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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.

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.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.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.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.

This is the schema of the clinical study design. This is a Phase 2 trial of TM in breast cancer at high risk of recurrence. Eligible patients received TM for 2 years to achieve a target CP level of < 17 mg/dL. Primary endpoint was effect on VEGFR2+ EPCS.

This is the demographics table containing brief summary of baseline patient characteristics of patients enrolled on trial.

This section contains details of all mixed models utilized in the statistical analyses. The inferential tests performed in this paper necessitates a multiple comparisons adjustment, and details of the adjustment procedure is included in this section as well.

Purpose: Bone marrow–derived progenitor cells, including VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models.Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition.Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II–III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012).Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.

This is the demographics table containing detailed baseline patient characteristics listed for each of the 75 patients. The data is de-identified.

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.

The objective is to examine the relationship between transcranial Doppler cerebral vasospasm (TCD-vasospasm), and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH).In a retrospective cohort study, using univariate and multivariate analysis, we examined the association between TCD-vasospasm (defined as Lindegaard ratio3) 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.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).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.

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.

This is a case report of a 35-year-old female pedestrian struck by a semi-truck. computed tomographic angiography (CTA) revealed a pseudoaneurysm at the proximal brachiocephalic artery measuring 1.8 cm in cranio-caudal length and 1.2 × 0.6 cm transverse. Just distal to the pseudoaneurysm, there was severe luminal narrowing caused by either a dissection flap or mural thrombus. Due to profound left-sided weakness, transcranial Doppler ultrasound was performed which demonstrated “hesitant” waveforms in the right middle cerebral and right vertebral arteries secondary to proximal obstruction. Hesitant waveforms display mid-systolic velocity deceleration and may also be referred to as the “bunny” waveform. Emboli monitoring of the right middle cerebral and basilar arteries were positive for active embolization

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

Introduction: Breast cancer survivors take vitamins and supplements to bolster their general health and to try to decrease the risk of cancer recurrence. Healthcare professionals are frequently unaware of the specific type and dose of vitamins and dietary supplements taken by their patients. This information is often poorly documented in the electronic medical record (EMR). The aim of this study was to document accurately patients’ dietary supplements and vitamins in the EMR and to inform patients’ medical teams of this important information.Methods: All patients seen between May 5th and June 24th, 2020, with a history of nonmetastatic breast cancer (mean years since diagnosis=13.9) were invited to participate in the study prior to their routine visits at the Weill Cornell Breast Cancer Survivorship Clinic. 50/51 women consented (ages 46 to 87, mean age=70). The nurse practitioner called each patient the day before their visit to obtain informed consent and to document their use of supplements and vitamins. The labels for each vitamin and supplement were reviewed and patients were asked the reason why they were taking each supplement. Study data were collected and managed using REDCap electronic data capture tools hosted at Weill Cornell Medicine. Due to COVID-19, 48/50 patient visits were conducted through telemedicine.Results: Of the 50 patients enrolled in the study, 72% were taking two or more vitamins and/or supplements (mean=2.4, range= 0-9). 82% were taking a Vitamin D supplement, 42% were taking a calcium supplement, and 24% were taking a vitamin C supplement. 16% were taking a daily multivitamin and 8% were taking no supplements or vitamins. Some of the rare supplements patients were taking included ginseng root tea, shiitake extract, and kamwo tea (one patient each). Patients reported a variety of reasons for their vitamin and supplement use. Some patients stated the supplement was recommended by their physician or a friend, some did not know why they were taking a specific supplement, some reported that they had “always taken it”, and many stated that the supplement was a preventative measure against bone loss or catching a cold. Five patients mentioned immunity or prevention of COVID-19. We compared the patient reported list with the medication list in the EMR. The majority of the participants had multiple providers who entered medications in the EMR. Of the 50 participants in our study, none had an accurate list of the vitamins and supplements in the EMR. Conclusion: 46 of the 50 breast cancer survivors in our study were taking vitamins and/or supplements. No study participant had a complete list of their vitamins and supplements in the EMR. Accurate vitamin and supplement documentation is important for optimal patient care. For example, vitamins and supplements may interfere with prescription medications taken by patients with a history of breast cancer. The inaccurate EMR documentation also precludes the investigation of vitamin and supplement use in future retrospective analyses. As a result of this study, we strongly recommend more attention to accurate vitamin and supplement recording by providers and the development of a more tailored and convenient method for documentation of vitamins and supplements in the EMR. Citation Format: Anne Moore, Julia Silver, Alyson Goldenberg. Vitamin and supplement use and documentation in a breast cancer survivorship clinic [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-12.

