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Frontloading is an alcohol drinking pattern where intake is skewed towards the onset of access. This study aimed to identify brain regions involved in frontloading. Whole brain imaging was performed in 63 C57Bl/6J (32 female, 31 male) mice that underwent 8 days of binge drinking using drinking-in-the-dark (DID). On Days 1-7 mice received 20% (v/v) alcohol or water for 2 h. Intake was measured in 1-min bins using volumetric sippers. On Day 8 mice were perfused 80 min into the DID session and brains were extracted. Brains were processed to stain for Fos protein using iDISCO+. Following light sheet imaging, ClearMap2.1 was used to register brains to the Allen Brain Atlas and detect Fos+ cells. For network analyses, Day 8 drinking patterns were used to characterize mice as frontloaders or non-frontloaders using a change-point analysis. Functional correlation matrices were calculated for each group from log10 Fos values. Euclidean distances were calculated from these R values and clustering was used to determine modules (highly connected groups of brain regions). In males, alcohol access decreased modularity (three modules in both frontloaders and non-frontloaders) as compared to water (seven modules). In females, an opposite effect was observed. Alcohol access (nine modules for frontloaders) increased modularity as compared to water (five modules). Further, different brain regions served as hubs in frontloaders as compared to control groups. In conclusion, alcohol consumption led to fewer, but more densely connected, groups of brain regions in males but not females and we identify several brain-wide signatures of frontloading.

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Marine animals are challenged by chronically raised temperatures alongside an increased frequency of discrete, severe warming events. Exposure to repeated heat shocks could result in heat hardening, where sub-lethal exposure to thermal stress temporarily enhances thermotolerance, and may be an important mechanism by which marine species will cope with future thermal challenges. However, we have relatively little understanding of the effects of heat hardening in comparison to chronic exposure to elevated temperatures. Therefore, we compared the effects of heat hardening from repeated exposure to acute heat shocks and chronic exposure to elevated temperatures on thermal tolerance in the European abalone, Haliotis tuberculata. Adult abalones were exposed to either control temperature (15 °C), chronic warming (20 °C) or a regime of two events of repeated acute heat shock cycles (23-25 °C) during six months, and their thermal tolerance and performance, based upon cardiac activity, compared using a dynamic ramping assay. The cost associated with each treatment was also estimated via measurements of condition index (CI). Abalone exposed to both temperature treatments had higher upper thermal limits than the control, but heat-hardened individuals had significantly higher CI values, indicating an enhancement in condition status. Differences in the shape of the thermal performance curve suggest different mechanisms may be at play under different temperature exposure treatments. We conclude that heat hardening can boost thermal tolerance in this species, without performance trade-offs associated with chronic warming.

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The timing, rate, and quantity of gestational alcohol consumption, collectively referred to here as Maternal Drinking Patterns (MDPs), are of known importance to fetal developmental outcomes. However, few studies have directly evaluated the impact of MDPs on offspring behavior. To do so, we used specialized equipment to record the precise amount and timing of alcohol consumption in pregnant dams, and then characterized MDPs using Principle Component Analysis (PCA). We next tested offspring on behaviors we have previously identified as impacted by prenatal alcohol exposure, and evaluated them where possible in the context of MDPs. Male alcohol exposed mice exhibited longer latencies to fall on the rotarod compared to their controls, which we attribute to a delayed decrease in body weight-gain. This effect was mediated by MDPs within the first 15 min of alcohol access (i.e. alcohol frontloading), where the highest performing male offspring came from dams exhibiting the highest rate of alcohol frontloading. Female alcohol exposed mice displayed reduced locomotor activity in the open field compared to controls, which was mediated by MDPs encompassing the entire drinking session. Surprisingly, total gestational alcohol exposure alone was not associated with any behavioral outcomes. Finally, we observed allodynia in alcohol exposed mice that developed more quickly in males compared to females, and which was not observed in controls. To our knowledge, this report represents the highest resolution assessment of alcohol drinking throughout gestation in mice, and one of few to have identified relationships between specific alcohol MDPs and neurobehavioral outcomes in offspring.

