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Extracellular vesicles (EVs) are mediators of physiological changes that occur during physical exertion. This study examined the effects of physical exertion with and without sleep and caloric restriction on EV size, concentration, and surface proteins in men and women. Twenty participants (10 men) completed a 5-day simulated military operational stress protocol with daily physical exertion. Blood was drawn before and immediately after exertion at baseline (D1) and following 48-h of sleep and caloric restriction (D3). EV size and concentration were assessed using nanoparticle tracking analysis. EVs were identified with markers associated with exosomes (CD63), microvesicles (VAMP3), apoptotic bodies (THSD1), and skeletal muscle-derived EVs (SGCA) and quantified using imaging flow cytometry. Interactive and main effects of sex, day, and time on EVs were assessed using three-way ANOVAs. EV concentration declined pre to postexertion in women on D1 and D3 but was stable in men. EV size increased from pre to postexertion and from D1 to D3 in men and women. Physical exertion following sleep and caloric restriction increased CD63+ EV concentration, proportion of total EVs, and CD63 surface protein expression regardless of sex. The proportion of SGCA+ EVs increased in men and women following exertion and from D1 to D3 but was higher in women than in men. No differences were observed in VAMP3+ and THSD1+ EVs. This study identified sexually dimorphic EV profiles in response to various stressors. Further investigations are necessary to determine if dimorphic EV responses affect health and performance outcomes during stress. NEW & NOTEWORTHY Sex is understudied in EV research, and most studies limit EV analysis to single stress conditions such as exercise. Multistress conditions consisting of physical exertion and sleep and caloric restriction are common in real-world settings. We demonstrate that physical exertion results in sex-specific EV signatures and that EV profiles vary according to single versus multistress conditions. Our data highlight important biological and ecological characteristics that should be considered in EV research.

Introduction Pharmacy graduates should be equipped for one inevitable aspect of health care, mortality, yet only 10% of United States pharmacy curricula courses cover end-of-life (EoL) with limited evidence of effectiveness. This study's objective was to evaluate the impact of an EoL elective on student pharmacists' empathy and attitudes toward mortality and caring for terminally ill persons. Methods First- through third-year student pharmacists enrolled in an EoL elective. Students completed pre- and post-course surveys on self-perceptions of empathy and mortality. Surveys included the following: Kiersma-Chen Empathy Scale (KCES), which assesses empathy of pharmacy and nursing students; revised Collett-Lester Fear of Death and Dying Scale (CL-FODS), which measures fear related to death; and Frommelt Attitudes Toward Care of the Dying Scale Form B (FATCOD-B), which measures health care professionals' attitudes toward EoL care. Anonymous identifiers were used to link pre- and post-course surveys and were collected with an online survey software. Data were analyzed using two-sided paired t-tests. Results Twenty-seven student pharmacists completed the elective. The change in overall mean scores for KCES, CL-FODS, and FATCOD-B correlated with increased empathy, reduced fear of death, and increased positive attitudes toward caring for terminal patients (KCES pre-course = 86.15 vs. post-course = 90.37; CL-FODS pre-course = 93.70 vs. post-course = 75.15; FATCOD-B pre-course = 115.89 vs. post-course = 124.04). Conclusions After the EoL elective, student empathy and attitudes toward mortality and caring for terminally ill persons improved. Implementing EoL concepts in pharmacy curricula should be explored to better prepare graduates in patient care.

Ten anadromous lamprey species (Petromyzontiformes) are recognized around the world, including four species in the Southern Hemisphere and six in the Northern Hemisphere. Eleven threats to these anadromous lampreys have been identified: climate change, shifting oceanographic regimes, artificial barriers, low water quantity/flow management, habitat degradation, poor water quality, reduced habitat availability, host and prey availability, predation, overharvest, and disease. Artificial barriers are a well-recognized threat to anadromous lampreys. Management strategies to improve access to spawning and larval rearing habitats have involved modifying these barriers, providing passage, and translocating adults around them. Habitat restoration targeting other fishes may also benefit some anadromous lampreys; however, research targeting lamprey responses to habitat restoration is lacking. The absence of recreational and commercial fisheries on many of the anadromous lampreys has created a paradigm where funding is unavailable to monitor and manage them. This has led to a general lack of awareness and scientific understanding for anadromous lampreys. We discuss management actions for each of the anadromous lampreys, and highlight key information gaps. Key information gaps include aspects of freshwater biology, distribution and abundance of anadromous lampreys, and the need to improve understanding of how to mitigate threats. In general, larger-bodied lampreys are the subject of more human interest (more harvest, research, and management).

