Effect of Increasing Blood Pressure on Brain Tissue Oxygenation in Adults After Severe Traumatic Brain Injury.

OBJECTIVES: To examine if increasing blood pressure improves brain tissue oxygenation (PbtO2) in adults with severe traumatic brain injury (TBI). DESIGN: Retrospective review of prospectively collected data. SETTING: Level-I trauma center teaching hospital. PATIENTS: Included patients greater than or equal to 18 years of age and with severe (admission Glasgow Coma Scale [GCS] score < 9) TBI who had advanced neuromonitoring (intracranial blood pressure [ICP], PbtO2, and cerebral autoregulation testing). INTERVENTIONS: The exposure was mean arterial pressure (MAP) augmentation with a vasopressor, and the primary outcome was a PbtO2 response. Cerebral hypoxia was defined as PbtO2 less than 20 mm Hg (low). MAIN RESULTS: MAP challenge test results conducted between ICU admission days 1-3 from 93 patients (median age 31; interquartile range [IQR], 24-44 yr), 69.9% male, White (n = 69, 74.2%), median head abbreviated injury score 5 (IQR 4-5), and median admission GCS 3 (IQR 3-5) were examined. Across all 93 tests, a MAP increase of 25.7% resulted in a 34.2% cerebral perfusion pressure (CPP) increase and 16.3% PbtO2 increase (no MAP or CPP correlation with PbtO2 [both R2 = 0.00]). MAP augmentation increased ICP when cerebral autoregulation was impaired (8.9% vs. 3.8%, p = 0.06). MAP augmentation resulted in four PbtO2 responses (normal and maintained [group 1: 58.5%], normal and deteriorated [group 2: 2.2%; average 45.2% PbtO2 decrease], low and improved [group 3: 12.8%; average 44% PbtO2 increase], and low and not improved [group 4: 25.8%]). The average end-tidal carbon dioxide (ETCO2) increase of 5.9% was associated with group 2 when cerebral autoregulation was impaired (p = 0.02). CONCLUSIONS: MAP augmentation after severe TBI resulted in four distinct PbtO2 response patterns, including PbtO2 improvement and cerebral hypoxia. Traditionally considered clinical factors were not significant, but cerebral autoregulation status and ICP responses may have moderated MAP and ETCO2 effects on PbtO2 response. Further study is needed to examine the role of MAP augmentation as a strategy to improve PbtO2 in some patients.

The mediation roles of intermuscular fat and inflammation in muscle mitochondrial associations with cognition and mobility.

BACKGROUND: Mitochondrial dysfunction may contribute to brain and muscle health through inflammation or fat infiltration in the muscle, both of which are associated with cognitive function and mobility. We aimed to examine the association between skeletal muscle mitochondrial function and cognitive and mobility outcomes and tested the mediation effect of inflammation or fat infiltration. METHODS: We analysed data from 596 Baltimore Longitudinal Study of Aging participants who had concurrent data on skeletal muscle oxidative capacity and cognitive and mobility measures of interest (mean age: 66.1, 55% women, 24% Black). Skeletal muscle oxidative capacity was assessed as post-exercise recovery rate (kPCr) via P31 MR spectroscopy. Fat infiltration was measured as intermuscular fat (IMF) via CT scan and was available for 541 participants. Inflammation markers [IL-6, C-reactive protein (CRP), total white blood cell (WBC), neutrophil count, erythrocyte sedimentation rate (ESR), or albumin] were available in 594 participants. We examined the association of kPCr and cognitive and mobility measures using linear regression and tested the mediation effect of IMF or inflammation using the mediation package in R. Models were adjusted for demographics and PCr depletion. RESULTS: kPCr and IMF were both significantly associated with specific cognitive domains (DSST, TMA-A, and pegboard dominant hand performance) and mobility (usual gait speed, HABCPPB, 400 m walk time) (all P < 0.05). IMF significantly mediated the relationship between kPCr and these cognitive and mobility measures (all P < 0.05, proportion mediated 13.1% to 27%). Total WBC, neutrophil count, and ESR, but not IL-6 or CRP, also mediated at least one of the cognitive and mobility outcomes (all P < 0.05, proportion mediated 9.4% to 15.3%). CONCLUSIONS: Skeletal muscle mitochondrial function is associated with cognitive performance involving psychomotor speed. Muscle fat infiltration and specific inflammation markers mediate the relationship between muscle mitochondrial function and cognitive and mobility outcomes. Future studies are needed to confirm these associations longitudinally and to understand their mechanistic underpinnings.

