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Transitioning to Cue-Based Feeding by Implementing an Evidence-Based ProtocolProblem: In an urban 70-bed level IV Neonatal Intensive Care Unit, cue-based feeding scores were previously implemented into the electronic medical record without sufficient education, leading to a lack of documentation by nursing staff. In a random chart audit, only 4% (n=1) of eligible patients had feeding scores documented. As a result, premature infants were not provided developmentally appropriate care that could improve their feeding outcomes. Purpose: The purpose of this quality improvement initiative was to improve the documentation of feeding scores by implementing and evaluating an electronic medical record alert and cue-based feeding rounds to notify providers of cue-based feeding eligibility. Methods: An EMR alert was developed to identify patient eligibility, and cue-based feeding rounds were utilized to notify providers of patients who qualified for cue-based feeding. Eligibility criteria included patients who were 34 weeks corrected gestational age or older, on 4 liters Vapotherm or less, and with a diet order to oral feed. The intent of the alert was to trigger the provider to order feeding score documentation as well as to remind nurses of cue-based feeding assessment and documentation. Results: Forty six percent of staff completed cue-based feeding education (n=105), 100% of eligible patients were identified (N=137), and 27% (n=37) of orders were documented in the EMR. Sixty one percent of eligible patients (n=83) had feeding scores documented. Conclusions: Two hundred forty-two interdisciplinary providers participated in the project. One hundred thirty-seven patients were included in the project. Findings suggest that cue-based feeding rounds can be useful in identifying patients who are eligible for cue-based feeding and reminding staff to document feeding scores. Weekly staff reminders are helpful in identification of eligible infants and in documentation.
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Role of cellular effectors in the induction and maintenance of IgA responses leading to protective immunity against enteric bacterial pathogensThe mucosal immune system is a critical first line of defense to infectious diseases, as many pathogens enter the body through mucosal surfaces, disrupting the balanced interactions between mucosal cells, secretory molecules, and microbiota in this challenging microenvironment. The mucosal immune system comprises of a complex and integrated network that includes the gut-associated lymphoid tissues (GALT). One of its primary responses to microbes is the secretion of IgA, whose role in the mucosa is vital for preventing pathogen colonization, invasion and spread. The mechanisms involved in these key responses include neutralization of pathogens, immune exclusion, immune modulation, and cross-protection. The generation and maintenance of high affinity IgA responses require a delicate balance of multiple components, including B and T cell interactions, innate cells, the cytokine milieu (e.g., IL-21, IL-10, TGF-b), and other factors essential for intestinal homeostasis, including the gut microbiota. In this review, we will discuss the main cellular components (e.g., T cells, innate lymphoid cells, dendritic cells) in the gut microenvironment as mediators of important effector responses and as critical players in supporting B cells in eliciting and maintaining IgA production, particularly in the context of enteric infections and vaccination in humans. Understanding the mechanisms of humoral and cellular components in protection could guide and accelerate the development of more effective mucosal vaccines and therapeutic interventions to efficiently combat mucosal infections.
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Role of circulating T follicular helper subsets following Ty21a immunization and oral challenge with wild type S. Typhi in humansDespite decades of intense research, our understanding of the correlates of protection against Salmonella Typhi (S. Typhi) infection and disease remains incomplete. T follicular helper cells (TFH), an important link between cellular and humoral immunity, play an important role in the development and production of high affinity antibodies. While traditional TFH cells reside in germinal centers, circulating TFH (cTFH) (a memory subset of TFH) are present in blood. We used specimens from a typhoid controlled human infection model whereby participants were immunized with Ty21a live attenuated S. Typhi vaccine and then challenged with virulent S. Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), which allowed us to assess the association of cTFH subsets in the development and prevention of typhoid disease. Of note, the frequencies of cTFH were higher in NoTD than in TD participants, particularly 7 days after challenge. Furthermore, the frequencies of cTFH2 and cTFH17, but not cTFH1 subsets were higher in NoTD than TD participants. However, we observed that ex-vivo expression of activation and homing markers were higher in TD than in NoTD participants, particularly after challenge. Moreover, cTFH subsets produced higher levels of S. Typhi-specific responses (cytokines/chemokines) in both the immunization and challenge phases. Interestingly, unsupervised analysis revealed unique clusters with distinct signatures for each cTFH subset that may play a role in either the development or prevention of typhoid disease. Importantly, we observed associations between frequencies of defined cTFH subsets and anti-S. Typhi antibodies. Taken together, our results suggest that circulating TFH2 and TFH17 subsets might play an important role in the development or prevention of typhoid disease. The contribution of these clusters was found to be distinct in the immunization and/or challenge phases. These results have important implications for vaccines aimed at inducing longlived protective T cell and antibody responses.