This paper synthesizes information on the at-sea ecology of ten anadromous lampreys, with emphasis on trophic ecology. The at-sea ecology of these lampreys concerns the juvenile stage, in which growth is most rapid. Anadromous lampreys can be categorized into four groups, based on feeding modalities: 1) scavenger (Caspian lamprey, Caspiomyzon wagneri); 2) parasite-predator (Pacific lamprey, Entosphenus tridentatus); 3) predators (western river lamprey, Lampetra ayresii; European river lamprey, L. fluviatilis; Arctic lamprey, Lethenteron camtschaticum; pouched lamprey, Geotria australis; and Argentinian pouched lamprey, G. macrostoma); and 4) parasites (sea lamprey, Petromyzon marinus; Chilean lamprey, Mordacia lapicida; and short-headed lamprey, M. mordax). This paper discusses direct evidence for lamprey feeding ecology, as observed through lamprey-induced wounds on hosts and prey, and lamprey attachments on hosts and prey; and indirect evidence for feeding ecology, via analyses of fatty acids, stable isotopes, contaminants, and bioenergetics modelling. A part of the information presented on feeding ecology is from landlocked sea lamprey, and in some instances this information can be generalizable to anadromous populations. For most anadromous lampreys, but particularly for Southern Hemisphere taxa, little is known about their feeding ecology at sea. Duration of the trophic marine phase and habitat use are still subjects of debate. Species identified as lamprey hosts can be demersal or pelagic, possibly reflecting marine habitat preferences. To unlock understanding of the marine phase of anadromous lampreys, direct evidence of feeding ecology should be coupled with natural (i.e., biomarkers) and artificial (e.g., biologgers) markers to identify habitat use, movement patterns and dispersal.

Clinical trials of pain are notoriously difficult and inefficient in demonstrating efficacy even for known efficacious treatments. Determining the appropriate pain phenotype to study can be problematic. Recent work has identified the extend of widespread pain as an important factor in the likelihood of response to therapy, but has not been tested in clinical trials. Using data from three previously published negative studies of the treatment of interstitial cystitis/ bladder pain with data on the extent of widespread pain, we examined the response of patients to different therapies base on the amount of pain beyond the pelvis. Participants with predominately local but not widespread pain responded to therapy targeting local symptoms. Participants with widespread and local pain responded to therapy targeting widespread pain. Differentiating patients with and without widespread pain phenotypes may be a key feature of designing future pain clinical trials to demonstrate treatments that are effective versus not.

Understanding and preserving intraspecific diversity (ISD) is important for species conservation. However, ISD units do not have taxonomic standards and are not universally recognized. The terminology used to describe ISD is varied and often used ambiguously. We compared definitions of terms used to describe ISD with use in recent studies of three fish taxa: sticklebacks (Gasterosteidae), Pacific salmon and trout (Oncorhynchus spp., “PST”), and lampreys (Petromyzontiformes). Life history describes the phenotypic responses of organisms to environments and includes biological parameters that affect population growth or decline. Life‐history pathway(s) are the result of different organismal routes of development that can result in different life histories. These terms can be used to describe recognizable life‐history traits. Life history is generally used in organismal‐ and ecology‐based journals. The terms paired species/species pairs have been used to describe two different phenotypes, whereas in some species and situations a continuum of phenotypes may be expressed. Our review revealed overlapping definitions for race and subspecies, and subspecies and ecotypes. Ecotypes are genotypic adaptations to particular environments, and this term is often used in genetic‐ and evolution‐based journals. “Satellite species” is used for situations in which a parasitic lamprey yields two or more derived, nonparasitic lamprey species. Designatable Units, Evolutionary Significant Units (ESUs), and Distinct Population Segments (DPS) are used by some governments to classify ISD of vertebrate species within distinct and evolutionary significant criteria. In situations where the genetic or life‐history components of ISD are not well understood, a conservative approach would be to call them phenotypes., The terminology used to describe intraspecific diversity is varied and often used ambiguously. “Ecotype” was originally used to describe patterns in genes and ecology, and recent studies employing this term tend to report a genetic basis in ISD. By contrast, “life history” describes biological parameters that affect demography, and this term tends to be used in organismal‐ and ecology‐based journals.