This report describes a 42 year old male with a 5 year history of transient ischemic attacks (TIAs), migraines, previous strokes, and symptoms referable to a left middle cerebral artery (MCA) territory event. Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) revealed severe stenoses in the proximal left MCA and proximal left anterior cerebral artery (ACA). Transcranial Doppler ultrasound/Transcranial Doppler imaging (TCD/TCI) and cerebral angiogram confirmed the stenoses with a mean flow velocity (MFV) at the proximal left MCA, with a velocity of 230 cm/s. A Wingspan Stent System stent was placed in the proximal left MCA. Cerebral angiogram and serial TCD examinations performed post stent placement showed a patent left MCA without stenosis and a MFV of 55 cm/s. The left ACA was occluded following proximal left MCA stent placement. This case highlights the usefulness of TCD in the assessment of the MCA and other basal cerebral arteries.

The clinical epidemiology of organ outcomes in pediatric traumatic brain injury (TBI) has not been examined. We describe associated markers of cerebral, cardiac and renal injury after pediatric TBI.Prospective observational study.Children 0-18 years who were hospitalized with TBI.Measures of myocardial (at least one elevated plasma troponin [cTnI] ≥ 0.4 ng/ml) and multiorgan (hemodynamic variables, cerebral perfusion, and renal) function were examined within the first ten days of hospital admission and within 24 h of each other.Data from 28 children who were 11[IQR 10.3] years, male (64.3%), with isolated TBI (67.9%), injury severity score (ISS) 25[10], and admission Glasgow coma score (GCS) 11[9] were examined. Overall, 50% (14 children) had elevated cTnI, including those with isolated TBI (57.9%; 11/19), polytrauma (33.3%; 3/9), mild TBI (57.1% 8/14), and severe TBI (42.9%; 6/11). Elevated cTnI occurred within the first six days of admission and across all age groups, in both sexes, and regardless of TBI lesion type, GCS, and ISS. Age-adjusted admission tachycardia was associated with cTnI elevation (AUC 0.82; p 0.001). Reduced urine output occurred more commonly in patients with isolated TBI (27.3% elevated cTnI vs. 0% normal cTnI).Myocardial injury commonly occurs during the first six days after pediatric TBI irrespective of injury severity, age, sex, TBI lesion type, or polytrauma. Age-adjusted tachycardia may be a clinical indicator of myocardial injury, and elevated troponin may be associated with cardio-cerebro-renal dysfunction.

The novel coronavirus, COVID-19, spend across the world in early 2020. Many countries imposed social isolation restrictions where people were confined to their homes unless their work was deemed an essential service or for short outings to obtain necessary food and household supplies. We hypothesised that a lack of face-to-face social interactions would contribute to feelings of loneliness and reductions in healthy coping behaviours, and predicted that use of media connections to liaise with others would mediate this negative relationship. Two hundred and ten participants responded to an online survey with useable data available from 181 persons (127 females) (age M = 37.82 years, SD = 13.24). Data from a series of scales designed for this study revealed moderate levels of loneliness that directly predicted reduced engagement in healthy coping behaviours. This direct relationship was mediated by the use of media connections to liaise with others during the period of social isolation. Exploratory Factor Analyses indicated media connections included two factors: Communication (e.g., phoning, texting) and social media (e.g., Facebook, Instagram). While the data were not representative of the wider population in terms of education and gender spread, the diversity of ages is a compensating factor. Suggestions for maintaining health and the importance of support during times of trauma, to wit, the COVID-19 pandemic, are discussed.

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.