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A key facet of alcohol use disorder is continuing to drink alcohol despite negative consequences (so called "aversion-resistant drinking"). In this study, we sought to assess the degree to which head-fixed mice exhibit aversion-resistant drinking and to leverage behavioral analysis techniques available in head-fixture to relate non-consummatory behaviors to aversion-resistant drinking. We assessed aversion-resistant drinking in head-fixed female and male C57BL/6 J mice. We adulterated 20% (v/v) alcohol with varying concentrations of the bitter tastant quinine to measure the degree to which mice would continue to drink despite this aversive stimulus. We recorded high-resolution video of the mice during head-fixed drinking, tracked body parts with machine vision tools, and analyzed body movements in relation to consumption. Female and male head-fixed mice exhibited heterogenous levels of aversion-resistant drinking. Additionally, non-consummatory behaviors, such as paw movement and snout movement, were related to the intensity of aversion-resistant drinking. These studies demonstrate that head-fixed mice exhibit aversion-resistant drinking and that non-consummatory behaviors can be used to assess perceived aversiveness in this paradigm. Furthermore, these studies lay the groundwork for future experiments that will utilize advanced electrophysiological techniques to record from large populations of neurons during aversion-resistant drinking to understand the neurocomputational processes that drive this clinically relevant behavior. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".

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A key facet of alcohol use disorder is continuing to drink alcohol despite negative consequences (so called "aversion-resistant drinking"). In this study, we sought to assess the degree to which head-fixed mice exhibit aversion-resistant drinking and to leverage behavioral analysis techniques available in head-fixture to relate non-consummatory behaviors to aversion-resistant drinking. We assessed aversion-resistant drinking in head-fixed female and male C57BL/6J mice. We adulterated 20% (v/v) alcohol with varying concentrations of the bitter tastant quinine to measure the degree to which mice would continue to drink despite this aversive stimulus. We recorded high-resolution video of the mice during head-fixed drinking, tracked body parts with machine vision tools, and analyzed body movements in relation to consumption. Female and male head-fixed mice exhibited heterogenous levels of aversion-resistant drinking. Additionally, non-consummatory behaviors, such as paw movement and snout movement, were related to the intensity of aversion-resistant drinking. These studies demonstrate that head-fixed mice exhibit aversion-resistant drinking and that non-consummatory behaviors can be used to assess perceived aversiveness in this paradigm. Furthermore, these studies lay the groundwork for future experiments that will utilize advanced electrophysiological techniques to record from large populations of neurons during aversion-resistant drinking to understand the neurocomputational processes that drive this clinically relevant behavior.

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RATIONALE: Female rodents consume more ethanol (EtOH) than males and exhibit greater aversion-resistant drinking in some paradigms. Ovarian hormones promote EtOH drinking but the contribution of ovarian hormones to aversion-resistant drinking has not been assessed. OBJECTIVES: We aimed to investigate the role of ovarian hormones to aversion-resistant drinking in female mice in a drinking in the dark (DID) task. METHODS: Female C57BL/6 J mice first underwent an ovariectomy (OVX, n = 16) or sham (SHAM, n = 16) surgery. Four weeks following surgery, mice underwent a DID paradigm where they were given access to water and 15% EtOH 3 h into the dark cycle for up to 4 h across 15 drinking sessions. To assess frontloading behavior, bottles were weighed at 30 min, 2 h, and 4 h. Aversion-resistance was tested by adding escalating concentrations of quinine (0, 100, 250, and 500 µM) to the 15% EtOH bottle on sessions 16 - 19. RESULTS: Removal of the ovaries reduced EtOH consumption in OVX subjects. When assessing aversion-resistant EtOH drinking, mice with ovarian hormones (SHAM) reduced consumption of 250 and 500 µM quinine in EtOH, while OVX subjects exhibited aversion-resistance at all quinine concentrations. OVX mice had greater frontloading for quinine + EtOH at higher concentrations of quinine. CONCLUSIONS: These results indicate that circulating ovarian hormones may be protective against the development of aversion-resistant EtOH drinking and call for further investigation of the role of ovarian hormones in models of addictive behavior.