Decreasing river flows and increasing water temperatures during the summer have been associated with holding behavior by pre-spawning Pacific lamprey Entosphenus tridentatus in the mainstem Willamette River (Oregon, USA). However, it is unclear if microhabitat use (≤ 2 m) by these lamprey is associated with particular habitat structure(s) or thermal refuge. We implanted radio tags into lamprey (n = 425) and conducted boat surveys to track individuals and document their microhabitat use in the mainstem Willamette River. 58 % of the lamprey were detected, representing 460 detections of 247 individuals across two years (2009 and 2010). Lamprey distributed significantly further upstream, and more were found in the main channel during a high flow year (2010) in comparison with a low flow year (2009). More lamprey held in the main channel across all river segments in 2010 than in 2009. Main channel habitats were significantly deeper than other microhabitats. Lamprey migrating into the upper river segment tended to use microhabitats other than the main channel. These other microhabitats included rock revetments and boulders/bedrock. Rock revetments were more prevalent in the middle – upper river segments, and a greater percentage of lamprey were associated with this microhabitat in these segments. The further upstream the lamprey migrated, the cooler, shallower, and faster water they encountered. One lamprey was associated with coolwater refuge (15.5 oC) in an alcove to the mainstem river (18.1 oC). We conclude that microhabitat use by pre-spawning Pacific lamprey differs by year (river flow), river segment, and availability in a large, regulated river.

Heterochronic blood exchange (HBE) has demonstrated that circulating factors restore youthful features to aged tissues. However, the systemic mediators of those rejuvenating effects remain poorly defined. We show here that the beneficial effect of young blood on aged muscle regeneration was diminished when serum was depleted of extracellular vesicles (EVs). Whereas EVs from young animals rejuvenate aged cell bioenergetics and skeletal muscle regeneration, aging shifts EV subpopulation heterogeneity and compromises downstream benefits on recipient cells. Machine learning classifiers revealed that aging shifts the nucleic acid, but not protein, fingerprint of circulating EVs. Alterations in sub-population heterogeneity were accompanied by declines in transcript levels of the pro-longevity protein, α-Klotho, and injection of EVs improved muscle regeneration in a Klotho mRNA-dependent manner. These studies demonstrate that EVs play a key role in the rejuvenating effects of HBE and that Klotho transcripts within EVs phenocopy the effects of young serum on aged skeletal muscle.

Background There are few data on how surgeons implement occupational safety measures to protect their own health and how they assess their subjective health burden. Objective In times of a shortage of surgeons it makes sense to examine these relationships in order to evaluate future-oriented adjustments to increase the attractiveness of the profession of "surgeon". Material and methods An online questionnaire was sent to the registered members of the German Society for General and Visceral Surgery (DGAV) in October 2016. The members were asked about the application of occupational safety measures, individual living conditions, working conditions and the subjective health burden depending on the level of training and type of hospital (basic, standard, maximum care). Results The response rate was 21% (1065/5011). Occupational safety measures were not strictly implemented: routine use of dosimeters, thyroid radiation protection, smoke extraction and protective goggles only took place in 40% (427/1065), 39% (411/1065), 10% (104/1065) and 5% (55/1065), respectively. The majority of surgeons (51%, 548/1065) rated their lifestyle as unhealthy. The majority of them are senior physicians, 46% (250/548) consider their job to be a health hazard. The proportion of chief physicians and assistant physicians is only 21% (115/548) and 18% (98/548). Conclusion Guidelines for standardizing the perioperative protection of German surgeons are desirable. Health-promoting behavior could have a positive effect on the occupational safety of surgeons and ultimately also on patient safety. This can contribute to increasing the attractiveness of the profession "surgeon" in the long term.