Purpose This paper aims to demonstrate the variety of ways institutions and their libraries approach student success both conceptionally and operationally. Design/methodology/approach Librarians from eight different institutions of higher education were given a series of questions about student success on their campuses and in their libraries. They responded with written essays describing their experiences and perspectives. Findings The contributed pieces in this second installment are collected together and a variety of ways the academic library engage with “student success” are discussed. Initiatives include high-impact practices, fostering academic rapport and creating a sense of belonging, experiential learning and creative spaces and professional development. Originality/value These examples help to observe what is happening throughout higher education and see potential paths forward at the institutions engaged in this work.

Background While cardiac dysfunction has been described following traumatic brain injury (TBI), its association with systemic and cerebral hemodynamics is not known. We examined the contemporaneous relationship between early cardiac function with systemic and cerebral hemodynamic parameters after moderate-severe TBI. Methods Bedside transthoracic echocardiography (TTE) and transcranial Doppler (TCD) ultrasonography were performed within 24 h in patients > 18 years with isolated moderate-severe TBI. Systemic hemodynamic parameters were quantified using routine monitoring [heart rate and mean arterial pressures (MAP)] and calculation from echocardiographic data [stroke volume index (SVI), cardiac index (CI), and systemic vascular resistance index (SVRI)]. Systolic dysfunction was defined using TTE as global longitudinal strain (GLS) > -16%. Mean middle cerebral artery velocity (FVm) was the measure of cerebral hemodynamics and quantified using TCD. Results Among 15 patients [mean age 43 ± 13 years, GCS 5 ± 3, 73% male], 15 TTE and 15 TCD exams were performed simultaneously. Five (33%) patients had systolic dysfunction, with significantly worse GLS (median [IQR] −12.1% [−14.1, −12] vs. −19.1% [−19.9, −17.7], p = 0.004). Median (IQR) MAP was 97 (89, 107) mmHg, SVI (29.0 [20.5, 31.0] mL m−2), and CI (2.83 [2.05, 3.10] L/min m−2) were low to normal, while SVRI (2704 dyne sec/cm5 m−2 [2210, 4084]) was normal to high. None of the patients had abnormal TCDs. Higher GLS (reduced systolic function) was associated with lower SVI (r2 = 0.274, p = 0.03) but not other parameters. Conclusion Systemic hemodynamic parameters were consistent with an early catecholamine-excess state. While reduced systolic function was associated with lower SVI, there was no relationship with reduced cerebral perfusion, possibly due to normal MAP.

Background The demand for total hip and total knee arthroplasty in the USA is projected to increase significantly. Traditionally, face-to-face physical therapy has been an essential component of recovery in patients after total joint arthroplasty. Emerging technology allows telerehabilitation, or virtual physical therapy, which may reduce costs and increase standardization, but its effects on outcomes are not known. Questions/Purpose We sought to review our initial experience using a telerehabilitation protocol for patients after primary total hip or total knee arthroplasty. Methods In this pilot study, we retrospectively compared our first 40 telerehabilitation patients after a primary total hip or knee arthroplasty with a historical cohort or literature referenced values and evaluated (1) readmission rates at 90 days, (2) emergency department visits, (3) patient-reported outcome scores, (4) incidence of closed knee manipulation within 90 days of primary total knee arthroplasty, and (5) patient satisfaction surveys. Results We observed no increase in the telerehabilitation group at 90 days in readmissions, emergency department visits, or closed knee manipulations. Accuracy of telerehabilitation exercises performed was 92%. Patient-reported outcome scores showed improvements comparable with traditional therapy. Extremely high patient satisfaction scores were reported with the telerehabilitation protocol. Conclusion Our early experience demonstrates the feasibility of implementing a telerehabilitation program following primary total hip or knee arthroplasty without compromising clinical quality and with high patient satisfaction. Electronic supplementary material The online version of this article (10.1007/s11420-019-09715-w) contains supplementary material, which is available to authorized users.