Lack of influence of social media on vaccine decision-making by university students in Ireland.

Vaccine hesitancy is a complex, context-specific issue that negatively impacts vaccine uptake. During the COVID-19 pandemic, vaccine mis- and dis-information on social media negatively impacted on COVID-19 vaccine acceptance. University students' beliefs and behaviors surrounding vaccine decision-making is less studied, but this population is important in disease transmission, vaccine uptake and effectiveness. Here, we surveyed students in a third-level Irish university, in September 2022, when pandemic restrictions had been removed, to primarily determine if their use of, and influence by, mainstream and social media correlated with their willingness to receive a COVID-19 vaccine or any vaccine. We analyzed 151 responses and found no significant correlation between students' willingness to receive either a COVID-19 vaccine or any vaccine and their use of social media. There were significant links between vaccine acceptance and a range of factors, namely accommodation type, social media behaviors, perceived exposure to vaccine mis- or dis-information and previous vaccine uptake. This study provides a preliminary insight into drivers of university student COVID-19 and general vaccine willingness. It provides initial data, in the context of post-pandemic restrictions, to support further development of interventions to enhance vaccine uptake in third-level students in Ireland.

Critical Care Experience With Clinical Cerebral Autoregulation Testing in Adults With Traumatic Brain Injury.

BACKGROUND: To describe the setting, feasibility, and safety of static cerebral autoregulation testing in critically injured adults with traumatic brain injury (TBI).  Methods: We reviewed static autoregulation testing using transcranial Doppler (TCD) ultrasound in patients > 18 years with TBI ICD codes between January 1, 2014, and December 31, 2021. Adverse events during testing were defined as systemic hypertension (systolic blood pressure (SBP>180 mmHg), bradycardia (HR<40 bpm), and high ICP (>30 mmHg). Impaired and absent cerebral autoregulation was defined as an autoregulatory index (ARI) <0.4 and ARI 0, respectively. We characterized prescribed changes in intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targets by autoregulation testing results.  Results: A total of 135 patients, median age 31 (interquartile range (IQR) 24, 43) years, 71.9% male, admission Glasgow coma scale (GCS) score 3 (IQR 3, 5.5), and 70.9% with subdural hematoma from severe (GCS 3-8; 133 (98.5%)) and moderate (GCS 9-12; 2 (1.5%)) TBI, underwent 309 attempted testing. All patients were mechanically ventilated and had ICP monitoring; 246 (80%) had brain tissue oxygen monitoring, and 68 (22%) had an external ventricular drain. The median number of autoregulation tests was two (range 1-3) tests/patient, and the median admission to the first test time was two days (IQR 1, 3). Of 55 (17.8%) tests not completed, systemic hypertension (32, 10.4%), intracranial hypertension (10, 3.2%), and bradycardia (3, 0.9%) were transient. Fifty-three (51%) of the first (n=104) autoregulation tests showed impaired/absent cerebral autoregulation. Impaired/absent autoregulation results at the first test were associated with repeat cerebral autoregulation testing (RR 2.25, 95% CI [1.40-3.60], p=0.0007) than intact cerebral autoregulation results. Pre-testing cerebral hemodynamic targets were maintained (n=131; 86.8%) when cerebral autoregulation was impaired (n=151; RR 1.49, 95% CI [1.25-1.77], p<0.0001). However, 15 (9.9%) test results led to higher ICP targets (from 20 mmHg to 25 mmHg), 5 (3.3%) results led to an increase in CPP target (from 60 mmHg to 70 mmHg), and five out of 131 (3.8%) patients underwent decompressive craniectomy and placement of an external ventricular drain. Intact cerebral autoregulation results (n=43/103, 41.7%) were associated with a change in ICP targets from 20 mmHg to 25 mmHg (RR 3.15, 95% CI [1.97-5.03], p<0.0001).  Conclusions: Static cerebral autoregulation testing was feasible, safe, and useful in individualizing the care of patients with moderate-severe TBI receiving multimodal neuromonitoring. Testing results guided future testing, cerebral hemodynamic targets, and procedural decisions. Impaired cerebral autoregulation was very common.

