Methods: The 5% Medicare sample was used to capture hospital and surgeon data for revision TKA from 2005 to 2014. The charge multiplier (CM) and ratio of hospital to surgeon charges, and the payment multiplier (PM) and ratio of hospital to surgeon payments were calculated. Year-to-year variation and regional trends in-patient demographics, Charlson Comorbidity Index, length of stay (LOS), CM, and PM were evaluated., Results: In total, 4570 AR, 1323 S1, and 863 S2 TKA patients were included. CM increased for all cohorts: 8.1-13.8 for AR (P < .001), 21.0-22.5 (P = .07) for S1, and 11.8-22.0 (P < .001) for S2. PM followed a similar trend, increasing 8.1-13.8 (P < .001) for AR, 19.8-27.3 (P = .005) for S1, and 14.7-30.7 (P < .001) for S2. Surgeon reimbursement decreased for all cohorts. LOS decreased for AR (3.8-2.8 days), S1 (12.8-6.9 days), and S2 (4.5-3.9 days). Charlson Comorbidity Index remained stable for AR patients but increased significantly for S1 and S2 cohorts., Conclusion: Hospital charges and payments relative to the surgeons have significantly increased for revision TKA in the setting of stable or increasing patient complexity and decreasing LOS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Perineuronal nets (PNNs) surrounding fast-spiking, parvalbumin (PV) interneurons provide excitatory:inhibitory balance, which is impaired in several disorders associated with altered diurnal rhythms, yet few studies have examined diurnal rhythms of PNNs or PV cells. We measured the intensity and number of PV cells and PNNs labeled with Wisteria floribunda agglutinin (WFA) and also the oxidative stress marker 8-oxo-deoxyguanosine (8-oxo-dG) in rat prelimbic medial prefrontal cortex (mPFC) at Zeitgeber times (ZT) ZT0 (lights-on, inactive phase), ZT6 (mid-inactive phase), ZT12 (lights-off, active phase), and ZT18 (mid-active phase). Relative to ZT0, the intensities of PNN and PV labeling were increased in the dark (active) phase compared with the light (inactive) phase. The intensity of 8-oxo-dG was decreased from ZT0 at all times (ZT6,12,18). We also measured GAD 65/67 and vGLUT1 puncta apposed to PV cells with and without PNNs. There were more excitatory puncta on PV cells with PNNs at ZT18 vs. ZT6, but no changes in PV cells without PNNs and no changes in inhibitory puncta. Whole-cell slice recordings in fast-spiking (PV) cells with PNNs showed an increased ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor:N-methyl-D-aspartate receptor (AMPA: NMDA) at ZT18 vs. ZT6. The number of PV cells and PV/PNN cells containing orthodenticle homeobox 2 (OTX2), which maintains PNNs, showed a strong trend toward an increase from ZT6 to ZT18. Diurnal fluctuations in PNNs and PV cells are expected to alter cortical excitatory:inhibitory balance and provide new insights into treatments for diseases impacted by disturbances in sleep and circadian rhythms.

Substance use disorder is a complex disease created in part by maladaptive learning and memory mechanisms following repeated drug use. Exposure to drug-associated stimuli engages prefrontal cortex circuits, and dysfunction of the medial prefrontal cortex (mPFC) is thought to underlie drug-seeking behaviors. Growing evidence supports a role for parvalbumin containing fast-spiking interneurons (FSI) in modulating prefrontal cortical microcircuit activity by influencing the balance of excitation and inhibition, which can influence learning and memory processes. Most parvalbumin FSIs within layer V of the prelimbic mPFC are surrounded by specialized extracellular matrix structures called perineuronal nets (PNN). Previous work by our group found that cocaine exposure altered PNN-surrounded FSI function, and pharmacological removal of PNNs reduced cocaine-seeking behavior. However, the role of FSIs and associated constituents (parvalbumin and PNNs) in cocaine-related memories was not previously explored and is still unknown. Here, we found that reactivation of a cocaine conditioned place preference memory produced changes in cortical PNN-surrounded parvalbumin FSIs, including decreased parvalbumin intensity, increased parvalbumin cell axis diameter, decreased intrinsic excitability, and increased excitatory synaptic input. Further investigation of intrinsic properties revealed changes in the interspike interval, membrane capacitance, and afterhyperpolarization recovery time. Changes in these specific properties suggest an increase in potassium-mediated currents, which was validated with additional electrophysiological analysis. Collectively, our results indicate that cocaine memory reactivation induces functional adaptations in PNN-surrounded parvalbumin neurons, which likely alters cortical output to promote cocaine-seeking behavior., (©2020 Society for the Study of Addiction.)