OBJECTIVES To examine cerebral autoregulation in children with complex mild traumatic brain injury. DESIGN Prospective observational convenience sample. SETTING PICU at a level I trauma center. PATIENTS Children with complex mild traumatic brain injury (trauma, admission Glasgow Coma Scale score 13-15 with either abnormal head CT, or history of loss of consciousness). INTERVENTIONS Cerebral autoregulation was tested using transcranial Doppler ultrasound between admission day 1 and 8. MEASUREMENTS AND MAIN RESULTS The primary outcome was prevalence of impaired cerebral autoregulation (autoregulation index < 0.4),determined using transcranial Doppler ultrasonography and tilt testing. Secondary outcomes examined factors associated with and evolution and extent of impairment. Cerebral autoregulation testing occurred in 31 children 10 years (SD, 5.2 yr), mostly male (59%) with isolated traumatic brain injury (91%), median admission Glasgow Coma Scale 15, Injury Severity Scores 14.2 (SD, 7.7), traumatic brain injury due to fall (50%), preadmission loss of consciousness (48%), and abnormal head CT scan (97%). Thirty-one children underwent 56 autoregulation tests. Impaired cerebral autoregulation occurred in 15 children (48.4%) who underwent 19 tests; 68% and 32% of tests demonstrated unilateral and bilateral impairment, respectively. Compared with children on median day 6 of admission after traumatic brain injury, impaired autoregulation was most common in the first 5 days after traumatic brain injury (day 1: relative risk, 3.7; 95% CI, 1.9-7.3 vs day 2: relative risk, 2.7; 95% CI, 1.1-6.5 vs day 5: relative risk, 1.33; 95% CI, 0.7-2.3). Children with impaired autoregulation were older (12.3 yr [SD, 1.3 yr] vs 8.7 yr [SD, 1.1 yr]; p = 0.04) and tended to have subdural hematoma (64% vs 44%), epidural hematoma (29% vs 17%), and subarachnoid hemorrhage (36% vs 28%). Eight children (53%) were discharged home with ongoing impaired cerebral autoregulation. CONCLUSIONS Impaired cerebral autoregulation is common in children with complex mild traumatic brain injury, despite reassuring admission Glasgow Coma Scale 13-15. Children with complex mild traumatic brain injury have abnormal cerebrovascular hemodynamics, mostly during the first 5 days. Impairment commonly extends to the contralateral hemisphere and discharge of children with ongoing impaired cerebral autoregulation is common.

Background Scalp cooling has demonstrated efficacy in preventing hair loss in women with early stage breast cancer receiving neo/adjuvant chemotherapy. Data from 2 prospective trials (Rugo et al, and Nangia et al, JAMA 2017) led to FDA clearance of 2 automated scalp-cooling devices to prevent chemotherapy induced alopecia (CIA). Although scalp metastases from breast cancer are rare, historical concerns about scalp cooling included a theoretical increase in risk of recurrence in scalp due to reduced delivery of chemotherapy to the scalp. Methods We conducted a multicenter prospective trial evaluating the efficacy and safety of the DigniCap in women with stage I-II breast cancer receiving neo/adjuvant chemotherapy excluding sequential or combination anthracycline/taxanes with concurrent matched controls. The primary endpoint was unblinded patient self-assessment of 5 photographs using the Dean scale to estimate hair loss 4 weeks following the last dose of chemotherapy, with success defined as a Dean score of 0-2 (≤ 50% hair loss); additional endpoints included quality of life (QOL) and both short and long-term safety. Results 106 patients using the scalp cooling device and 16 concurrent controls were enrolled. As previously reported, the use of scalp cooling was associated with less alopecia and improvement in several measures of QOL (Rugo et al, JAMA 2017). 91 patients have follow-up (FU) out to 3 years; 73 with estrogen receptor (ER) positive and 18 with ER negative disease. 5 DigniCap patients have developed recurrent breast cancer in breast (n=1), liver (n=1), bone, liver and breast (n=1), bone, liver, lung, and nodes (1), and bone, breast, GI tract and bladder (n=1). Of 12 control patients with available FU, 1 developed metastases to liver. 2 patients have died of metastatic disease, one in the DigniCap arm and one in the control arm. No new safety signals have been detected. Conclusion Scalp cooling using the DigniCap system in patients with early stage breast cancer receiving taxane based neo/adjuvant chemotherapy is safe and effective. No scalp metastases have been reported 3 years following completion of study treatment. 4 year FU data will be presented. The study was funded by The Lazlo Tauber Family Foundation (UCSF), the Anne Moore Breast Cancer Research Fund (Weil Cornell), and the Friedman Family Foundation (Mount Sinai Beth Israel), as well as partially by Dignitana. Citation Format: Rugo HS, Klein P, Melin SA, Hurvitz SA, Melisko ME, Moore A, D'Agostino, Jr. RB, Deluca A, Cigler T. Long-term safety follow-up of patients with early stage breast cancer treated with scalp cooling on the Dignitana scalp cooling trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-04.