The impact of fingolimod on Treg function in brain ischaemia.

Fingolimod has generally shown neuroprotective effects in stroke models. Here, we tested the hypothesis that fingolimod modulates T-cell cytokine production towards a regulatory phenotype. Second, we investigated how fingolimod altered the Treg suppressive function and the sensitivity of effector T cells to regulation. Mice that had underwent the permanent electrocoagulation of the left middle cerebral artery received saline or fingolimod (0.5 mg/kg) daily for 10-days post-ischaemia. Fingolimod improved neurobehavioural recovery compared to saline control and increased Treg frequency in the periphery and brain. Tregs from fingolimod-treated animals had a higher expression of CCR8. Fingolimod increased the frequencies of CD4+ IL-10+ , CD4+ IFN-γ+ and CD4+ IL-10+ IFN-γ+ cells in spleen and blood, and CD4+ IL-17+ cells in the spleen, with only minor effects on CD8+ T-cell cytokine production. Treg from post-ischaemic mice had reduced suppressive function compared to Treg from non-ischaemic mice. Fingolimod treatment rescued this function against saline-treated but not fingolimod-treated CD4+ effector T cells. In conclusion, fingolimod seems to improve the suppressive function of Treg post-stroke while also increasing the resistance of CD4+ effector cells to this suppression. Fingolimod's capacity to increase both effector and regulatory functions may explain the lack of consistent improvement in functional recovery in experimental brain ischaemia.

Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi.

BACKGROUND: In this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity. METHODS: Hospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF). RESULTS: One hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex. CONCLUSION: Low dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered. TRIAL REGISTRATION: The trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021.

Skin-Based Vaccination: A Systematic Mapping Review of the Types of Vaccines and Methods Used and Immunity and Protection Elicited in Pigs.

The advantages of skin-based vaccination include induction of strong immunity, dose-sparing, and ease of administration. Several technologies for skin-based immunisation in humans are being developed to maximise these key advantages. This route is more conventionally used in veterinary medicine. Skin-based vaccination of pigs is of high relevance due to their anatomical, physiological, and immunological similarities to humans, as well as being a source of zoonotic diseases and their livestock value. We conducted a systematic mapping review, focusing on vaccine-induced immunity and safety after the skin immunisation of pigs. Veterinary vaccines, specifically anti-viral vaccines, predominated in the literature. The safe and potent skin administration to pigs of adjuvanted vaccines, particularly emulsions, are frequently documented. Multiple methods of skin immunisation exist; however, there is a lack of consistent terminology and accurate descriptions of the route and device. Antibody responses, compared to other immune correlates, are most frequently reported. There is a lack of research on the underlying mechanisms of action and breadth of responses. Nevertheless, encouraging results, both in safety and immunogenicity, were observed after skin vaccination that were often comparable to or superior the intramuscular route. Further research in this area will underlie the development of enhanced skin vaccine strategies for pigs, other animals and humans.

Identifying intervention strategies to improve HPV vaccine decision-making using behaviour change theory.