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Mass mortality events caused by vibriosis have emerged in hatchery-reared scallop larvae from Chile, threatening scallop aquaculture. In an attempt to mitigate this emerging infectious disease and provide candidates for marker-assisted selective breeding, we tested here the existence of a genetic component of Argopecten purpuratus scallop resistance to the pathogen Vibrio bivalvicida. Through a dual RNA-seq approach we analyzed the basal transcriptome and the transcriptional response to infection in two resistant and two susceptible families as well as the pathogen transcriptomic response to host colonization. The results highlighted a genetic basis in the resistance of scallop larvae to the pathogen. The Vibrio response was characterized by a general metabolic adaptation to the host environment, along with several predicted virulence factors overexpressed in infected scallop larvae with no difference between resistant and susceptible host phenotypes. On the host side, several biological processes were enriched in uninfected resistant larvae. Within these enriched categories, immune-related processes were overexpressed, while morphogenesis, biomineral tissue development, and angiogenesis were under expressed. Particularly, genes involved in immune recognition and antimicrobial response, such as lipopolysaccharide-binding proteins (LBPs), lysozyme, and bactericidal permeability-increasing protein (BPI) were overexpressed in uninfected resistant larvae. As expected, immune-related biological processes were enriched in Vibrio-infected larvae, but they were more numerous in resistant larvae. Overexpressed immune genes in response to infection included several Toll-like receptors, TNF and NF-κB immune signaling genes, and the antimicrobial peptide Big defensin ApBD1. Results strongly suggest that both a front-loading of immune genes and an enhanced antimicrobial response to infection contribute to the resistance, while pathogen infective strategy does not discriminate between host phenotypes. Overall, early expression of host immune genes appears as a strong determinant of the disease outcome that could be used in marker-assisted selective breeding.

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Introduction: Rates of relapse to drug use during abstinence are among the highest for opioid use disorder (OUD). In preclinical studies, reinstatement to drug-seeking has been extensively studied as a model of relapse-but the work has been primarily in males. We asked whether biological sex contributes to behaviors comprising self-administration of the prescription opioid oxycodone in rats, and we calculated the relative contribution of these behavioral measures to reinstatement in male and female rats. Materials and methods: Rats were trained to self-administer oxycodone (8 days, training phase), after which we examined oxycodone self-administration behaviors for an additional 14 days under three conditions in male and female rats: short access (ShA, 1 h/d), long access (LgA, 6 h/d), and saline self-administration. All rats were then tested for cue-induced reinstatement of drug-seeking after a 14-d forced abstinence period. We quantified the # of infusions, front-loading of drug intake, non-reinforced lever pressing, inter-infusion intervals, escalation of intake, and reinstatement responding on the active lever. Results: Both male and female rats in LgA and ShA conditions escalated oxycodone intake to a similar extent. However, males had higher levels of non-reinforced responding than females under LgA conditions, and females had greater levels of reinstatement responding than males. We then correlated each addiction-related measure listed above with reinstatement responding in males and females and ranked their respective relative contributions. Although the majority of behavioral measures associated with oxycodone self-administration did not show sex differences on their own, when analyzed together using partial least squares regression, their relative contributions to reinstatement were sex-dependent. Front-loading behavior was calculated to have the highest relative contribution to reinstatement in both sexes, with long and short inter-infusion intervals having the second greatest contribution in females and males, respectively. Discussion: Our results demonstrate sex differences in some oxycodone self-administration measures. More importantly, we demonstrate that a sex- dependent constellation of self-administration behaviors can predict the magnitude of reinstatement, which holds great promise for relapse prevention in people.