Extracellular vesicles (EVs) transport biological content between cells to mediate physiological processes. The association between EVs and resilience, the ability to cope with stress, is unknown. Using unbiased machine learning approaches, we aimed to identify a biological profile of resilience. Twenty servicemen (27.8 ± 5.9 years) completed the Connor Davidson Resilience (CD-RISC) questionnaire and were exposed to daily physical and cognitive exertion with 48-hr sleep and caloric restriction. Blood samples from baseline and the second day of stress were analyzed for neuroendocrine biomarkers impacted by military stress. EVs were isolated from plasma and stained with antibodies associated with exosomes (CD63), microvesicles (VAMP3), and apoptotic bodies (THSD1). Individuals were separated into high (n = 10, CD-RISC 90) and low (n = 10, CD-RISC 79) resilience. EV features were stratified by size, then down-selected using regression trees and compared between groups. Diagnostic accuracy was assessed using receiver operating characteristic curves. Compared to low resilience, high resilience demonstrated a greater increase in variability of THSD1 local bright spot intensities among large-sized EVs in response to stress (p = 0.002, Hedges' g = 1.59). Among medium-sized EVs, high resilience exhibited a greater decrease in side scatter intensity (p = 0.014, Hedges' g = 1.17). Both features demonstrated high to moderate diagnostic accuracy for high resilience (AUC = 0.90 and 0.79). In contrast, neuroendocrine biomarker concentrations were similar between groups. The increase in variability among THSD1 + EVs in high, but not low, resilient individuals following stress may suggest high resilience is accompanied by stress-triggered apoptotic adaptations to the environment that are not detected in neuroendocrine biomarkers.

Background SARS-CoV-2-mediated COVID-19 may cause sudden cardiac death (SCD). Factors contributing to this increased risk of potentially fatal arrhythmias include thrombosis, exaggerated immune response, and treatment with QT-prolonging drugs. However, the intrinsic arrhythmic potential of direct SARS-CoV-2 infection of the heart remains unknown. Objective To assess the cellular and electrophysiological effects of direct SARS-CoV-2 infection of the heart using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods hiPSC-CMs were transfected with recombinant SARS-CoV-2 spike protein (CoV-2 S) or CoV-2 S fused to a modified Emerald fluorescence protein (CoV-2 S-mEm). Cell morphology was visualized using immunofluorescence microscopy. Action potential duration (APD) and cellular arrhythmias were measured by whole cell patch-clamp. Calcium handling was assessed using the Fluo-4 Ca2+ indicator. Results Transfection of hiPSC-CMs with CoV-2 S-mEm produced multinucleated giant cells (syncytia) displaying increased cellular capacitance (75±7 pF, n = 10 vs. 26±3 pF, n = 10; PP2+ handling returned to normal. Conclusion The SARS-CoV-2 spike protein can directly perturb both the cardiomyocyte’s repolarization reserve and intracellular calcium handling that may confer the intrinsic, mechanistic substrate for the increased risk of SCD observed during this COVID-19 pandemic.

Pacific Lamprey Entosphenus tridentatus is an anadromous fish native to the west coast of North America and the Pacific coast of Asia. In the 1950s, construction of dams on the Middle Fork Willamette River blocked upstream migration of adult Pacific Lamprey which resulted in their extirpation from otherwise suitable habitats. We report evidence of landlocked Pacific Lamprey surviving for >40 years after the construction of two high-head flood control dams (Dexter and Lookout Point) in the Middle Fork Willamette River 355.0 and 360.3 km upstream of the Pacific Ocean, respectively. In 2001, six putative Pacific Lamprey (two juveniles and four larvae) were captured using an electro shocker during a stream survey, 21.7 km upstream of Lookout Point Dam (the uppermost of these dams) and were entered into the Smithsonian National Museum of Natural History’s Division of Fishes collection. We re-examined these specimens, and their morphometric measurements and dentition are consistent with Pacific Lamprey. Additional evidence supports the existence of a landlocked population of Pacific Lamprey that resided upstream of these two impassable dams for approximately five generations. To our knowledge, this is the first report of Pacific Lamprey surviving for multiple generations upstream of impassable impoundments. However, no Pacific Lamprey have been detected in recent targeted surveys, indicating that this population has since been extirpated or exists in very low numbers.