Although the HPV vaccine is highly safe and effective, its uptake is sub-optimal in many countries, including Ireland. There is therefore a need to identify appropriate interventions that will increase HPV vaccine acceptance by parents. In this study, we took a systematic approach to understand the factors that influence HPV vaccine uptake by parents of adolescent girls in Ireland to define suitable behaviour change interventions that would support positive vaccine decision-making in the future. Specifically, we conducted semi-structured interviews, used a Theoretical Domains Framework (TDF)-based topic guide, to gain insight into the knowledge, beliefs, attitudes and current behaviours of parents with respect to their HPV vaccine decision. Transcripts were analysed using the TDF. The Behaviour Change Wheel (BCW) was used to identify relevant intervention functions and the Behaviour Change Technique Taxonomy version 1 (BCTTv1), to identify relevant intervention techniques. All parents discussed the essential role of healthcare providers in vaccine decision-making. Complacency and confidence were important factors in decision-making by vaccine hesitant parents. Five BCW intervention functions were identified as appropriate, namely; education; persuasion; environmental restructuring; modelling and enablement. To our knowledge, this is the first study to systematically evaluate HPV vaccine decision-making using behaviour change theory and identify suitable intervention strategies to promote positive vaccine decision-making using this approach.

Ophthalmic artery reversal predicts contralateral body weakness symptoms better than carotid Doppler velocity-preliminary results.

Background: The measurement of blood velocity in the carotid artery has been the most popular noninvasive method of identifying and classifying carotid stenosis for half a century. Carotid stenosis is an indicator of elevated risk of stroke; anatomic revascularization reduces the chance of stroke by more than half. Controversy persists on how patients with severe carotid stenosis should be selected for anatomic revascularization. Patients with a connected circle of Willis (coW) might not benefit from anatomic revascularization; patients with two segments missing in the coW are most likely to benefit from revascularization. Methods: Based on this analysis of data from carotid duplex examinations and transcranial Doppler examinations including ophthalmic artery (OA) direction in 28 patients, a refined carotid examination protocol is proposed. This refinement includes Doppler measurement of OA flow direction and documentation of internal carotid artery (ICA) bruit in addition to the adoption of an ICA peak systolic velocity (PSV) criterion exceeding 350 cm/s for identification of the patient most likely to benefit from carotid stenosis treatment. Results: Sensitivity and specificity of OA direction or carotid bruit are 84.6%±5.4%, 71.4%±2.1% and for PSV >350 cm/s are 84.6%±5.4%, 59.5%±2.3% for predicting contralateral body weakness. Conclusions: The proposed examination can be performed with the same duplex scanner and scan head currently used for carotid examinations with little additional time.

Associations Between Transcranial Doppler Vasospasm and Clinical Outcomes After Aneurysmal Subarachnoid Hemorrhage: A Retrospective Observational Study.

OBJECTIVE: The objective is to examine the relationship between transcranial Doppler cerebral vasospasm (TCD-vasospasm), and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In a retrospective cohort study, using univariate and multivariate analysis, we examined the association between TCD-vasospasm (defined as Lindegaard ratio >3) and patient's ability to ambulate without assistance, the need for tracheostomy and gastrostomy tube placement, and the likelihood of being discharged home from the hospital. RESULTS: We studied 346 patients with aSAH; median age 55 years (Interquartile range IQR 46,64), median Hunt and Hess 3 [IQR 1-5]. Overall, 68.6% (n=238) had TCD-vasospasm, and 28% (n=97) had delayed cerebral ischemia. At hospital discharge, 54.3% (n=188) were able to walk without assistance, 5.8% (n=20) had received a tracheostomy, and 12% (n=42) had received a gastrostomy tube. Fifty-three percent (n=183) were discharged directly from the hospital to their home. TCD-vasospasm was not associated with ambulation without assistance at discharge (adjusted odds ratio, aOR 0.54, 95% 0.19,1.45), tracheostomy placement (aOR 2.04, 95% 0.23,18.43), gastrostomy tube placement (aOR 0.95, 95% CI 0.28,3.26), discharge to home (aOR 0.36, 95% CI 0.11,1.23). CONCLUSION: This single-center retrospective study finds that TCD-vasospasm is not associated with clinical outcomes such as ambulation without assistance, discharge to home from the hospital, tracheostomy, and gastrostomy feeding tube placement. Routine screening for cerebral vasospasm and its impact on vasospasm diagnostic and therapeutic interventions and their associations with improved clinical outcomes warrant an evaluation in large, prospective, case-controlled, multi-center studies.

Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemia.

Background: The well-characterised role of the immune system in acute ischaemic stroke has prompted the search for immunomodulatory therapies. Pregnancy-specific glycoproteins (PSGs) are a group of proteins synthesised by placental trophoblasts which show immunomodulatory properties. The aim of this study was to determine whether a proposed PSG1-based therapeutic enhanced recovery in a mouse model of brain ischaemia and to explore possible immunomodulatory effects. Methods: Mice underwent permanent electrocoagulation of the left middle cerebral artery (pMCAO). They received saline (n = 20) or recombinant pregnancy-specific glycoprotein-1-alpha "fused" to the Fc domain of IgG1 (rPSG1-Fc) (100 µg) (n = 22) at 1 h post-ischaemia. At 3 and 5 days post-ischaemia, neurobehavioural recovery was assessed by the grid-walking test. At 5 days post-ischaemia, lesion size was determined by NeuN staining. Peripheral T cell populations were quantified via flow cytometry. Immunohistochemistry was used to quantify ICAM-1 expression and FoxP3+ cell infiltration in the ischaemic brain. Immunofluorescence was employed to determine microglial activation status via Iba-1 staining.Results: rPSG1-Fc significantly enhanced performance in the grid-walking test at 3 and 5 days post-ischaemia. No effect on infarct size was observed. A significant increase in circulating CD4+ FoxP3+ cells and brain-infiltrating FoxP3+ cells was noted in rPSG1-Fc-treated mice. Among CD4+ cells, rPSG1-Fc enhanced the expression of IL-10 in spleen, blood, draining lymph nodes, and non-draining lymph nodes, while downregulating IFN-γ and IL-17 in spleen and blood. A similar cytokine expression pattern was observed in CD8+ cells. rPSG1-Fc reduced activated microglia in the infarct core. Conclusion: The administration of rPSG1-Fc improved functional recovery in post-ischaemic mice without impacting infarct size. Improved outcome was associated with a modulation of the cytokine-secreting phenotype of CD4+ and CD8+ T cells towards a more regulatory phenotype, as well as reduced activation of microglia. This establishes proof-of-concept of rPSG1-Fc as a potential stroke immunotherapy.

Preclinical Evaluation of Fingolimod in Rodent Models of Stroke With Age or Atherosclerosis as Comorbidities.

Preclinical data indicate that fingolimod improves outcome post-ischaemia. This study used a rigorous study design in normal male C57BL/6JOlaHsd mice and in mice with common stroke comorbidities to further evaluate the translational potential of fingolimod. Stroke was induced via middle cerebral artery electrocoagulation in 8-9-week old mice (young mice), 18 month old mice (aged mice), and in high-fat diet-fed 22-week old ApoE-/- mice (hyperlipidaemic mice). Recovery was evaluated using motor behavioural tests 3 and 7 days after stroke. Tissue damage was evaluated at 7 days. A lower dose of fingolimod, 0.5 mg/kg, but not 1 mg/kg, increased lesion size but decreased ipsilateral brain atrophy in younger mice, without an effect on behavioural outcomes. Fingolimod-treated aged mice showed a significant improvement over saline-treated mice in the foot fault test at 7 days. Fingolimod-treated hyperlipidaemic mice showed a decreased infarct size but no difference in behavioural performance. Increasing fingolimod treatment time to 10 days showed no benefit in young mice. Pooled data showed that fingolimod improved performance in the foot fault test. Flow cytometry studies showed that fingolimod had marked effects on T cell frequencies in various tissues. The results show that the effects of fingolimod in stroke are less robust than the existing literature might indicate and may depend on the inflammatory status of the animals.