The skeletal muscle microenvironment transiently remodels and stiffens after exercise and injury, as muscle ages, and in myopathic muscle; however, how these changes in stiffness affect resident muscle stem cells (MuSCs) remains understudied. Following muscle injury, muscle stiffness remained elevated after morphological regeneration was complete, accompanied by activated and proliferative MuSCs. To isolate the role of stiffness on MuSC behavior and determine the underlying mechanotransduction pathways, we cultured MuSCs on strain-promoted azide-alkyne cycloaddition hydrogels capable of in situ stiffening by secondary photocrosslinking of excess cyclooctynes. Using pre- to post-injury stiffness hydrogels, we found that elevated stiffness enhances migration and MuSC proliferation by localizing yes-associated protein 1 (YAP) and WW domain-containing transcription regulator 1 (WWTR1; TAZ) to the nucleus. Ablating YAP and TAZ in vivo promotes MuSC quiescence in postinjury muscle and prevents myofiber hypertrophy, demonstrating that persistent exposure to elevated stiffness activates mechanotransduction signaling maintaining activated and proliferating MuSCs., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Stereolithography (SLA) and digital light processing (DLP) are powerful additive manufacturing techniques that address a wide range of applications including regenerative medicine, prototyping, and manufacturing. Unfortunately, these printing processes introduce micrometer-scale anisotropic inhomogeneities due to the resin absorptivity, diffusivity, reaction kinetics, and swelling during the requisite photoexposure. Previously, it has not been possible to characterize high-resolution mechanical heterogeneity as it develops during the printing process. By combining DLP 3D printing with atomic force microscopy in a hybrid instrument, heterogeneity of a single, in situ printed voxel is characterized. Here, we describe the instrument and demonstrate three modalities for characterizing voxels during and after printing. Sensing Modality I maps the mechanical properties of just-printed, resin-immersed voxels, providing the framework to study the relationships between voxel sizes, print exposure parameters, and voxel-voxel interactions. Modality II captures the nanometric, in situ working curve and is the first demonstration of in situ cure depth measurement. Modality III dynamically senses local rheological changes in the resin by monitoring the viscoelastic damping coefficient of the resin during patterning. Overall, this instrument equips researchers with a tool to develop rich insight into resin development, process optimization, and fundamental printing limits., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CP-AMPARs in the nucleus accumbens (NAc) mediate cue-triggered motivation for food and cocaine. In addition, increases in NAc CP-AMPAR expression and function can be induced by cocaine or sugary, fatty junk-foods. However, the precise nature of these alterations and the degree to which they rely on the same underlying mechanisms is not well understood. This has important implications for understanding adaptive vs. maladaptive plasticity that drives food- and drug-seeking behaviors. Furthermore, effects of junk-foods on glutamatergic plasticity in females are unknown. Here, we use a combination of protein biochemistry and whole-cell patch clamping to determine effects of diet manipulation on glutamatergic plasticity within the NAc of males and females. We found that junk-food consumption increases silent synapses and subsequently increases CP-AMPAR levels in males in the NAc of male rats. In addition, a brief period of junk-food deprivation is needed for the synaptic insertion of CP-AMPARs and the maturation of silent synapses in males. In contrast, junk-food did not induce AMPAR plasticity in females but may instead alter NMDAR-mediated transmission. Thus, these studies reveal sex differences in the effects of junk-food on NAc synaptic plasticity. In addition, they provide novel insights into how essential food rewards alter NAc function.

Nutrition care plays a critical role in the provision of best practice care to head and neck cancer (HNC) patients, with carers playing an important role in supporting patients to maintain nutrition intake. This qualitative systematic review investigated patient and carer experience of nutrition care throughout and beyond HNC treatment. Five databases were systematically searched for qualitative studies reporting on patient and carer experience of nutrition care throughout HNC. Twenty-five studies including 435 patients and 46 carers were identified, revealing three themes: information and support in the healthcare setting, enteral feeding challenges and management, and life outside hospital. Findings highlight the importance of providing individualised person-centred nutrition care to patients with HNC and their carers. Further qualitative research is needed to inform healthcare professionals about the needs of patients and carers to provide appropriate support throughout the treatment trajectory across and between different treatment modalities.