Expression of inflammatory (interleukin-6 [IL-6]) and vascular homeostatic (angiopoietin-2 [AP-2], endothelin-1 [ET-1], endocan-2 [EC-2]) biomarkers in pediatric traumatic brain injury (TBI) was examined in this prospective, observational cohort study of 28 children hospitalized with mild, moderate, and severe TBI by clinical measures (age, sex, Glasgow Coma Scale score [GCS], Injury Severity Score [ISS], and cerebral autoregulation status). Biomarker patterns suggest an inverse relationship between GCS and AP-2, GCS and IL-6, ISS and ET-1, but a direct relationship between GCS and ET-1 and ISS and AP-2. Biomarker patterns suggest an inverse relationship between AP-2 and ET-1, AP-2 and EC-2, but a direct relationship between AP-2 and IL-6, IL-6 and EC-2, and IL-6 and ET-1. Plasma concentrations of inflammatory and vascular homeostatic biomarkers suggest a role for inflammation and disruption of vascular homeostasis during the first 10 days across the severity spectrum of pediatric TBI. Although not statistically significant, without impact on cerebral autoregulation, biomarker patterns suggest a relationship between inflammation and alterations in vascular homeostasis. The large variation in biomarker levels within TBI severity and age groups, and by sex suggests other contributory factors to biomarker expression.

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 regarding 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 in an IRB-approved prospectively-maintained database of TNBC patients treated at two academic institutions in the United States from 1999-2018. Primary tumor size, histology, and nodal status were based upon definitive surgical pathology. Mean follow-up was 5.3 years.Results: 756 TNBC cases were analyzed; 258 T1N0 TNBC patients were identified. Adjuvant chemotherapy was delivered to 30.5% of T1a, 64.7% T1b, and 83.9% T1c (p < 0.0001). Factors associated with delivery of adjuvant chemotherapy were age, histology, high-grade disease, and postoperative adjuvant radiation therapy. At a mean follow-up of 5.3 years, increase in overall survival was associated with use of chemotherapy in patients with T1c disease (93.2% v. 75.2% p = 0.008) but not in those with T1a (100% v. 100% p = 0.3778) or T1b (100% v. 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 cases of T1a and T1b disease, regardless of whether adjuvant chemotherapy was delivered.

Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry.MethodsWe present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety 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. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load.ResultsData is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups.ConclusionIn hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.

Policing in America has lost more officers to suicides than line of duty deaths over the past four years. As the gatekeepers to the criminal justice system, the well-being of officers is critical as unhealthy police using poor coping strategies to handle their stress can lead to a multitude of negative consequences for the communities they serve, their departments, their fellow officers, and themselves. While the technology of policing is quickly advancing, the routine duties of officers remain stressful. This stress requires officers to use effective coping strategies to deal with it, but the traditional subculture of policing promotes maladaptive, rather than adaptive, coping strategies. To understand how the subculture influences police and the coping strategies they use, research must understand the socialization process of recruits entering the job. The current research seeks to understand how police recruits are socialized into the police subculture and how this affects the coping strategies they use to deal with the stressors they will confront on the job. The research analyzes how the network position of recruits influences their adoption of the police subculture and how this, in turn, affects their development of coping strategies. Recruits were surveyed three times during their academy training to examine the transitioning and socialization that occurs throughout the police academy. Results reveal that networks affect the adoption of the police subculture by recruits and this socialization process impacts the development of coping strategies by recruits. Findings highlight the need for future work to continue the longitudinal research approach to examine how the networks change once recruits complete their field training and probationary period. Doctor of Philosophy Police officers are engaged in an occupation that induces a vast amount of stress, leading to burnout and poor coping strategies. Blue H.E.L.P. began tracking the suicide rates of law enforcement and found that officers are dying more often by their own hands than in line of duty deaths. We have also seen growing tensions between police and communities, further leading to lower retention rates of current officers. The current study seeks to understand how police recruits are trained to endure the stress of their occupation. Policing is comprised of a unique occupational culture that creates solidarity among its members, which can influence how officers learn to utilize coping mechanisms. The current research examines how new police recruits fit into this occupational culture and how this affects their coping strategies over time. Results show that how new recruits are socialized into the occupational culture matter in terms of how they learn to cope with their job. Understanding how new recruits are taught to cope is imperative to destigmatize the notion of well-being to train healthier officers and to potentially lower suicide rates among our nation's law enforcement.