A Video-Based Behavioral Intervention Associated with Improved HPV Knowledge and Intention to Vaccinate.

The aim of this study was to design, develop, and evaluate the feasibility of a theory- and evidence-based intervention to improve human papillomavirus (HPV) and HPV vaccine knowledge and intention to vaccinate, among parent-daughter dyads. A theory- and evidence-based online behavioral intervention, "Is the HPV vaccine for me?", was developed to improve HPV and HPV vaccine knowledge and intention to vaccinate. Knowledge, intention to vaccinate, and feasibility of the intervention were evaluated in a prospective, randomized, controlled feasibility trial. A total of 49 parent-daughter dyads completed the baseline knowledge assessment (n = 24 control, n = 25 intervention), and 35 dyads completed the knowledge assessment at week 2 (n = 17 control, n = 18 intervention). The intervention resulted in a statistically significant increase in HPV and HPV vaccine knowledge and intention to vaccinate. All intervention participants found the video interesting, while 96% found it useful. This intervention was found to be useful, effective, safe, and acceptable in this feasibility study.

Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Trends in drug- and vaccine-based dissolvable microneedle materials and methods of fabrication.

Microneedlepatches, also called microarray patches(MAP),are an emergingtechnology for deliveryand samplingof drugs, vaccines and other materials. This review focuses on the materials and methods used to fabricate dissolvable microneedles(DMN)for pharmaceutical use.We outlinethe relative use ofexcipients, active pharmaceutical ingredients (API) and methods usedfor DMN fabrication. An extensive search of primary literature, up to April 2021,identified 328 papers under the key terms "dissolvable microneedles" or "polymeric microneedles".We based the classification of materials on pharmacopoeia definitions.The majority (76%) ofthe identifiedpublications examined licensed or model therapeutic small molecule drugs. Mostreports (58%)focused ondrugs or vaccinesthat are licensed for clinical use. Therelativeuse of excipientswith drug-containing compared to vaccine-containing DMN is discussed.Tenpolymers and sugarswereused for both drug and vaccine DMN.Themost frequentmethods to produce DMNwerecasting into moulds using centrifugationorvacuum filling. Novel methods reported include centrifugal lithography and 3D printing. This review provides insight intomaterialselection,thefeasibilityofproductionmethodsat industrial scaleand outlines considerations for novel DMN patch fabrication.

Benefit of adjuvant chemotherapy in node-negative T1a versus T1b and T1c triple-negative breast cancer.

PURPOSE: National comprehensive cancer network guidelines recommend delivery of adjuvant chemotherapy in node-negative triple-negative breast cancer (TNBC) if the tumor is > 1 cm and consideration of adjuvant chemotherapy for T1b but not T1a disease. These recommendations are based upon sparse data on the role of adjuvant chemotherapy in T1a and T1b node-negative TNBC. Our objective was to clarify the benefits of chemotherapy for patients with T1N0 TNBC, stratified by tumor size. METHODS: We performed a retrospective analysis of survival outcomes of TNBC patients at two academic institutions in the United States from 1999 to 2018. Primary tumor size, histology, and nodal status were based upon surgical pathology. The Kaplan-Meier plot and 5-year unadjusted survival probability were evaluated. RESULTS: Among 282 T1N0 TNBC cases, the status of adjuvant chemotherapy was known for 258. Mean follow-up was 5.3 years. Adjuvant chemotherapy was delivered to 30.5% of T1a, 64.7% T1b, and 83.9% T1c (p < 0.0001). On multivariable analysis, factors associated with delivery of adjuvant chemotherapy were tumor size and grade 3 disease. Improved overall survival was associated with use of chemotherapy in patients with T1c disease (93.2% vs. 75.2% p = 0.008) but not T1a (100% vs. 100% p = 0.3778) or T1b (100% vs. 95.8% p = 0.2362) disease. CONCLUSION: Our data support current guidelines indicating benefit from adjuvant chemotherapy in node-negative TNBC associated with T1c tumors but excellent outcomes were observed in the cases of T1a and T1b disease, regardless of whether adjuvant chemotherapy was delivered.

