Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.

OBJECTIVES: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling. MATERIALS AND METHODS: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale. RESULTS: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes. CONCLUSION: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.

Clinical pharmacokinetics of atropine oral gel formulation in healthy volunteers.

Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off-label treatment to manage sialorrhea. However, the off-label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off-label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single-dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two-compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL-1 , respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h-1 . Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well-tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.

Impact of disability-based discrimination in healthcare on parents of children with medical complexity.

AIM: To qualitatively assess the impact of disability-based discrimination in healthcare on the parents of children with medical complexity (CMC). METHOD: In this qualitative study, we conducted in-depth, semi-structured interviews with the parents of CMC. Data collection and analysis occurred iteratively; constant comparison methods were used to identify themes describing the impact of disability-based discrimination in pediatric healthcare on the parents of CMC. RESULTS: Thirty participants from 15 US states were interviewed. Four themes were developed regarding the impact of disability-based discrimination in healthcare on parents. The themes were: (1) discrimination leads to a loss of trust in healthcare providers; (2) discrimination increases the burden of caregiving; (3) discrimination impacts parental well-being; and (4) racism and poverty-based discrimination amplifies disability-based discrimination. INTERPRETATION: The experience of discrimination toward their child results in loss of trust and therapeutic relationship between provider and parent, causes increased burden to the family, and contributes to decreased parental well-being. These experiences are magnified in minoritized families and in families perceived to have a lower socioeconomic status based on insurance type.

Trauma-Informed Yoga Teacher Training: Impact on Incarcerated Men's Wellness.

In late 2021, the United States had a total of 1.2 million individuals confined in state and federal prisons, with approximately 1.1 million of these people being men. Although existing research provides evidence that engaging in yoga programs within prison settings can enhance the well-being of incarcerated individuals, with several studies supporting this claim, knowledge regarding the specific effects of participating in a yoga teacher training program during confinement is still lacking. The purpose of the present investigation was to evaluate the effect of completing a prison-based 200-hour trauma-sensitive yoga teacher training program on the perceived physical, mental, social, and spiritual wellness of men in prison. We hypothesized that men who successfully completed the training program would report notable improvements in all four dimensions of wellness. Focus groups, participant workbook reviews, and demographic surveys were used to understand how participation in yoga teacher training influenced men's perceived wellness. Participants identified a variety of wellness gains associated with yoga teacher training. These gains have the potential to contribute to improved individual health, improved relationships with others, and safer communities.

Perceived Disability-Based Discrimination in Health Care for Children With Medical Complexity.

BACKGROUND AND OBJECTIVES: Disability-based discrimination in health care can lead to low quality of care, limited access to care, and negative health consequences. Yet, little is known regarding the experiences of disability-based discrimination in health care for children with medical complexity and disability. An understanding of disability-based discrimination in pediatrics is needed to drive change and improve care. METHODS: We conducted in-depth, semistructured interviews with caregivers of children with medical complexity and disability. Participants were purposefully recruited through national advocacy and research networks. Interviews were conducted via video conferencing, recorded, and transcribed. Data collection and analysis occurred iteratively. An inductive thematic analysis approach with constant comparison methods was used to identify themes that form a conceptual framework of disability-based discrimination in health care. RESULTS: Thirty participants from diverse backgrounds were interviewed. Six themes emerged, forming a conceptual framework of disability-based discrimination in health care. Three themes described drivers of discrimination: lack of clinician knowledge, clinician apathy, and clinician assumptions. Three themes described manifestations of discrimination: limited accessibility to care, substandard care, and dehumanization. CONCLUSIONS: Children with medical complexity may face disability-based discrimination in health care. Themes describing the drivers and manifestations of discrimination offer a conceptual framework of disability-based discrimination. Understanding the drivers and acknowledging perceived manifestations can provide insight into improving patient care for children with disabilities.

High Parental Concern in Children With Medical Complexity: An Early Indicator of Illness.