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Changes in monocyte subsets in volunteers who received an oral wild-type Salmonella Typhi challenge and reached typhoid diagnosis criteriaAn oral Controlled Human Infection Model (CHIM) with wild-type S. Typhi was re-established allowing us to explore the development of immunity. In this model, ~55% of volunteers who received the challenge reached typhoid diagnosis criteria (TD), while ~45% did not (NoTD). Intestinal macrophages are one of the first lines of defense against enteric pathogens. Most organs have selfrenewing macrophages derived from tissue-resident progenitor cells seeded during the embryonic stage; however, the gut lacks these progenitors, and all intestinal macrophages are derived from circulating monocytes. After infecting gut-associated lymphoid tissues underlying microfold (M) cells, S. Typhi causes a primary bacteremia seeding organs of the reticuloendothelial system. Following days of incubation, a second bacteremia and clinical disease ensue. S. Typhi likely interacts with circulating monocytes or their progenitors in the bone marrow. We assessed changes in circulating monocytes after CHIM. The timepoints studied included 0 hours (pre-challenge) and days 1, 2, 4, 7, 9, 14, 21 and 28 after challenge. TD participants provided extra samples at the time of typhoid diagnosis, and 48-96 hours later (referred as ToD). We report changes in Classical Monocytes -CM-, Intermediate Monocytes -IM- and Non-classical Monocytes -NCM-. Changes in monocyte activation markers were identified only in TD participants and during ToD. CM and IM upregulated molecules related to interaction with bacterial antigens (TLR4, TLR5, CD36 and CD206). Of importance, CM and IM showed enhanced binding of S. Typhi. Upregulation of inflammatory molecules like TNF-a were detected, but mechanisms involved in limiting inflammation were also activated (CD163 and CD354 downregulation). CM upregulated molecules to interact/modulate cells of the adaptive immunity, including T cells (HLA-DR, CD274 and CD86) and B cells (CD257). Both CM and IM showed potential to migrate to the gut as integrin a4b7 was upregulated. Unsupervised analysis revealed 7 dynamic cell clusters. Five of these belonged to CM showing that this is the main population activated during ToD. Overall, we provide new insights into the changes that diverse circulating monocyte subsets undergo after typhoid diagnosis, which might be important to control this disease since these cells will ultimately become intestinal macrophages once they reach the gut.
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Mobilization of endocannabinoids by midbrain dopamine neurons is required for the encoding of reward predictionBrain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) shape motivated behavior and nucleus accumbens (NAc) dopamine release. However, it is not clear whether mobilization of 2-AG specifically from midbrain dopamine neurons is necessary for dopaminergic responses to external stimuli predicting forthcoming reward. Here, we use a viral-genetic strategy to prevent the expression of the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) from ventral tegmental area (VTA) dopamine cells in adult mice. We find that DGLα deletion fromVTA dopamine neurons prevents depolarizationinduced suppression of excitation (DSE), a form of 2-AG-mediated synaptic plasticity, in dopamine neurons. DGLα deletion also decreases effortful, cuedriven reward-seeking but has no effect on non-cued or low-effort operant tasks and other behaviors. Moreover, dopamine recording in the NAc reveals that deletion of DGLα impairs the transfer of accumbal dopamine signaling from a reward to its earliest predictors. These results demonstrate that 2-AG mobilization from VTA dopamine neurons is a necessary step for the generation of dopamine-based predictive associations that are required to direct and energize reward-oriented behavior.