Background: The use of extracorporeal circulation (ECC) for intraoperative cardiopulmonary support during lung transplantation has been increasing in the recent years. Our group previously described a novel hybrid extracorporeal membrane oxygenation (ECMO) circuit for use in lung transplantation., Technique: Our approach for intraoperative management of our novel hybrid ECMO circuit for lung transplantation is driven by two main goals: The first is to deliver management that ensures an appropriate balance between the native and ECMO cardiac outputs in order to provide a stable environment that promotes attenuation of ischemic-reperfusion injury during implantation. The second is to provide a stable hemodynamic environment that results in an appropriate global perfusion guided by multiple monitors and an organ systems-based approach during implantation., Comments: Our novel technique for intraoperative management of this circuit during lung transplantation is described., (© 2020 Wiley Periodicals LLC.)

Background: It is important to identify risk factors for periprosthetic joint infection (PJI) following total joint arthroplasty in order to mitigate the substantial social and economic burden. The objective of this study is to evaluate early aseptic revision surgery as a potential risk factor for PJI following total hip (THA) and total knee arthroplasty (TKA)., Methods: Patients who underwent primary THA or TKA with early aseptic revision were identified in 2 national insurance databases. Control groups of patients who did not undergo revision were identified and matched 10:1 to study patients. Rates of PJI at 1 and 2 years postoperatively following revision surgery were calculated and compared to controls using a logistic regression analysis., Results: In total, 328 Medicare and 222 Humana patients undergoing aseptic revision THA within 1 year of index THA were found to have significantly increased risk of PJI at 1 year (5.49% vs 0.91%, odds ratio [OR] 5.61, P < .001 for Medicare; 7.21% vs 0.68%, OR 11.34, P < .001 for Humana) and 2 years (5.79% vs 1.10%, OR 4.79, P < .001 for Medicare; 8.11% vs 1.04%, OR 9.05, P < .001 for Humana). Similarly for TKA, 190 Medicare and 226 Humana patients who underwent aseptic revision TKA within 1 year were found to have significantly higher rates of PJI at 1 year (6.48% vs 1.16%, OR 7.69, P < .001 for Medicare; 6.19% vs 1.28%, OR 4.89, P < .001 for Humana) and 2 years (8.42% vs 1.58%, OR 6.57, P < .001 for Medicare; 7.08% vs 1.50%, OR 4.50, P < .001 for Humana)., Conclusion: Early aseptic revision surgery following THA and TKA is associated with significantly increased risks of subsequent PJI within 2 years., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Extracorporeal circulation (ECC) support using intraoperative extracorporeal membrane oxygenation (ECMO) during lung transplantation (LTx) is now a routine practice for many high volume centers. Circuits that are dedicated to ECMO alone can be expensive and do not allow full cardiopulmonary bypass (CPB) to be performed. We describe our technique of instituting venoarterial ECMO during LTx using a less-expensive hybrid circuit that facilitates easy and immediate conversion to full CPB if needed, without interruption of ECC.

Background Cardiac fibroblasts (CFs) have the ability to sense stiffness changes and respond to biochemical cues to modulate their states as either quiescent or activated myofibroblasts. Given the potential for secretion of bioactive molecules to modulate the cardiac microenvironment, we sought to determine how the CF secretome changes with matrix stiffness and biochemical cues and how this affects cardiac myocytes via paracrine signaling. Methods and Results Myofibroblast activation was modulated in vitro by combining stiffness cues with TGFβ1 (transforming growth factor β 1) treatment using engineered poly (ethylene glycol) hydrogels, and in vivo with isoproterenol treatment. Stiffness, TGFβ1, and isoproterenol treatment increased AKT (protein kinase B) phosphorylation, indicating that this pathway may be central to myofibroblast activation regardless of the treatment. Although activation of AKT was shared, different activating cues had distinct effects on downstream cytokine secretion, indicating that not all activated myofibroblasts share the same secretome. To test the effect of cytokines present in the CF secretome on paracrine signaling, neonatal rat ventricular cardiomyocytes were treated with CF conditioned media. Conditioned media from myofibroblasts cultured on stiff substrates and activated by TGFβ1 caused hypertrophy, and one of the cytokines in that media was insulin growth factor 1, which is a known mediator of cardiac myocyte hypertrophy. Conclusions Culturing CFs on stiff substrates, treating with TGFβ1, and in vivo treatment with isoproterenol all caused myofibroblast activation. Each cue had distinct effects on the secretome or genes encoding the secretome, but only the secretome of activated myofibroblasts on stiff substrates treated with TGFβ1 caused myocyte hypertrophy, most likely through insulin growth factor 1.