OBJECTIVES: High concern about child's health is a common reason parents of children with medical complexity (CMC) seek care in emergency departments and hospitals. Factors driving parental concern are unknown. This study explores associations of parent's sociodemographic and child's clinical factors with high parental concern. PATIENT AND METHODS: Secondary analysis of a pilot study of CMC and parents who used daily for 3 months MyChildCMC, a home monitoring app. Parents recorded their child's vital signs (temperature, heart rate, respiratory rate, oximetry), symptoms (pain, seizures, fluid intake/feeding, mental status), and oxygen use, and received immediate feedback. Parents rated their child's health concern on a 4-point Likert scale. Concern scores were dichotomized (3-4 = high, 1-2 = low) and modeled in a mixed-effects logistic regression to explore important associations. RESULTS: We analyzed 1223 measurements from 24 CMC/parents, with 113 (9.24%) instances of high concern. Child factors associated with high parental concern were increased pain (odds ratio [OR], 5.10; 95% confidence interval [CI], 2.53-10.29; P < .01), increased oxygen requirement (OR, 28.91; 95% CI, 10.07-82.96; P < .01), reduced nutrition/fluid intake (OR, 71.58; 95% CI, 13.01-393.80; P < .01), and worsened mental status (OR, 2.15; 95% CI, 1.10-4.17, P = .02). No other associations existed. CONCLUSIONS: Changes in CMC's clinical parameters were associated with high concern, which may be an early indicator of acute illness in CMC when it is the primary complaint. Monitoring and responding to high parental concerns may support CMC care at home.

Metabolic Adaptations and Substrate Oxidation are Unaffected by Exogenous Testosterone Administration during Energy Deficit in Men.

INTRODUCTION/PURPOSE: The effects of testosterone on energy and substrate metabolism during energy deficit are unknown. The objective of this study was to determine the effects of weekly testosterone enanthate (TEST; 200 mg·wk -1 ) injections on energy expenditure, energy substrate oxidation, and related gene expression during 28 d of energy deficit compared with placebo (PLA). METHODS: After a 14-d energy balance phase, healthy men were randomly assigned to TEST ( n = 24) or PLA ( n = 26) for a 28-d controlled diet- and exercise-induced energy deficit (55% below total energy needs by reducing energy intake and increasing physical activity). Whole-room indirect calorimetry and 24-h urine collections were used to measure energy expenditure and energy substrate oxidation during balance and deficit. Transcriptional regulation of energy and substrate metabolism was assessed using quantitative reverse transcription-polymerase chain reaction from rested/fasted muscle biopsy samples collected during balance and deficit. RESULTS: Per protocol design, 24-h energy expenditure increased ( P < 0.05) and energy intake decreased ( P < 0.05) in TEST and PLA during deficit compared with balance. Carbohydrate oxidation decreased ( P < 0.05), whereas protein and fat oxidation increased ( P < 0.05) in TEST and PLA during deficit compared with balance. Change (∆; deficit minus balance) in 24-h energy expenditure was associated with ∆activity factor ( r = 0.595), but not ∆fat-free mass ( r = 0.147). Energy sensing (PRKAB1 and TP53), mitochondria (TFAM and COXIV), fatty acid metabolism (CD36/FAT, FABP, CPT1b, and ACOX1) and storage (FASN), and amino acid metabolism (BCAT2 and BCKHDA) genes were increased ( P < 0.05) during deficit compared with balance, independent of treatment. CONCLUSIONS: These data demonstrate that increased physical activity and not exogenous testosterone administration is the primary determinate of whole-body and skeletal muscle metabolic adaptations during diet- and exercise-induced energy deficit.

Palliative Care Needs Assessment for Pediatric Complex Care Providers.

CONTEXT: Children with medical complexity (CMC) are often cared for by both complex care and palliative care pediatric teams. No prior research has investigated the relationship between these two disciplines. OBJECTIVES: The purpose of this article is to investigate challenges that complex care programs face in caring for children with medical complexity (CMC), as well as to explore whether identified challenges could be met through collaboration with pediatric palliative care or additional training for complex care teams. METHODS: Medical providers who self-identified as providing clinical care to children with medical complexity were asked to complete an online anonymous survey. Subjects were recruited through a Complex Care listerv. Data were analyzed using descriptive statistics. RESULTS: 85 subjects completed the survey, of whom 87.1% (n=74) were physicians, and 12.0% (n=11) were nurse practitioners. Subjects reported several challenges in caring for CMC, including symptom management, establishing goals of care, advance care planning, and coordination of care. A majority of subjects reported benefitting from palliative care consultative assistance in each subject area. Most subjects described their relationship with palliative care as a close partnership with frequent overlap. CONCLUSIONS: The evolving field of pediatric complex care is associated with an array of challenges in caring for CMC. Many of these challenges include competency areas where palliative care providers receive concerted training. Our research suggests greater palliative care involvement in the CMC population can benefit complex care teams and patients, given the expertise palliative providers can bring to the population and the discipline of complex care.