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Antidepressant treatment initiation among children and adolescents with acute versus long COVID: a large retrospective cohort studyBackground Child and adolescent antidepressant use increased post-pandemic, but it is unknown if this disproportionally affected those who develop post-acute sequelae of coronavirus disease 2019 (COVID) or long COVID. This study compared the risk of antidepressant initiation among children and adolescents with long COVID with those who had COVID but did not have evidence of long COVID. Methods Our retrospective cohort study of children and adolescents aged 3–17 years at the first evidence of COVID or long COVID from October 1, 2021 through April 4, 2022 was conducted within Komodo’s Healthcare Map™ database. The index date was the earliest date of a medical claim associated with a COVID (COVID comparators) or long COVID diagnosis (long COVID cases). The baseline period was six months before the index date. The outcome was antidepressant initiation within twelve months after the index date. Due to the large number of COVID relative to long COVID cases, COVID comparators were randomly selected with a ratio of 2 COVID to 1 long COVID. We used propensity score matching to control for confounding due to imbalances in the baseline covariates. Log-binomial models estimated the relative risk (RR) of antidepressant initiation in the propensity score matched sample. We conducted several sensitivity analyses to test the robustness of our findings to several assumptions. Results Our child and adolescent sample included 18 274 with COVID and 9137 with long COVID. Compared with those with COVID, a larger proportion of long COVID children and adolescents had psychiatric disorders, psychotropic use, medical comorbidities, were previously hospitalized, or visited the emergency department. In the propensity score-adjusted analysis, the long COVID group had a statistically significant higher risk of antidepressant initiation relative to the COVID comparator (adjusted-RR: 1.40, 95% CI = 1.20, 1.62). Our findings were robust across sensitivity analyses. Conclusions The increased risk of antidepressant initiation following long COVID warrants further study to better understand the underlying reasons for this higher risk. Emerging evidence of long COVID’s impact on child mental health has important implications for prevention and early interventions.
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Impact of the US Food and Drug Administration warning regarding increased risk of aortic aneurysms or aortic dissections on fluoroquinolone prescribing trendsBackground The US Food and Drug Administration (FDA) issued a warning in December 2018 regarding an increased risk of aortic aneurysms and aortic dissections associated with fluoroquinolone (FQ) use. This warning specifically targeted older adults and patients with conditions such as hypertension, Marfan syndrome, Ehlers-Danlos syndrome, atherosclerosis, peripheral vascular disease and history of aneurysms. Objective To evaluate the impact of the safety warning on prescribing trends of FQs in the targeted population. Methods This cross-sectional study with an interrupted time series (ITS) analysis (January 2018–December 2019) used a 25% random sample of IQVIA PharMetrics® Plus for Academics health plan claims database. The impact of the warning on FQ utilisation was quantified among the targeted population and a non-targeted population. Results From 2018 to 2019, both study populations saw a decrease in the year-over- year percent change of FQ prescriptions per 100 000 beneficiaries (−11%, from 14 227 to 12 662, targeted; −15%, from 5227 to 4446, non-targeted) and proportion of FQ use versus other antibiotics (from 15.6% to 13.8%, targeted; from 9.4% to 8%, non-targeted). In the targeted population, the ITS analysis did not show a significant trend change, a change in level or postwarning trend in the monthly rate of FQ prescriptions per 1000 beneficiaries. A positive trend change was observed in the non-targeted population (0.07, <0.01–0.13), but there were no significant changes in level or post-warning trend. Conclusion We did not find a change in FQ prescription rates after the warning. The utility of safety advisories as a primary tool for mitigating FQ use in high-risk populations should be revisited.