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Front-loading is a drinking pattern in which alcohol intake is skewed toward the onset of reward access. This phenomenon has been reported across several different alcohol self-administration protocols in a wide variety of species, including humans. The hypothesis of the current review is that front-loading emerges in response to the rewarding effects of alcohol and can be used to measure the motivation to consume alcohol. Alternative or additional hypotheses that we consider and contrast with the main hypothesis are that: (1) front-loading is directed at overcoming behavioral and/or metabolic tolerance and (2) front-loading is driven by negative reinforcement. Evidence for each of these explanations is reviewed. We also consider how front-loading has been evaluated statistically in previous research and make recommendations for defining this intake pattern in future studies. Because front-loading may predict long-term maladaptive alcohol drinking patterns leading to the development of alcohol use disorder (AUD), several future directions are proposed to elucidate the relationship between front-loading and AUD.

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After an extended alcohol-drinking history, alcohol use can transition from controlled to compulsive, causing deleterious consequences. Alcohol use can be segregated into two distinct behaviors, alcohol seeking and alcohol taking. Expression of habitual and compulsive alcohol seeking depends on the dorsolateral striatum (DLS), a brain region thought to engage after extended alcohol access. However, it is unknown whether the DLS is also involved in compulsive-like alcohol taking. The purpose of this experiment was to identify whether the DLS gates compulsive-like binge alcohol drinking. To ask this question, we gave adult male and female C57BL/6J mice a binge-like alcohol-drinking history, which we have previously demonstrated to produce compulsive-like alcohol drinking (Bauer, McVey, & Boehm, 2021), or a water-drinking history. We then tested the involvement of the DLS on gating binge-like alcohol drinking and compulsive-like quinine-adulterated alcohol drinking via intra-DLS AMPA receptor antagonism. We hypothesized that pharmacological lesioning of the DLS would reduce compulsive-like quinine-adulterated alcohol (QuA) drinking, but not non-adulterated alcohol drinking, in male and female C57BL/6J mice. Three important findings were made. First, compulsive-like alcohol drinking is significantly blunted in cannulated mice. Because of this, we conclude that we were not able to adequately assess the effect of intra-DLS lesioning on compulsive-like alcohol drinking. Second, we found that the DLS gates binge-like alcohol drinking initially, which replicates findings in our previous work (Bauer, McVey, Germano, Zhang, & Boehm, 2022). However, following an extended alcohol history, the DLS no longer drives this behavior. Finally, alcohol and QuA front-loading is DLS-dependent in alcohol-history mice. Intra-DLS NBQX altered these drinking behaviors without altering ambulatory locomotor activity. These data demonstrate the necessity of the DLS in binge-like alcohol drinking before, but not following, an extended binge-like alcohol-drinking history and in alcohol front-loading in alcohol-history mice.

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BACKGROUND: Excessive alcohol (ethanol) consumption, such as binge drinking, is extremely commonplace and represents a major health concern. Through modeling excessive drinking in rodents, we are beginning to uncover the neurobiological and neurobehavioral causes and consequences of this pattern of ethanol intake. One important factor for modeling binge drinking in mice is that they reliably drink to blood ethanol concentrations (BECs) of 80 mg/dl or higher. Drinking-in-the-dark (DID) is a commonly used mouse model of binge drinking, and we have shown that this method reliably results in robust ethanol front-loading and binge-level BECs in C57BL/6J (B6) mice and other ethanol-preferring mouse strains/lines. However, establishing the DID model in a new vivarium space forced us to consider the use of rodent diet formulations that we had not previously used. METHODS: The current set of experiments were designed to investigate the role of two standard rodent diet formulations on binge drinking and the development of ethanol front-loading using DID. RESULTS: We found that BECs in animals maintained on LabDiet 5001 (LD01) were double those found in mice maintained on Teklad 2920x (TL20). Interestingly, this effect was paralleled by differences in the degree of front-loading, such that LD01-fed mice consumed approximately twice as much ethanol in the first 15 min of the 2-h DID sessions as the TL20-fed mice. Surprisingly, however, mice that developed front-loading during maintenance on the LD01 diet continued to display front-loading behavior after being switched to the TL20 diet. CONCLUSIONS: These data emphasize the importance of choosing and reporting diet formulations when conducting voluntary drinking studies and support the need for further investigation into the mechanisms behind diet-induced differences in binge drinking, particularly front-loading.