Carbohydrate intake in recovery from aerobic exercise differentiates skeletal muscle microRNA expression.

Posttranscriptional regulation by microRNA (miRNA) facilitates exercise and diet-induced skeletal muscle adaptations. However, the impact of diet on miRNA expression during postexercise recovery remains unclear. The objective of this study was to examine the effects of consuming carbohydrate or a nutrient-free control on skeletal muscle miRNA expression during 3 h of recovery from aerobic exercise. Using a randomized, crossover design, seven men (means ± SD, age: 21 ± 3 yr; body mass: 83 ± 13 kg; V̇o2peak: 43 ± 2 mL/kg/min) completed two-cycle ergometry glycogen depletion trials followed by 3 h of recovery while consuming either carbohydrate (CHO: 1 g/kg/h) or control (CON: nutrient free). Muscle biopsy samples were obtained under resting fasted conditions at baseline and at the end of the 3-h recovery (REC) period. miRNA expression was determined using unbiased RT-qPCR microarray analysis. Trials were separated by 7 days. Twenty-five miRNAs were different (P < 0.05) between CHO and CON at REC, with Let7i-5p and miR-195-5p being the most predictive of treatment. In vitro overexpression of Let7i-5p and miR-195-p5 in C2C12 skeletal muscle cells decreased (P < 0.05) the expression of protein breakdown (Foxo1, Trim63, Casp3, and Atf4) genes, ubiquitylation, and protease enzyme activity compared with control. Energy sensing (Prkaa1 and Prkab1) and glycolysis (Gsy1 and Gsk3b) genes were lower (P < 0.05) with Let7i-5p overexpression compared with miR-195-5p and control. Fat metabolism (Cpt1a, Scd1, and Hadha) genes were lower (P < 0.05) in miR-195-5p than in control. These data indicate that consuming CHO after aerobic exercise alters miRNA profiles compared with CON, and these differences may govern mechanisms facilitating muscle recovery.NEW & NOTEWORTHY Results provide novel insight into effects of carbohydrate intake on the expression of skeletal muscle microRNA during early recovery from aerobic exercise and reveal that Let7i-5p and miR-195-5p are important regulators of skeletal muscle protein breakdown to aid in facilitating muscle recovery.

Circulating and skeletal muscle microRNA profiles are more sensitive to sustained aerobic exercise than energy balance in males.

MicroRNAs (miRNAs) regulate molecular processes governing muscle metabolism. Physical activity and energy balance influence both muscle anabolism and substrate metabolism, but whether circulating and skeletal muscle miRNAs mediate those effects remains unknown. This study assessed the impact of sustained physical activity with participants in energy balance (BAL) or deficit (DEF) on circulating and skeletal muscle miRNAs. Using a randomized cross-over design, 10 recreational active healthy males (mean ± SD, 22 ± 5 years, 87 ± 11 kg) completed 72 h of high aerobic exercise-induced energy expenditures in BAL (689 ± 852 kcal/day) or DEF (-2047 ± 920 kcal/day). Blood and muscle samples were collected under rested/fasted conditions before (PRE) and immediately after 120 min load carriage exercise bout at the end (POST) of the 72 h. Trials were separated by 7 days. Circulating and skeletal muscle miRNAs were measured using microarray RT-qPCR. Independent of energy status, 36 circulating miRNAs decreased (P < 0.05), while 10 miRNAs increased and three miRNAs decreased in skeletal muscle (P < 0.05) at POST compared to PRE. Of these, miR-122-5p, miR-221-3p, miR-222-3p and miR-24-3p decreased in circulation and increased in skeletal muscle. Two circulating (miR-145-5p and miR-193a-5p) and four skeletal muscle (miR-21-5p, miR-372-3p, miR-34a-5p and miR-9-5p) miRNAs had time-by-treatment effects (P < 0.05). These data suggest that changes in miRNA profiles are more sensitive to increased physical activity compared to energy status, and that changes in circulating miRNAs in response to high levels of daily aerobic exercise are not reflective of changes in skeletal muscle miRNAs. KEY POINTS: Circulating and skeletal muscle miRNA profiles are more sensitive to high levels of aerobic exercise-induced energy expenditure compared to energy status. Changes in circulating miRNA in response to high levels of daily sustained aerobic exercise are not reflective of changes in skeletal muscle miRNA.