The multilateral efforts, led by the Organisation for Economic Cooperation and Development (OECD), to address base erosion and profit shifting (BEPS) have attracted much attention from tax policy makers, practitioners and academics. In 2012, the OECD/G20 BEPS Project was launched to address BEPS through a range of international tax policy measures. A key part of the BEPS package was the Action 11 report, which considered the fiscal and economic impacts of BEPS and produced an empirical estimate of the global corporate income tax (CIT) revenue losses arising from BEPS of between 4 per cent and 10 per cent of global CIT revenues. This research note highlights some of the data-related and methodological challenges facing researchers attempting to estimate the fiscal impacts of BEPS, discusses some of the methodological approaches that have recently been applied to this end, and provides a preview of the forthcoming release of the first edition of the OECD Corporate Tax Statistics.

Librarians from Purdue University wanted to determine which social media platforms students use, which platforms they would like the library to use, and what content they would like to see from the library on each of these platforms. We conducted a survey at four of the nine campus libraries to determine student social media habits and preferences. Results show that students currently use Facebook, YouTube, and Snapchat more than other social media types; however, students responded that they would like to see the library on Facebook, Instagram, and Twitter. Students wanted nearly all types of content from the libraries on Facebook, Twitter, and Instagram, but they did not want to receive business news or content related to library resources on Snapchat. YouTube was seen as a resource for library service information. We intend to use this information to develop improved communication channels, a clear libraries social media presence, and a cohesive message from all campus libraries.

Background: Tumor infiltrating lymphocytes (TILs) evaluated in the primary tumor biopsy or surgical resection have been well established as having prognostic significance in patients with triple negative breast cancer (TNBC) and HER2+ breast cancer treated with adjuvant chemotherapy (Savas et. al, Nat Rev Clin Oncol 2016). In TNBC, stromal TILs behave as a continuous variable with every 10% increase in TIL resulting in a decrease in risk of recurrence and death. The definition of lymphocyte-predominant breast cancer (LPBC) has been used for tumors that contain 50%–60% TILs and usually have a particularly good outcome (Salgado et al, Ann Oncol 2015). Our group recently demonstrated in a phase II single arm study that tetrathimolybdate (TM), a copper-depleting agent, resulted in improved event free survival (EFS) for TNBC patients compared to historical controls. The 2-year event-free survival (EFS) for stage 2-3 and stage 4 NED was 91% and 67%, respectively. In this analysis, our goal was to explore whether the encouraging results we observed were influenced by enrolling TNBC patients with better prognostic factors at initial diagnosis, namely higher stromal TIL score, in our copper depletion trial. Methods: Archived primary breast tissue was available from 67 of the 75 patients enrolled in the phase II TM trial. The phase II study included patients with stage II TNBC or stage III or IV NED breast cancer patients, who were treated with TM for 2 years or until relapse. Here we focused on the 30 patients with TNBC. The demographic data for the patients is included in the following table. Patient DemographicsAge at diagnosisStage at study entryPrior Adjuvant or Neoadjuvant therapyNumber of prior chemotherapy regimens in metastatic setting%Tumor Infiltrating Lymphocytes504Adjuvant110543AAdjuvantn/a30563AAdjuvantn/a20513CNeoadjuvantn/a The number of TILs in each sample was calculated by an experienced pathologist using published criteria (Salgado et al, Ann Oncol 2015). We used TILs >50% to define LPBC. Results: Overall, we found that only 3/30 (10%) of TNBC patients had TILs >50%. In addition, 14/30 (46.7%) of TNBC patients had tumors with 10% v. Conclusions: Only 10% of TNBC patients enrolled in the study had LPBC at diagnosis thus indicating that this cohort was not enriched for patients with immunogenic tumors. When stratified by TILs >10% or Citation Format: Rybstein MD, Nackos E, Kornhauser N, Cigler T, Andreopoulou E, Moore A, Cobham M, Fitzpatrick V, Demaria S, Vahdat LT. Tumor infiltrating lymphocytes (TILS) among high risk for recurrence breast cancer patients treated with tetrathimolybdate (TM) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-10.