A Pilot Prospective Observational Study of Cerebral Autoregulation and 12-Month Outcomes in Children With Complex Mild Traumatic Brain Injury: The Argument for Sufficiency Conditions Affecting TBI Outcomes.

BACKGROUND: The relationship between cerebral autoregulation and outcomes in pediatric complex mild traumatic brain injury (TBI) is unknown, and explored in this study. METHODS: We conducted a prospective observational study of patients aged 0 to 18 years hospitalized with complex mild TBI (admission Glasgow Coma Scale score 13 to 15 with either abnormal computerized tomogram of the head or history of loss of consciousness). Cerebral autoregulation was tested using transcranial Doppler ultrasonography, and impaired autoregulation defined as autoregulation index<0.4. We collected Glasgow Outcome Scale Extended-Pediatrics score and health-related quality of life data at 3, 6, and 12 months after discharge. RESULTS: Twenty-four patients aged 1.8 to 16.6 years (58.3% male) with complete 12-month outcome data were included in the analysis. Median admission Glasgow Coma Scale score was 15 (range: 13 to 15), median injury severity score was 12 (range: 4 to 29) and 23 patients (96%) had isolated TBI. Overall, 10 (41.7%) patients had impaired cerebral autoregulation. Complete recovery was observed in 6 of 21 (28.6%) children at 3 months, in 4 of 16 (25%) children at 6 months, and in 8 of 24 (33.3%) children at 12 months. There was no difference in median (interquartile range) Glasgow Outcome Scale Extended-Pediatrics score (2 [2.3] vs. 2 [interquartile range 1.3]) or health-related quality of life scores (91.5 [21.1] vs. 90.8 [21.6]) at 12 months between those with intact and impaired autoregulation, respectively. Age-adjusted hypotension occurred in 2/24 (8.3%) patients. CONCLUSION: Two-thirds of children with complex mild TBI experienced incomplete functional recovery at 1 year. The co-occurrence of hypotension and cerebral autoregulation may be a sufficiency condition needed to affect TBI outcomes.

Dietary supplement use and documentation in a breast cancer survivorship clinic.

PURPOSE: Breast cancer survivors take vitamins and supplements to bolster their general health and to decrease the risk of cancer recurrence. Healthcare providers are frequently unaware of their patients non-prescription supplement use. The aim of this study was to study the type and the documentation of patients' dietary supplements and vitamins in the electronic medical record (EMR). METHODS: 50/51 female breast cancer survivors seen over a 7 week period consented to the study. Mean age was 70 and mean years since diagnosis was 13.9. Informed consent and documentation of supplement and vitamin use was obtained by the nurse practitioner the day before the visit. Study data were collected and managed using REDCap electronic data capture tools hosted at Weill Cornell Medicine. RESULTS: Of the 50 study patients, 90% were taking one or more vitamins and/or supplements (mean = 2.4, range = 1-9). The most common were Vitamin D, calcium, and vitamin C. Reasons for vitamin and supplement use included the recommendation by their physician or friend and prevention of bone loss or catching a cold. Five patients mentioned immunity or prevention of COVID-19. The patient reported list was compared with the medication list used by multiple providers in the electronic medical record (EMR). None of the 50 study patients had an accurate list of their vitamins and supplements in the EMR. CONCLUSION: 90% of the breast cancer survivors in our study were taking dietary supplements for a variety of reasons. None had an accurate list in the EMR. We strongly recommend more attention to accurate and easily accessed vitamin and supplement recording by providers.