Perineuronal nets (PNNs) are specialized extracellular matrix structures that primarily surround fast-spiking parvalbumin (PV)-containing interneurons within the PFC. They regulate PV neuron function and plasticity to maintain cortical excitatory/inhibitory balance. For example, reductions in PNN intensity are associated with reduced local inhibition and enhanced pyramidal neuron firing. We previously found that exposure to dietary high fat reduced PNN intensity within the PFC of male Sprague-Dawley (SD) rats. However, how high fat affects PNNs in the PFC of females or in obesity-vulnerable vs. -resistant models is unknown. Therefore, we gave male and female SD, selectively bred obesity-prone (OP), and obesity-resistant rats (OR) free access to standard lab chow or 60% high fat for 21 days. We then measured the number of PNN positive cells and PNN intensity (determined by Wisteria floribunda agglutinin [WFA] staining) as well as the number of PV positive neurons using immunohistochemistry. We found sex and region-specific effects of dietary high fat on PNN intensity, in the absence of robust changes in cell number. Effects were comparable in SD and OP but differed in OR rats. Specifically, high fat reduced PNN intensities in male SD and OP rats but increased PNN intensities in female SD and OP rats. In contrast, effects in ORs were opposite, with males showing increases in PNN intensity and females showing a reduction in intensity. Finally, these effects were also region specific, with diet-induced reductions in PNN intensity found in the prelimbic PFC (PL-PFC) and ventral medial orbital frontal cortex (vmOFC) of SD and OP males in the absence of changes in the infralimbic PFC (IL-PFC), and increases in PNN intensity in the IL-PFC of SD and OP females in the absence of changes in other regions. These results are discussed in light of roles PNNs may play in influencing PFC neuronal activity and the differential role of these sub-regions in food-seeking and motivation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Despite the fact that negative mood and executive dysfunction are common after risk-reducing salpingo-oophorectomy (RRSO), occurring in up to a third of women, little is known about risk factors predicting these negative outcomes. Adverse childhood experiences (ACE) predict poorer health in adulthood and may be a risk factor for negative outcomes after RRSO. Given the complex relationship between early life stress, affective disorders, and cognitive dysfunction, we hypothesized that ACE would be associated with poorer executive function and that mood symptoms would partially mediate this relationship., Methods: Women who had undergone RRSO were included in the study (N = 552; age 30-73 y). We measured executive function (continuous performance task, letter n-back task, and Brown Attention Deficit Disorder Scale Score), exposure to early life stress (ACE questionnaire), and mood symptoms (Hospital Anxiety and Depression Scale). Generalized estimating equations were used to evaluate the association between ACE and executive dysfunction and the role of mood symptoms as a mediator in this relationship., Results: ACE was associated with greater severity of subjective executive dysfunction (adjusted mean difference [aMD] = 7.1, P = 0.0005) and worse performance on both cognitive tasks (continuous performance task: aMD = -0.1, P = 0.03; n-back: aMD = -0.17, P = 0.007). Mood symptoms partially mediated ACE associations with sustained attention (21.3% mediated; 95% CI: 9.3%-100%) and subjective report of executive dysfunction (62.8% mediated; 95% CI: 42.3%-100%)., Conclusions: The relationship between childhood adversity and executive dysfunction is partially mediated by mood symptoms. These data indicate that assessing history of childhood adversity and current anxiety and depression symptoms may play a role in treating women who report cognitive complaints after RRSO. : Video Summary:http://links.lww.com/MENO/A571.