Background Loss-of-function variants in the KCNH2-encoded Kv11.1 potassium channel cause long QT syndrome (LQTS) type 2 (LQT2). Presently, hundreds of KCNH2 missense variants (MVs) have been published as "disease-causative." However, an estimated 10% of rare published LQTS MVs may be "false positives." Objective The purpose of this study was to determine which published KCNH2 MVs are likely false positives and warrant demotion to "likely benign" status. Methods A list of 337 LQT2-associated MVs from 6 large compendia was compiled. MV frequency within the Genome Aggregation Database (gnomAD) (n = 141,352 individuals) was assessed, and MVs were analyzed with 8 in silico tools. Variants with minor allele frequency (MAF) >7*10E-6, the calculated maximum credible frequency of LQT2, and predicted "benign" by all tools were demoted to "likely benign." Ultra-rare variants (n = 8) absent in gnomAD but predicted "benign" by all tools were considered as potential false positives and were characterized functionally using whole-cell patch clamp. Results Overall, 14 of 337 published KCNH2 MVs (4%) were observed at MAF >7*10E-6, whereas 252 of 337 (75%) were absent in gnomAD. Among the latter, 8 variants (I96V, G187S, A203T, P241L, H254Q, G314S, P935S, P963T) were predicted benign by 8 tools and lacked characterization. Patch clamp showed no functional perturbation for these 8 MVs. Conclusion This study offers compelling evidence for the demotion of 22 of 337 KCNH2 variants (6.5%) in the literature. Meticulous "pruning" of compendia using exome/genome databases, in silico tools, and in vitro functional studies must be conducted not only for putatively pathogenic LQTS MVs but for the entire field of genetic heart disease.

The functional maturation status of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has a notable impact upon their use in pharmacological studies, disease modeling, and therapeutic applications. Non-cardiomyocytes (non-CMs) produced in the differentiation process have previously been identified as having an extrinsic influence upon hiPSC-CM development, yet the underlying mechanisms are not fully understood. Herein, we aimed to modulate electrophysiological properties of hiPSC-CMs within co-cultures containing varied proportions of non-CMs and investigate the nature of interactions between these different cell types. Therefore, we sorted cardiac differentiations on day 10 and subsequently replated the cells at ratios of 7:3, 1:1, 3:7, and 1:9 non-CMs to CMs. After a month of co-culture, we evaluated electrophysiological properties through the genetically encoded voltage indicator ArcLight. We ultimately identified that co-cultures with approximately 70%–90% CM purity demonstrated the highest action potential (AP) amplitude and maximum upstroke velocity by day 40 of differentiation, indicative of enhanced electrophysiological maturation, as well as more ventricular-like AP morphologies. Notably, these findings were distinct from those observed for co-cultures of hiPSC-CMs and dermal fibroblasts. We determined that the co-culture phenotypes could not be attributed to paracrine effects of non-CMs due to the inability of conditioned media to recapitulate the observed effects. This led to the further observation of a distinctive expression pattern of connexin 43 (Cx43) at cell-cell interfaces between both CMs and non-CMs. Depletion of Cx43 by short hairpin RNA (shRNA) specifically in the non-CM population within a co-culture environment was able to recapitulate electrophysiological phenotypes of a purer hiPSC-CM population. Collectively, our data demonstrate that abundant non-CM content exerts a significant negative influence upon the electrophysiological maturation of hiPSC-CMs through Cx43-mediated cell-cell-contacts, and thus should be considered regarding the future production of purpose-built hiPSC-CM systems.

Pacific lamprey Entosphenus tridentatus has an anadromous life cycle that begins with larvae that filter-feed in freshwater, followed by transformation into juveniles that migrate to the ocean where they parasitize hosts, and adults that migrate into freshwater to spawn and die. The marine-phase (i.e., juvenile life stage) is important yet poorly understood, and is associated with growth opportunities to achieve maximum body size and recruitment. The four goals of this paper are to: (1) synthesize the literature to identify patterns in the marine biology of Pacific lamprey; (2) develop hypotheses to explain these patterns; (3) identify limiting factors and threats, and (4) identify research needs. We hypothesize that recruitment of adult lamprey to spawning populations is influenced by oceanographic regimes through impacts on host abundance. Three marine factors that may be limiting lamprey abundance include: (1) predation and fisheries bycatch; (2) host availability; and (3) host contaminant loads. Four potential marine-related threats to lamprey include: (1) pollution; (2) climate change; (3) unfavorable oceanographic regimes; and (4) the effects of interactions between climate and regimes. Pacific lamprey is not philopatric and the extent to which host migrations and other factors influence lamprey entry into rivers is unclear. Research is needed to fill information gaps on how, when, why, and where lamprey move, feed, and grow in the ocean. Their widespread distribution, parasitic life history, diverse hosts, and multiple predators suggest that Pacific lamprey is integrated into diverse marine ecosystems.