Experience with clinical cerebral autoregulation testing in children hospitalized with traumatic brain injury: Translating research to bedside.

Objective: To report our institutional experience with implementing a clinical cerebral autoregulation testing order set with protocol in children hospitalized with traumatic brain injury (TBI). Methods: After IRB approval, we examined clinical use, patient characteristics, feasibility, and safety of cerebral autoregulation testing in children aged <18 years between 2014 and 2021. A clinical order set with a protocol for cerebral autoregulation testing was introduced in 2018. Results: 25 (24 severe TBI and 1 mild TBI) children, median age 13 years [IQR 4.5; 15] and median admission GCS 3[IQR 3; 3.5]) underwent 61 cerebral autoregulation tests during the first 16 days after admission [IQR1.5; 7; range 0-16]. Testing was more common after implementation of the order set (n = 16, 64% after the order set vs. n = 9, 36% before the order set) and initiated during the first 2 days. During testing, patients were mechanically ventilated (n = 60, 98.4%), had invasive arterial blood pressure monitoring (n = 60, 98.4%), had intracranial pressure monitoring (n = 56, 90.3%), brain-tissue oxygenation monitoring (n = 56, 90.3%), and external ventricular drain (n = 13, 25.5%). Most patients received sedation and analgesia for intracranial pressure control (n = 52; 83.8%) and vasoactive support (n = 55, 90.2%) during testing. Cerebral autoregulation testing was completed in 82% (n = 50 tests); 11 tests were not completed [high intracranial pressure (n = 5), high blood pressure (n = 2), bradycardia (n = 2), low cerebral perfusion pressure (n = 1), or intolerance to blood pressure cuff inflation (n = 1)]. Impaired cerebral autoregulation on first assessment resulted in repeat testing (80% impaired vs. 23% intact, RR 2.93, 95% CI 1.06:8.08, p = 0.03). Seven out of 50 tests (14%) resulted in a change in cerebral hemodynamic targets. Conclusion: Findings from this series of children with TBI indicate that: (1) Availability of clinical order set with protocol facilitated clinical cerebral autoregulation testing, (2) Clinicians ordered cerebral autoregulation tests in children with severe TBI receiving high therapeutic intensity and repeatedly with impaired status on the first test, (3) Clinical cerebral autoregulation testing is feasible and safe, and (4) Testing results led to change in hemodynamic targets in some patients.

Parent Attitudes about Childhood Vaccines: Point Prevalence Survey of Vaccine Hesitancy in an Irish Population.

Understanding parental attitudes to their children's vaccination is critical to developing and implementing interventions that address parents' hesitancy and improve vaccine uptake. The Parent Attitudes about Childhood Vaccines (PACV) survey is a validated tool for identifying vaccine hesitancy in parents. We evaluated the rate of vaccine hesitancy and areas of concern regarding childhood vaccinations using an adapted version of the PACV survey, in a convenience sample of parents attending a STEM (Science, Technology, Engineering and Mathematics) outreach event in Ireland, in 2018. A score ≥ 50 identified vaccine hesitant parents. Of 105 parents who completed the survey, the prevalence of vaccine hesitancy was 6.7%, (7/105). Parents had concerns around vaccine side effects (36.2%, n = 38), vaccine safety (20%, n = 21) and the number of vaccines administered (13.3%, n = 14). Parents trusted the vaccine information they received (85.6%, n = 90) and 81.9% (n = 86) believed that the vaccine schedule was good for their child. The findings indicate the presence of vaccine hesitancy in parents in Ireland regarding paediatric vaccines with further research necessary to address parents' vaccine concerns. Future research should explore further, by qualitative methods, parents' vaccine concerns. There is also potential to identify vaccine hesitant parents with the PACV survey as a surveillance method in healthcare settings; for example, in community pharmacies, family doctor clinics and out-patient clinics.