Mild to Moderate Food Deprivation Increases Hepcidin and Results in Hypoferremia and Tissue Iron Sequestration in Mice.

BACKGROUND: Short-term starvation and severe food deprivation (FD) reduce dietary iron absorption and restricts iron to tissues, thereby limiting the amount of iron available for erythropoiesis. These effects may be mediated by increases in the iron regulatory hormone hepcidin; however, whether mild to moderate FD has similar effects on hepcidin and iron homeostasis is not known. OBJECTIVES: To determine the effects of varying magnitudes and durations of FD on hepcidin and indicators of iron status in male and female mice. METHODS: Male and female C57BL/6J mice (14 wk old; n = 170) were randomly assigned to consume AIN-93M diets ad libitum (AL) or varying magnitudes of FD (10%, 20%, 40%, 60%, 80%, or 100%). FD was based on the average amount of food consumed by the AL males or females, and food was split into morning and evening meals. Mice were euthanized at 48 h and 1, 2, and 3 wk, and hepcidin and indicators of iron status were measured. Data were analyzed by Pearson correlation and one-way ANOVA. RESULTS: Liver hepcidin mRNA was positively correlated with the magnitude of FD at all time points (P < 0.05). At 3 wk, liver hepcidin mRNA increased 3-fold with 10% and 20% FD compared with AL and was positively associated with serum hepcidin (R = 0.627, P < 0.0001). Serum iron was reduced by ∼65% (P ≤ 0.01), and liver nonheme iron concentrations were ∼75% greater (P ≤ 0.01) with 10% and 20% FD for 3 wk compared with AL. Liver hepcidin mRNA at 3 wk was positively correlated with liver Bmp6 (R = 0.765, P < 0.0001) and liver gluconeogenic enzymes (R = >0.667, P < 0.05) but not markers of inflammation (P > 0.05). CONCLUSIONS: FD increases hepcidin in male and female mice and results in hypoferremia and tissue iron sequestration. These findings suggest that increased hepcidin with FD may contribute to the disturbances in iron homeostasis with undernutrition.

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity.

Bivalent proteolysis-targeting chimeras (PROTACs) drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhance degradation. Here, we designed trivalent PROTACs consisting of a bivalent bromo and extra terminal (BET) inhibitor and an E3 ligand tethered via a branched linker. We identified von Hippel-Lindau (VHL)-based SIM1 as a low picomolar BET degrader with preference for bromodomain containing 2 (BRD2). Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anticancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL, exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.

Initiating aerobic exercise with low glycogen content reduces markers of myogenesis but not mTORC1 signaling.

BACKGROUND: The effects of low muscle glycogen on molecular markers of protein synthesis and myogenesis before and during aerobic exercise with carbohydrate ingestion is unclear. The purpose of this study was to determine the effects of initiating aerobic exercise with low muscle glycogen on mTORC1 signaling and markers of myogenesis. METHODS: Eleven men completed two cycle ergometry glycogen depletion trials separated by 7-d, followed by randomized isocaloric refeeding for 24-h to elicit low (LOW; 1.5 g/kg carbohydrate, 3.0 g/kg fat) or adequate (AD; 6.0 g/kg carbohydrate, 1.0 g/kg fat) glycogen. Participants then performed 80-min of cycle ergometry (64 ± 3% VO2peak) while ingesting 146 g carbohydrate. mTORC1 signaling (Western blotting) and gene transcription (RT-qPCR) were determined from vastus lateralis biopsies before glycogen depletion (baseline, BASE), and before (PRE) and after (POST) exercise. RESULTS: Regardless of treatment, p-mTORC1Ser2448, p-p70S6KSer424/421, and p-rpS6Ser235/236 were higher (P < 0.05) POST compared to PRE and BASE. PAX7 and MYOGENIN were lower (P < 0.05) in LOW compared to AD, regardless of time, while MYOD was lower (P < 0.05) in LOW compared to AD at PRE, but not different at POST. CONCLUSION: Initiating aerobic exercise with low muscle glycogen does not affect mTORC1 signaling, yet reductions in gene expression of myogenic regulatory factors suggest that muscle recovery from exercise may be reduced.