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BACKGROUND: Incentives to promote drinking ("happy hour") can encourage faster rates of alcohol consumption, especially in women. Sex differences in drinking dynamics may underlie differential health vulnerabilities relating to alcohol in women versus men. Herein, we used operant procedures to model the happy hour effect and gain insight into the alcohol drinking dynamics of male and female rats. METHODS: Adult male and female Wistar rats underwent operant training to promote voluntary drinking of 10% (w/v) alcohol (8 rats/sex). We tested how drinking patterns changed after manipulating the effort required for alcohol (fixed ratio, FR), as well as the length of time in which rats had access to alcohol (self-administration session length). Rats were tested twice within the 12 h of the dark cycle, first at 2 h (early phase of the dark cycle, "early sessions") and then again at 10 h into the dark cycle (late phase of the dark cycle, "late sessions") with an 8-h break between the two sessions in the home cage. RESULTS: Adult females consumed significantly more alcohol (g/kg) than males in the 30-min sessions with the FR1 schedule of reinforcement when tested late in the dark cycle. Front-loading of alcohol was the primary factor driving higher consumption in females. Changing the schedule of reinforcement from FR1 to FR3 reduced total consumption. Notably, this manipulation had minimal effect on front-loading behavior in females, whereas front-loading behavior was significantly reduced in males when more effort was required to access alcohol. Compressing drinking access to 15 min to model a happy hour drove up front-loading behavior, generating alcohol drinking patterns in males that were similar to patterns in females (faster drinking and higher intake). CONCLUSIONS: This strategy could be useful for exploring sex differences in the neural mechanisms underlying alcohol drinking and related health vulnerabilities. Our findings also highlight the importance of the time of testing for detecting sex differences in drinking behavior.

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BACKGROUND: Previous research has demonstrated the utility of subanesthetic doses of ketamine in decreasing binge (Drinking-in-the-Dark, or DID) 20% alcohol intake in female inbred (C57BL/6J) mice when administered 12 hours prior to alcohol access (Crowley et al., 2019). In the current study, we assess the efficacy of a similar ketamine pretreatment using male and female selectively bred, crossed High Alcohol Preferring (cHAP) mice, which also drink to intoxication, but are not inbred. We hypothesized that ketamine would decrease binge alcohol intake without impacting locomotor activity. METHODS AND RESULTS: Subjects were 28 adult cHAP mice. Mice first received a 2-week DID drinking history using 2-h/day alcohol access. On day 12, prior to ketamine treatment, the average blood ethanol concentration (BEC) was 130 mg/dL, confirming that mice reliably reached intoxicating BECs. On day 15, mice were given 0, 3, or 10 mg/kg of ketamine 12 hours prior to the DID session. Ketamine did not decrease total (2-h) alcohol consumption or locomotion. Interestingly, the 10 mg/kg dose of ketamine did alter the drinking pattern in male mice, decreasing front-loading for a single day. We opted to then increase the doses to 32 or 100 mg/kg (i.e., an anesthetic dose) two days after the initial treatment, keeping the saline control. Mice of both sexes decreased total binge alcohol intake at the 100 mg/kg dose only, but again, the effect only lasted one day. CONCLUSIONS: The current study found that cHAP mice reached more than double the BECs observed in C57BL/6J mice during DID, but did not respond to subanesthetic ketamine. Modest efficacy was found for ketamine pretreatment at anesthetic doses. Differences in findings may be due to differential intake during DID, or genetic differences between C57Bl/6J mice and cHAP mice. Drug efficacy in multiple models is important for discovering reliable pharmacotherapies for alcoholism.