Background: Metals have emerged as a viable therapeutic target for a new generation of anti-cancer and anti-metastatic agents. Copper, an essential trace element, serves as an important catalytic cofactor in several biological functions and has emerged as an essential factor in carcinogenesis. Among other elements, bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX) are key elements in tumor progression. We hypothesized tetrathiomolybdate (TM)-associated copper depletion (CD) inhibits tumor metastases by reducing the number of EPCs and other copper dependent processes in the pre-metastatic niche. These results are an update of our previously reported study (Chan N, Willis A, Kornhauser N et al. Influencing the Tumor Microenvironment: Phase 2 Study of Copper Depletion with Tetrathiomolybdate in High Risk Breast Cancer and Preclinical Models of Lung Metastases. Clin Cancer Res. October 21, 2016) with longer follow-up. Methods: A single arm phase II study of breast cancer (BC) patients (pts) at high risk for recurrence, defined as node+ triple negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. TM was given to maintain ceruloplasmin (Cp) levels between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was a change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS and LOXL-2 levels. Results: Seventy-five pts received 2778 cycles of TM on the primary and extension study. The primary study treatment duration was 24 cycles (each cycle is 28 days) plus an extension phase. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. Forty-eight percent of pts are TNBC and 40% of pts are stage 4 NED. Median Cp levels were monitored with each cycle. A decrease from 28 to 16 (p Conclusions: TM is safe, well tolerated and appears to affect multiple components of the tumor microenvironment that have been identified in pre-clinical models as important for progression. Ongoing studies in banked specimens are underway to further delineate its effect on copper dependent processes necessary for metastases. Randomized trials are warranted, especially in patients who are at high risk for relapse such as those with TNBC. Citation Format: Sahota S, Willis A, Kornhauser N, Ward M, Cobham M, Cigler T, Moore A, Andreopoulou E, Fitzpatrick V, Schneider S, Prima N, Wiener A, Ko D, De Laurentiis A, Warren JD, Rubinchik A, Mittal V, Vahdat LT. A phase II study of copper-depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence: Updated results [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-02.

To examine early cerebral haemodynamic changes among youth hospitalized with sports-related traumatic brain injury (TBI).Youth 0-18 years admitted to a level one trauma centre with sports-related TBI were enrolled. Daily measures included clinical symptoms and Glasgow Coma Scale (GCS) score. Using Transcranial Doppler (TCD) ultrasonography and tilt testing, we measured middle cerebral artery flow velocity (Vmca) and cerebral autoregulation index (ARI).Six previously healthy males age 14 (IQR 12-16) years with headache and abnormal head CT were admitted with median admission GCS 15. Six patients underwent 12 TCD examinations between hospital days 0-9. Low Vmca occurred in 3/6 patients and on the side of TBI, whereas high Vmca occurred in 2/6 patients. Five patients had at least one measurement of impaired and five patients had absent cerebral autoregulation of at least one hemisphere; all these five patients had GCS 15 and headache during TCD examinations. Three patients were discharged with absent cerebral autoregulation. Five (83%) patients were discharged to home and one patient was discharged to a rehabilitation facility.Headache, abnormal Vmca and impaired cerebral autoregulation occur after sports-related TBI, despite normal GCS. Headache may signal underlying neurovascular abnormality in sports-related TBI.