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County-level factors associated with a mismatch between opioid overdose mortality and availability of opioid treatment facilitiesOpioid overdose deaths in the United States remain a major public health crisis. Little is known about counties with high rates of opioid overdose mortality but low availability of opioid use disorder (OUD) treatment facilities. We sought to identify characteristics of United States (US) counties with high rates of opioid overdose mortality and low rates of opioid treatment facilities. Rates of overdose mortality from 3,130 US counties were compared with availability of opioid treatment facilities that prescribed or allowed medications for OUD (MOUD), from 2018- 2019. The outcome variable, “risk-availability mismatch” county, was a binary indicator of a high rate (above national average) of opioid overdose mortality with a low (below national average) rate of opioid treatment facilities. Covariates of interest included county-level sociodemographics and rates of insurance, unemployment, educational attainment, poverty, urbanicity, opioid prescribing, depression, heart disease, Gini index, and Theil index. Multilevel logistic regression, accounting for the clustering of counties within states, was used to determine associations with being a “risk-availability mismatch” county. Of 3,130 counties, 1,203 (38.4%) had high rates of opioid overdose mortality. A total of 1,098 counties (35.1%) lacked a publicly-available opioid treatment facility in 2019. In the adjusted model, counties with an additional 1% of: white residents (odds ratio, OR, 1.02; 95% CI, 1.01-1.03), unemployment (OR, 1.11; 95% CI, 1.05-1.19), and residents without insurance (OR, 1.04; 95% CI, 1.01-1.08) had increased odds of being a mismatch county. Counties that were metropolitan (versus non-metropolitan) had an increased odds of being a mismatch county (OR, 1.85; 95% CI, 1.45-2.38). Assessing mismatch between treatment availability and need provides useful information to characterize counties that require greater public health investment. Interventions to reduce overdose mortality are unlikely to be effective if they do not take into account diverse upstream factors, including sociodemographics, disease burden, and geographic context of communities.
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Opioid use disorder in pregnancy: leveraging provider perceptions to inform comprehensive treatmentBackground: Medications for opioid use disorder (MOUD) are recommended with adjuvant behavioral therapies, counseling, and other services for comprehensive treatment of maternal opioid use disorder. Inadequate access to treatment, lack of prescribing providers and complex delivery models are among known barriers to care. Multidisciplinary provider input can be leveraged to comprehend factors that facilitate or inhibit treatment. The objective of this study is to explore provider perceptions of MOUD and factors critical to comprehensive treatment delivery to improve the care of pregnant women with opioid use disorder. Methods: A qualitative research approach was used to gather data from individual provider and group semistructured interviews. Providers (n = 12) responded to questions in several domains related to perceptions of MOUD, treatment delivery, access to resources, and challenges/barriers. Data were collected, transcribed, coded (by consensus) and emerging themes were analyzed using grounded theory methodology. Results: Emerging themes revealed persistent gaps in treatment and challenges in provider, health systems and patient factors. Providers perceived MOUD to be a “lifeline” to women. Conclusions: Inconsistencies in treatment provision, access and uptake can be improved by leveraging provider perceptions, direct experiences and recommendations for an integrated team-based, patient-centered approach to guide the care of pregnant women with opioid use disorder.
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Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon CancerCancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers.