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The adaptive value of phenotypic plasticity for performance under single stressors is well documented. However, plasticity may only truly be adaptive in the natural multifactorial environment if it confers resilience to stressors of a different nature, a phenomenon known as cross-tolerance. An understanding of the mechanistic basis of cross-tolerance is essential to aid prediction of species resilience to future environmental change. Here, we identified mechanisms underpinning cross-tolerance between two stressors predicted to increasingly challenge aquatic ecosystems under climate change, chronic warming and hypoxia, in an ecologically-important aquatic invertebrate. Warm acclimation improved hypoxic performance through an adaptive hypometabolic strategy and changes in the expression of hundreds of genes that are important in the response to hypoxia. These 'frontloaded' genes showed a reduced reaction to hypoxia in the warm acclimated compared to the cold acclimated group. Frontloaded genes included stress indicators, immune response and protein synthesis genes that are protective at the cellular level. We conclude that increased constitutive gene expression as a result of warm acclimation reduced the requirement for inducible stress responses to hypoxia. We propose that transcriptional frontloading contributes to cross-tolerance between stressors and may promote fitness of organisms in environments increasingly challenged by multiple anthropogenic threats.

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Coral reefs are experiencing unprecedented declines in health on a global scale leading to severe reductions in coral cover. One major cause of this decline is increasing sea surface temperature. However, conspecific colonies separated by even small spatial distances appear to show varying responses to this global stressor. One factor contributing to differential responses to heat stress is variability in the coral's micro-environment, such as the amount of water flow a coral experiences. High flow provides corals with a variety of health benefits, including heat stress mitigation. Here, we investigate how water flow affects coral gene expression and provides resilience to increasing temperatures. We examined host and photosymbiont gene expression of Acropora cf. pulchra colonies in discrete in situ flow environments during a natural bleaching event. In addition, we conducted controlled ex situ tank experiments where we exposed A. cf. pulchra to different flow regimes and acute heat stress. Notably, we observed distinct flow-driven transcriptomic signatures related to energy expenditure, growth, heterotrophy and a healthy coral host-photosymbiont relationship. We also observed disparate transcriptomic responses during bleaching recovery between the high- and low-flow sites. Additionally, corals exposed to high flow showed "frontloading" of specific heat-stress-related genes such as heat shock proteins, antioxidant enzymes, genes involved in apoptosis regulation, innate immunity and cell adhesion. We posit that frontloading is a result of increased oxidative metabolism generated by the increased water movement. Gene frontloading may at least partially explain the observation that colonies in high-flow environments show higher survival and/or faster recovery in response to bleaching events.

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BACKGROUND: Beyond yielding high blood ethanol (EtOH) concentrations (BECs), binge-drinking models allow examination of drinking patterns which may be associated with EtOH's rewarding effects, including front-loading and consummatory successive negative contrast (cSNC), a decrease in intake when only water is available to subjects expecting EtOH. The goals of the current study were to broaden our understanding of these reward-related behaviors during binge EtOH access in high alcohol-preferring (HAP) replicate lines (HAP2 and HAP3) of mice selectively bred to prefer alcohol. We hypothesized that both lines would show evidence of front-loading during binge EtOH access and that we would find a cSNC effect in groups where EtOH was replaced with water, as these results have been shown previously in HAP1 mice. METHODS: HAP replicate 2 and replicate 3 female and male mice were given 2 hours of EtOH or water access in the home cage for 15 consecutive days using "drinking in the dark" (DID) procedures. Mice received the same fluid (either 20% unsweetened EtOH or water) for the first 14 days. However, on the 15th day, half of the mice from these 2 groups were provided with the opposite assigned fluid (EtOH groups received water and vice versa). Intake was measured in 1-minute bins using specialized sipper tubes, which allowed within-session analyses of binge-drinking patterns. RESULTS: EtOH front-loading was observed in both replicates. HAP3 mice displayed front-loading on the first day of EtOH access, whereas front-loading developed following alcohol experience in HAP2 mice, which may suggest differences in initial sensitivity to EtOH reward. Consummatory SNC, which manifests as lower water intake in mice expecting EtOH as compared to mice expecting water, was observed in both replicates. CONCLUSIONS: These findings increase confidence that defined changes in home cage consummatory behavior are driven by the incentive value of EtOH. The presence of cSNC across HAP replicates indicates that this reaction to loss of reward is genetically mediated, which suggests that there is a biological mechanism that might be targeted.