Home-Monitoring Application for Children With Medical Complexity: A Feasibility Trial.

OBJECTIVES: Mobile apps are suggested for supporting home monitoring and reducing emergency department (ED) visits and hospitalizations for children with medical complexity (CMC). None have been implemented. We sought to assess the MyChildCMC app (1) feasibility for CMC home monitoring, (2) ability to detect early deteriorations before ED and hospital admissions, and (3) preliminary impact. METHODS: Parents of CMC (aged 1-21 years) admitted to a children's hospital were randomly assigned to MyChildCMC or usual care. MyChildCMC subjects recorded their child's vital signs and symptoms daily for 3 months postdischarge and received real-time feedback. Feasibility measures included parent's enrollment, retention, and engagement. The preliminary impact was determined by using quality of life, parent satisfaction with care, and subsequent ED and hospital admissions and hospital days. RESULTS: A total of 62 parents and CMC were invited to participate: 50 enrolled (80.6% enrollment rate) and were randomly assigned to MyChildCMC (n = 24) or usual care (n = 26). Retention at 1 and 3 months was 80% and 74%, and engagement was 68.3% and 62.6%. Run-chart shifts in vital signs were common findings preceding admissions. The satisfaction score was 26.9 in the MyChildCMC group and 24.1 in the control group (P = .035). No quality of life or subsequent admission differences occurred between groups. The 3-month hospital days (pre-post enrollment) decreased from 9.25 to 4.54 days (rate ratio = 0.49; 95% confidence interval = 0.39-0.62; P < .001) in the MyChildCMC group and increased from 1.08 to 2.46 days (rate ratio = 2.29; 95% confidence interval = 1.47-3.56; P < .001) in the control group. CONCLUSIONS: MyChildCMC was feasible and appears effective, with the potential to detect early deteriorations in health for timely interventions that might avoid ED and hospitalizations. A larger and definitive study of MyChildCMC's impact and sustainability is needed.

Flipped learning: A shift in graduate nursing education.

ABSTRACT: The coronavirus (COVID-19) pandemic has caused a shift in education. Nursing education must respond to these changing times by redesigning classroom instruction. Flipped learning (FL) is a proposed method for teaching advanced practice nurses that is student-centered and engaging, both critical areas for contemporary learners. This qualitative study explored the perspectives and experiences of the family nurse practitioner faculty and the family nurse practitioner nursing students who participated in FL. The type and level of FL practices faculty can apply to support students coming to class prepared to engage in active learning activities was also investigated. The study used an insider action research design. There were two arms of the study, faculty and student. Ten faculty-led learning circles with four faculty and three family nurse practitioner student focus groups, each with six students, were held over the course of the study. Thematic findings were developed from both student and faculty data. The results revealed that family nurse practitioner students had a positive attitude toward FL. Many expressed FL provided perceptions of gained confidence, personalized learning, increased engagement, and preparedness for classroom instruction. Overall, faculty preferred FL over traditional teaching approaches. Several active learning activities were used by faculty with clinical case studies being the most preferred by student participants. This study confirms FL is a plausible and promising approach to traditional classroom instruction. However, more robust studies are needed to determine its benefits in advanced practice nursing education.

N-Acetylcysteine treatment of neonatal acetaminophen toxicity caused by transplacental transfer - a case report.

We describe a case of maternal acetaminophen toxicity leading to Caesarean section delivery of a pre-term neonate with acetaminophen-induced hepatic injury and encephalopathy at 33 weeks gestational age. Delayed treatment with N-acetylcysteine (NAC) was initiated in the baby 11 h after delivery, with eventual discharge of a healthy baby at 12 days of age. The baby was treated with a standard but extended duration NAC protocol. Post-operatively, liver biopsy of the mother demonstrated acetaminophen-induced hepatic injury overlying mild hepatic steatosis. This was also managed with NAC therapy leading to complete clinical resolution of acetaminophen induced hepatic injury and discharge on post-operative day 10. This case of delayed NAC therapy for the treatment of pre-term neonatal acetaminophen toxicity is one of very few reported in the literature and can be used as a guide in the management of subsequent cases.