Intestinal organoids are useful in vitro models for basic and translational studies aimed at understanding and treating disease. However, their routine culture relies on animal-derived matrices that limit translation to clinical applications. In fact, there are few fully defined, synthetic hydrogel systems that allow for the expansion of intestinal organoids. Here, an allyl sulfide photodegradable hydrogel is presented, achieving rapid degradation through radical addition-fragmentation chain transfer (AFCT) reactions, to support routine passaging of intestinal organoids. Shear rheology to first characterize the effect of thiol and allyl sulfide crosslink structures on degradation kinetics is used. Irradiation with 365 nm light (5 mW cm -2 ) in the presence of a soluble thiol (glutathione at 15 × 10 -3 m), and a photoinitiator (lithium phenyl-2,4,6-trimethylbenzoylphosphinate at 1 × 10 -3 m), leads to complete hydrogel degradation in less than 15 s. Allyl sulfide hydrogels are used to support the formation of epithelial colonies from single intestinal stem cells, and rapid photodegradation is used to achieve repetitive passaging of stem cell colonies without loss in morphology or organoid formation potential. This platform could support long-term culture of intestinal organoids, potentially replacing the need for animal-derived matrices, while also allowing systematic variations to the hydrogel properties tailored for the organoid of interest., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Executive function (EF) deficits are not generally considered synonymous with attention-deficit/hyperactivity disorder (ADHD). Evidence suggests stimulants improve ADHD symptoms and EF deficits in adults with ADHD, but the relationships between improvements in these domains have not been studied., Methods: These post hoc analyses used data from a 10-week double-blind, placebo-controlled study of adults with ADHD and EF deficits treated with lisdexamfetamine dimesylate (30-70 mg) or placebo conducted from May 2010 to November 2010. Efficacy endpoints included change from baseline at week 10/early termination (ET) in self-report Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Global Executive Composite (GEC) T-score and ADHD-Rating Scale with Adult Prompts total score (ADHD-RS-AP-TS). Relationships between ADHD symptom and EF changes were examined using recursive path analyses., Results: Mediation proportions were 0.62 (indirect and total treatment effect coefficients [95% CI]: -6.85 [-9.83 to -3.86] and -11.12 [-14.88 to -7.37]) for self-report BRIEF-A GEC T-score change from baseline at week 10/ET on ADHD-RS-AP-TS change from baseline at week 10/ET and 0.93 (indirect and total treatment effect coefficients [95% CI]: -10.34 [-14.11 to -6.57] and -11.18 [-15.80 to -6.55]) for ADHD-RS-AP-TS change from baseline at week 10/ET on self-report BRIEF-A GEC T-score change from baseline at week 10/ET., Conclusions: Although these data suggest ADHD symptom and EF deficit improvement following lisdexamfetamine are interdependent, it is advantageous to use measures like the BRIEF-A to assess stimulant effects on the wide range of EF deficits associated with ADHD that are not captured by the ADHD-RS-AP alone., Trial Registration: Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT01101022., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

The rapid spread of Coronavirus Disease 2019 (COVID-19) has sparked a search for effective therapies. The discovery that the virus binds the angiotensin-converting enzyme 2 (ACE2) receptor has led to investigation of the renin-angiotensin system for possible therapeutic targets. We present a case of an elderly woman with multiple comorbidities who developed severe acute respiratory distress syndrome (ARDS), a cardiomyopathy, and vasodilatory shock secondary to COVID-19 and was treated with exogenous angiotensin II. She rapidly demonstrated significant hemodynamic improvement without noted adverse effects. Thus, we propose further investigation into possible benefits of angiotensin II in shock secondary to COVID-19.

Intestinal organoid protocols rely on the use of extracellular scaffolds, typically Matrigel, and upon switching from growth to differentiation promoting media, a symmetry breaking event takes place. During this stage, the first bud like structures analogous to crypts protrude from the central body and differentiation ensues. While organoids provide unparalleled architectural and functional complexity, this sophistication is also responsible for the high variability and lack of reproducibility of uniform crypt-villus structures. If function follows form in organoids, such structural variability carries potential limitations for translational applications (e.g., drug screening). Consequently, there is interest in developing synthetic biomaterials to direct organoid growth and differentiation. It has been hypothesized that synthetic scaffold softening is necessary for crypt development, and these mechanical requirements raise the question, what compressive forces and subsequent relaxation are necessary for organoid maturation? To that end, allyl sulfide hydrogels are employed as a synthetic extracellular matrix mimic, but with photocleavable bonds that temporally regulate the material's bulk modulus. By varying the extent of matrix softening, it is demonstrated that crypt formation, size, and number per colony are functions of matrix softening. An understanding of the mechanical dependence of crypt architecture is necessary to instruct homogenous, reproducible organoids for clinical applications., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)