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OBJECTIVE/BACKGROUND: The objectives of this study are to describe the acid-fast bacilli (AFB) yield of a front-loaded scheme in which an additional on-the-spot specimen (Xspot [Xs]) was collected 1h after the first spot specimen and to compare the default rate between the front-loaded and standard schemes. The performance of the front-loaded sputum microscopy was also compared with the standard World Health Organization (WHO) method for the diagnosis of pulmonary tuberculosis (PTB) in Anambra State, Nigeria. METHODS: A total of 1487 individuals with presumptive pulmonary TB participated. Participants' age ranged from 15years and above. Three sputum specimens were submitted as spot-early morning-spot. An additional specimen (Xs) was submitted 1h after the first spot. The sputum smears were stained using the Ziehl-Neelsen technique. RESULTS: A total of 183 (12.3%) patients were AFB positive. The front-loaded scheme identified 182 (99%) TB patients, whereas the standard scheme identified 183 (100%) TB patients. The difference was not statistically significant (p>.05). The first two specimens of each scheme (S-Xs vs. S-M) identified 176 (96.2%) and 181 (98.9%) of PTB patients, respectively. Neither difference was statistically significant (p>.05). Default during the diagnostic process was 11% in the standard but only 0.7% in the front-load scheme. The difference was significant (p<.05). CONCLUSION: Front-loaded smear microscopy has similar performance compared with the standard scheme. More presumptive PTB cases defaulted in the standard than in the front-loaded scheme. Front-loaded smear microscopy could therefore be used in the diagnosis in PTB in Anambra State.

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Frontloading of skilled nursing visits is one way home health providers have attempted to reduce hospital readmissions among skilled home health patients. Upon review of the frontloading evidence, visit intensity emerged as being closely related. This state of the science presents a critique and synthesis of the published empirical evidence related to frontloading and visit intensity. OVID/Medline, PubMed, and Scopus were searched. Seven studies were eligible for inclusion. Further research is required to define frontloading and visit intensity, identify patients most likely to benefit, and to provide a better understanding of how home health agencies can best implement these strategies.

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Dual antiplatelet therapy with aspirin plus clopidogrel is not recommended for secondary stroke prevention because of lack of effectiveness and increased hemorrhagic risk. Recent studies show that in patients with a very recent transient ischemic attack or minor ischemic stroke loading with 300 mg clopidogrel plus aspirin, followed by clopidogrel 75 mg plus aspirin once daily for up to 90 days significantly decreases the rate of recurrent stroke, especially strokes that occur within few days from the event that led to medical attention, without an increase in severe bleedings. This article reviews the pharmacokinetics and pharmacodynamics of clopidogrel, focusing on loading doses, and summarizes the results of the studies that have shown the effectiveness of the front-loading approach in the early secondary prevention of stroke.

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Hospitalization among older adults receiving skilled home health services continues to be prevalent. Frontloading of skilled nursing visits, defined as providing 60% of the planned skilled nursing visits within the first two weeks of home health episode, is one way home health agencies have attempted to reduce the need for readmission among this chronically ill population. This was a retrospective observational study using data from five Medicare-owned, national assessment and claim databases from 2009. An independent randomized sample of 4500 Medicare-reimbursed home health beneficiaries was included in the analyses. Propensity score analysis was used to reduce known confounding among covariates prior to the application of logistic analysis. Although whether skilled nursing visits were frontloaded or not was not a significant predictor of 30-day hospital readmission (p = 0.977), additional research is needed to refine frontloading and determine the type of patients who are most likely to benefit from it.

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