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Successful Profiling of Plasmodium falciparum var Gene Expression in Clinical Samples via a Custom Capture Arrayvar genes encode Plasmodium falciparum erythrocyte membrane protein- 1 (PfEMP1) antigens. These highly diverse antigens are displayed on the surface of infected erythrocytes and play a critical role in immune evasion and sequestration of infected erythrocytes. Studies of var expression using non-leukocyte-depleted blood are challenging because of the predominance of host genetic material and lack of conserved var segments. Our goal was to enrich for parasite RNA, allowing de novo assembly of var genes and detection of expressed novel variants. We used two overall approaches: (i) enriching for total mRNA in the sequencing library preparations and (ii) enriching for parasite RNA with a custom capture array based on Roche’s SeqCap EZ enrichment system. The capture array was designed with probes based on the whole 3D7 reference genome and an additional .4,000 full-length var gene sequences from other P. falciparum strains. We tested each method on RNA samples from Malian children with severe or uncomplicated malaria infections. All reads mapping to the human genome were removed, the remaining reads were assembled de novo into transcripts, and from these, var-like transcripts were identified and annotated. The capture array produced the longest maximum length and largest numbers of var gene transcripts in each sample, particularly in samples with low parasitemia. Identifying the most-expressed var gene sequences in whole-blood clinical samples without the need for extensive processing or generating sample-specific reference genome data is critical for understanding the role of PfEMP1s in malaria pathogenesis.
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Malian adults maintain serologic responses to virulent PfEMP1s amid seasonal patterns of fluctuationPlasmodium falciparum erythrocyte membrane protein-1s (PfEMP1s), diverse malaria proteins expressed on the infected erythrocyte surface, play an important role in pathogenesis, mediating adhesion to host vascular endothelium. Antibodies to particular non-CD36-binding PfEMP1s are associated with protection against severe disease. We hypothesized that given lifelong P. falciparum exposure, Malian adults would have broad PfEMP1 serorecognition and high seroreactivity levels during follow-up, particularly to non-CD36-binding PfEMP1s such as those that attach to endothelial protein C receptor (EPCR) and intercellular adhesion molecule-1 (ICAM-1). Using a protein microarray, we determined serologic responses to 166 reference PfEMP1 fragments during a dry and subsequent malaria transmission season in Malian adults. Malian adult sera had PfEMP1 serologic responses throughout the year, with decreased reactivity to a small subset of PfEMP1 fragments during the dry season and increases in reactivity to a different subset of PfEMP1 fragments during the subsequent peak malaria transmission season, especially for intracellular PfEMP1 domains. For some individuals, PfEMP1 serologic responses increased after the dry season, suggesting antigenic switching during asymptomatic infection. Adults were more likely to experience variable serorecognition of CD36- binding PfEMP1s than non-CD36-binding PfEMP1s that bind EPCR or ICAM-1, which remained serorecognized throughout the year. Sustained seroreactivity to non-CD36-binding PfEMP1s throughout adulthood amid seasonal fluctuation patterns may reflect underlying protective severe malaria immunity and merits further investigation.
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Outcomes in Hepatitis C Positive Liver Transplantation: Timing of Direct-Acting Antiviral Treatment and Impact on Graft FibrosisLiver transplantation for hepatitis C virus (HCV)-related disease has the lowest five-year graft survival among all liver transplant recipients. Graft failure due to accelerated fibrosis from unrestrained HCV replication is common. Optimal timing of HCV treatment with direct-acting antiviral agents remains unknown. We compared HCV liver transplant recipients successfully treated for HCV before transplant to those treated within 1 year of transplant to determine if graft fibrosis, measured by Fib-4 scores, differs with timing of treatment. Fib-4 scores less than or equal to 1.45 defined minimal fibrosis and greater than 1.45 defined greater than minimal fibrosis. We identified 117 liver transplant recipients: 52 treated before transplantation and 65 treated within 1 year of transplantation. Overall, 34% of recipients had minimal fibrosis, and the likelihood of having minimal fibrosis following treatment and liver transplantation did not differ by timing of treatment. The odds ratio of having greater than minimal fibrosis was 0.65 (95% CI 0.30, 1.42) among those treated within 1 year after transplantation compared to those treated before transplantation (p-value 0.28). Importantly, nearly 2/3 of these patients had evidence of fibrosis progression one year after sustained virologic response, supporting recommendations for early antiviral-based treatment to prevent accumulation of HCV-related disease.