Schools often provide medication management to children at school, yet, most U.S. schools lack a full-time, licensed nurse. Schools rely heavily on unlicensed assistive personnel (UAP) to perform such tasks. This systematic review examined medication management among K-12 school nurses. Keyword searches in three databases were performed. We included studies that examined: (a) K-12 charter, private/parochial, or public schools, (b) UAPs and licensed nurses, (c) policies and practices for medication management, or (d) nurse delegation laws. Three concepts were synthesized: (a) level of training, (b) nurse delegation, and (c) emergency medications. One-hundred twelve articles were screened. Of these, 37.5% (42/112) were comprehensively reviewed. Eighty-one percent discussed level of training, 69% nurse delegation, and 57% emergency medications. Succinct and consistent policies within and across the United States aimed at increasing access to emergency medications in schools remain necessary.

Native lampreys continue to be misunderstood by some citizens in the Pacific Northwest (PNW; USA). This misunderstanding is caused by persistent misperceptions reinforced in media and exacerbated by a long‐running (mid‐1900s to present) and pervasive outreach campaign on the control of the invasive sea lamprey (Petromyzon marinus) in the Laurentian Great Lakes, Lake Champlain and the Finger Lakes of New York. The use of outreach to encourage conservation of native lampreys in the PNW has been comparatively recent. Along with other native non‐salmonid fishes, lampreys were perceived by Euro‐American settlers as “undesirable”, “coarse” or “trash” fish that parasitized desirable trouts and salmon (Oncorhynchus spp.) and competed with them for environmental resources. These concerns have been magnified by the seemingly physical and ecological similarities between native and invasive sea lampreys. To dispel the misperceptions of native lampreys, we recommend a multi‐prong approach that: sharpens the specificity of outreach materials on sea lamprey control; develops outreach media that distinguishes invasive and native lampreys, includes recognition of the multiple ecosystem benefits that native lampreys offer, and includes hands‐on, place‐based learning led by or in collaboration with local tribes that can provide cultural context, and employs a broad outreach campaign to facilitate conservation of native lampreys.

Background With the recent announcement that Step 1 score reporting will soon change to pass/fail, residency programs will need to reconsider their recruitment processes. Objective We (1) evaluated the feasibility of blinding residency programs to applicants' Step 1 scores and their number of attempts throughout the recruitment process; (2) described the selection process that resulted from the blinding; and (3) reviewed if a program's initial rank list, created before scores were known, would be changed before submission for the Match. Methods During the 2018–2019 and 2019–2020 recruitment seasons, all programs at a single sponsoring institution were invited to develop selection criteria in the absence of Step 1 data, and to remain blinded to this data throughout recruitment. Participating programs were surveyed to determine factors affecting feasibility and metrics used for residency selection. Once unblinded to Step 1 scores, programs had the option to change their initial rank lists. Results Of 24 residency programs, 4 participated (17%) in the first year: emergency medicine, neurology, pediatrics, and psychiatry. The second year had the same participants, with the addition of family and community medicine and radiation oncology (n = 6, 25%). Each program was able to determine mission-specific qualities in the absence of Step 1 data. In both years, one program made changes to the final rank list. Conclusions It was feasible for programs to establish metrics for residency recruitment in the absence of Step 1 data, and most programs made no changes to final rank lists after Step 1 scores were known.

Sensory preconditioned and second-order conditioned responding are each well-documented. The former occurs in subjects (typically rats) exposed to pairings of two relatively neutral stimuli, S2 and S1, and then to pairings of S1 and a motivationally significant event [an unconditioned stimulus (US)]; the latter occurs when the order of these experiences is reversed with rats being exposed to S1-US pairings and then to S2-S1 pairings. In both cases, rats respond when tested with S2 in a manner appropriate to the affective nature of the US, e.g., approach when the US is appetitive and withdrawal when it is aversive. This paper reviews the neural substrates of sensory preconditioning and second-order conditioning. It identifies commonalities and differences in the substrates of these so-called higher-order conditioning protocols and discusses these commonalities/differences in relation to what is learned. In so doing, the review highlights ways in which these types of conditioning enhance our understanding of how the brain encodes and retrieves different types of information to generate appropriate behavior.