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Therapeutic Efficacy of Variable Biological Effectiveness of Proton Therapy in U-CH2 and MUG-Chor1 Human Chordoma Cell DeathBackground: Chordoma is a cancer of spinal cord, skull base, and sacral area. Currently, the standard of care to treat chordoma is resection followed by radiation therapy. Since, chordoma is present in the spinal cord and these are very sensitive structures and often complete removal by surgery is not possible. As a result, chordoma has a high chance of recurrence and developing resistance to radiation therapy. In addition, treatment of chordoma by conventional radiation therapy can also damage normal tissues surrounding chordoma. Thus, current therapeutic options to treat chordoma are insufficient and novel therapies are desperately needed to treat locally advanced and metastatic chordoma. (2) Methods: In the present investigation, human chordoma cell lines of sacral origin MUG-Chor1 and U-CH2 were cultured and irradiated with Proton Beam Radiation using the clinical superconducting cyclotron and pencil-beam (active) scanning at Middle and End of the Spread-Out Bragg Peak (SOBP). Proton radiation was given at the following doses: Mug-Chor1 at 0, 1, 2, 4, and 8 Gy and U-CH2 at 0, 4, 8, 12, and 16 Gy. These doses were selected based on a pilot study in our lab and attempted to produce approximate survival fractions in the range of 1, 0.9, 0.5, 0.1, and 0.01, respectively, chosen for linear quadratic model fitting of the dose response. (3) Results: In this study, we investigated relative biological effectiveness (RBE) of proton radiation at the end of Spread Out Bragg Peak assuming that the reference radiation is a proton radiation in the middle of the SOBP.We observed differences in the survival of both Human chordoma cell lines, U-CH2 and MUG-Chor1. The data showed that there was a significantly higher cell death at the end of the Bragg peak as compared to middle of the Bragg peak. Based on the linear quadratic (LQ) fit for cell survival we calculated the RBE between M-SOBP and E-SOBP at 95% CI level and it was observed that RBE was higher than 1 at E-SOBP caused complex DNA damage in comparison to M-EOBP and the genes such as DNA topoisomerase 1, GTSE1, RAD51B were downregulated in E-SOBP treated cells. Thus, we conclude that there seems to be substantial variation in RBE (1.3-1.7) at the E-SOBP compared with the M-SOBP.
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The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivoCytokines are typically single gene products, except for the heterodimeric interleukin (IL)-12 family. The two subunits (IL-12p40 and IL-12p35) of the prototype IL-12 are known to be simultaneously co-expressed in activated myeloid cells, which secrete the fully active heterodimer to promote interferon (IFN)g production in innate and adaptive cells. We find that chimeric mice containing mixtures of cells that can only express either IL-12p40 or IL-12p35, but not both together, generate functional IL-12. This alternate two-cell pathway requires IL-12p40 from hematopoietic cells to extracellularly associate with IL-12p35 from radiation-resistant cells. The two-cell mechanism is sufficient to propel local T cell differentiation in sites distal to the initial infection and helps control systemic dissemination of a pathogen, although not parasite burden, at the site of infection. Broadly, this suggests that early secretion of IL-12p40 monomers by sentinel cells at the infection site may help prepare distal host tissues for potential pathogen arrival.
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Acute Limb Ischemia Caused by Inadvertent Arterial Drug Self-Injection: A Case ReportObjective: Unusual clinical course Background: A predictable consequence of long-term injection drug use is the destruction of the native venous system; as a consequence, people who inject drugs may eventually move to injection into skin and subcutaneous tissue, wounds, muscles, and arteries. These practices put people who inject drugs at risk for injection-related softtissue infection, vascular damage, ischemia, and compartment syndrome, all of which have overlapping presenting symptoms. Case Report: A 35-year-old man who injects drugs presented with foot swelling and discoloration initially concerning for necrotizing fasciitis or compartment syndrome. After progression despite appropriate antimicrobial and surgical treatment for soft-tissue infection, he was diagnosed with arterial insufficiency and resultant distal ischemia. This diagnosis was discovered only after obtaining additional history of the patient’s drug use practices. Just prior to his symptoms, he had unintentionally injected a formed thrombus into his dorsalis pedis artery. Conclusions: Intra-arterial injection of drugs can cause ischemia through a variety of mechanisms, including direct vessel trauma, arterial spasm, toxicity from the drug of abuse or an adulterant, embolism of particulate matter, and as proposed here, direct injection of preformed thrombus. Medical providers should be aware of the steps of injection drug use and their associated risks so that they can ask appropriate questions to focus their differential diagnosis, increase their understanding of common or current local injection practices, and develop rapport with the patient. Patient education on safe injection techniques may also reduce the risk of serious complications.
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Effect of Stretching of Spastic Elbow Under Intelligent Control in Chronic Stroke Survivors—A Pilot StudyObjective: To assess the short-termeffects of strenuous dynamic stretching of the elbow joint using an intelligent stretching device in chronic spastic stroke survivors. Methods: The intelligent stretching device was utilized to provide a single session of intensive stretching to the spastic elbow joint in the sagittal plane (i.e., elbow flexion and extension). The stretching was provided to the extreme range, safely, with control of the stretching velocity and torque to increase the joint range of motion (ROM) and reduce spasticity and joint stiffness. Eight chronic stroke survivors (age: 52.6 ± 8.2 years, post-stroke duration: 9.5 ± 3.6 years) completed a single 40-min stretching intervention session. Elbow passive and active ROM, strength, passive stiffness (quantifying the non-reflex component of spasticity), and instrumented tendon reflex test of the biceps tendon (quantifying the reflex component of the spasticity) were measured before and after stretching. Results: After stretching, there was a significant increase in passive ROM of elbow flexion (p = 0.021, r = 0.59) and extension (p = 0.026, r = 0.59). Also, elbow active ROM and the spastic elbow flexors showed a trend of increase in their strength. Conclusion: The intelligent stretching had a short-term positive influence on the passive movement ROM. Hence, intelligent stretching can potentially be used to repeatedly and regularly stretch spastic elbow joints, which subsequently helps to reduce upper limb impairments post-stroke.
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Comparative Ca2D channel contributions to intracellular Ca2D levels in the circadian clockABSTRACT Circadian rhythms in mammals are coordinated by the central clock in the brain, located in the suprachiasmatic nucleus (SCN). Multiple molecular and cellular signals display a circadian variation within SCN neurons, including intracellular Ca2þ, but the mechanisms are not definitively established. SCN cytosolic Ca2þ levels exhibit a peak during the day, when both action potential firing and Ca2þ channel activity are increased, and are decreased at night, correlating with a reduction in firing rate. In this study, we employ a single-color fluorescence anisotropy reporter (FLARE), Venus FLARE-Cameleon, and polarization inverted selective-plane illumination microscopy to measure rhythmic changes in cytosolic Ca2þ in SCN neurons. Using this technique, the Ca2þ channel subtypes contributing to intracellular Ca2þ at the peak and trough of the circadian cycle were assessed using a pharmacological approach with Ca2þ channel inhibitors. Peak (218 5 16 nM) and trough (172 5 13 nM) Ca2þ levels were quantified, indicating a 1.3-fold circadian variance in Ca2þ concentration. Inhibition of ryanodine-receptor-mediated Ca2þ release produced a larger relative decrease in cytosolic Ca2þ at both time points compared to voltage-gated Ca2þchannels. These results support the hypothesis that circadian Ca2þ rhythms in SCN neurons are predominantly driven by intracellular Ca2þ channels, although not exclusively so. The study provides a foundation for future experiments to probe Ca2þ signaling in a dynamic biological context using FLAREs.