Physical or perceived (i.e. loneliness) social isolation is increasing in Western cultures. Unfortunately, social isolation is associated with a range of negative physical and mental health outcomes, including increased incidence of obesity and smoking. Here we monitored the impact of social isolation on a range of physical measures, and then tested whether social isolation in adult rats changes how reward-related stimuli motivate sucrose- or nicotine-seeking. Socially isolated rats showed elevated baseline CORT, gained significantly less weight across the study, were more active in response to a novel or familiar environment. Isolated rats also acquired nose-poking for a food pellet more rapidly, and showed increased susceptibility to cue-, but not reward-induced reinstatement. Notably, these effects are partially mitigated by a return to group housing, suggesting that they are not necessarily permanent, and that a return to a social setting can quickly reverse any deficits or changes associated with social isolation. This study advances our understanding of altered reward-processing in socially isolated individuals and reiterates the importance of socialisation in the treatment of disorders such as overeating and addiction.

Item does not contain fulltext OBJECTIVE: To assess the effectiveness of prehabilitation in patients with degenerative disorders of the lumbar spine who are scheduled for spine surgery. DESIGN: Intervention systematic review with meta-analysis. LITERATURE SEARCH: Seven electronic databases were systematically searched for randomized controlled trials or propensity-matched cohorts. STUDY SELECTION CRITERIA: Studies that measured the effect of prehabilitation interventions (ie, exercise therapy and cognitive behavioral therapy [CBT]) on physical functioning, pain, complications, adverse events related to prehabilitation, health-related quality of life, psychological outcomes, length of hospital stay, use of analgesics, and return to work were included. DATA SYNTHESIS: Data were extracted at baseline (preoperatively) and at short-term (6 weeks or less), medium-term (greater than 6 weeks and up to 6 months), and long-term (greater than 6 months) follow-ups. Pooled effects were analyzed as mean differences and 95% confidence intervals (CIs). Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS: Cognitive behavioral therapy interventions were no more effective than usual care for all outcomes. Pooled effect sizes were -2.0 (95% CI: -4.4, 0.4) for physical functioning, -1.9 (95% CI: -5.2, 1.4) for back pain, and -0.4 (95% CI: -4.1, 0.4) for leg pain. Certainty of evidence for CBT ranged from very low to low. Only 1 study focused on exercise therapy and found a positive effect on short-term outcomes. CONCLUSION: There was very low-certainty to low-certainty evidence of no additional effect of CBT interventions on outcomes in patients scheduled for lumbar surgery. Existing evidence was too limited to draw conclusions about the effects of exercise therapy. J Orthop Sports Phys Ther 2021;51(3):103-114. Epub 25 Dec 2020. doi:10.2519/jospt.2021.9748.

Viruses spread between hosts through particles, but within hosts, viral genomes can spread from cell to cell through fusion, evading antiviral defenses and obviating costly infectious virion production1-3. Billions of electromechanically coupled cardiomyocytes (CMs) make myocardium inherently vulnerable to pathological electromechanical short circuits caused by intercellular viral spread 4-6. Beyond respiratory illness, COVID-19 affects the heart7 and cardiac injury and arrhythmias are serious public health concerns8-12. By studying myocardium of a young woman who died suddenly, diagnosed postmortem with COVID-19, we discovered highly focal myocardial SARS-CoV-2 infection spreading from one CM to another through intercellular junctions identified by highly concentrated sarcolemmal t-tubule viral spike glycoprotein. SARS-CoV-2 permissively infected beating human induced pluripotent stem cell (hiPSC)-CMs building multinucleated cardiomyotubes (CMTs) through cell type-specific fusion driven by proteolytically-activated spike glycoprotein. Recombinant spike glycoprotein, co-localizing to sarcolemma and sarcoplasmic reticulum, produced multinucleated CMTs with pathological structure, electrophysiology and Ca2+ excitation-contraction coupling. Blocking cleavage, a peptide-based protease inhibitor neutralized SARS-CoV-2 spike glycoprotein pathogenicity. We conclude that SARS-CoV-2 spike glycoprotein, efficiently primed, activated and strategically poised during biosynthesis, can exploit the CM’s inherent membranous connectivities to drive heart damage directly, uncoupling clinically common myocardial injury from lymphocytic myocarditis, often suspected but rarely confirmed in COVID-19.