Background Carotid intraplaque hemorrhage (IPH) seen on vessel wall MRI is associated with an increased risk of stroke or transient ischemic attack, as are microembolic signals (MES) detected by transcranial Doppler (TCD). We sought to examine the association between IPH and MES in acute stroke patients with symptomatic carotid atherosclerosis. Methods Through a retrospective chart review, we included patients from 2011 to 2013 with acute ischemic stroke due to carotid atherosclerosis of varying stenosis who had both 3D volumetric MRI of the neck and TCD emboli monitoring. Results Twenty-four patients met the inclusion criteria. Mean time from stroke to MRI was 1.4 ± 1.9 days and to TCD was 2.6 ± 2.4 days. MES was seen in 10 patients (42%) and IPH was present in seven patients (29%), but we did not find a relationship between MES and IPH ( p = 0.64). Conclusion In patients with recent acute ischemic stroke attributed to carotid atherosclerosis, we did not detect an association between the presence of IPH and MES. While this small study may be underpowered, an alternate explanation is that MES and IPH reflect vulnerable carotid atherosclerosis through different mechanisms. This untested concept warrants prospective study in a larger cohort.

Along with symptoms of anxiety and depression, many breast cancer survivors experience symptoms of posttraumatic stress disorder (PTSD) that may worsen in the setting of other stressful life events. The aim of this pilot study was to evaluate whether a 4-week version of our Contemplative Self-Healing program would have different effects in reducing PTSD symptoms between breast cancer survivors with or without chronic stress at baseline. PTSD symptoms were measured using the Impact of Events scale (IES). A linear mixed model analysis was used to evaluate within patients changes in IES score. Results showed that breast cancer patients who were experiencing chronic stress reported greater improvement in IES score than those without chronic stress. Our preliminary findings shed light on the need to evaluate life stressors in breast cancer patients. Evaluating chronic stress may be essential in predicting which cancer patients may benefit most from a psychological intervention.

We analyze the profit shifting behavior of U.S. multinational firms using a unique panel data set of U.S. tax returns over the period 2002–2012. Prior research has found significant effects of tax rates in affiliate and parent countries on the profit shifting behavior of multinational entities, with semi-elasticities ranging from close to zero to well above one. We build on this prior work by allowing more heterogeneity in response across the distribution of tax rates and by including affiliates located in tax havens around the world. Our findings suggest that elasticities based on a log-linear specification may severely understate the sensitivity of profits to tax in low-tax jurisdictions while simultaneously overstating this elasticity in high-tax jurisdictions. Accounting for this type of nonlinearity appears crucial in considering how the global allocation of firm profits might change in response to tax rate changes.

Background: Most women consider hair to be an important part of body image. Alopecia is an emotionally traumatic side effect for breast cancer patients undergoing adjuvant chemotherapy. The DigniCap™ Scalp Cooling System is the first scalp cooling system cleared by the US Food and Drug Administration to reduce the likelihood of chemotherapy induced alopecia. Methods: Quality of Life (QOL) data were collected as part of a prospective clinical trial evaluating the clinical performance of scalp cooling in women with early stage BC receiving adjuvant chemotherapy. The study's primary endpoint was hair loss as evaluated by patient self-assessment. Treatment success was defined as ≤ 50% hair loss. QOL was evaluated by the EORTC-QLQ-BR23 (BR23) administered at baseline, last chemotherapy cycle, and one month later. For BR23, 4 response categories were collapsed to 2 categories (Not at all/A little bit and Quite a bit/Very much) for analysis. QOL was compared between those with success vs. failure of scalp cooling. Results: 101 patients were evaluable for the primary endpoint: Success was seen in 67 (66.3%) pts. QOL at study entry was comparable between pts with scalp cooling success or failure for each item in the BR23 questionnaire. Results reported as percentages of patients in each group who answered either quite a bit or very much to body image-related questions on the BR23 questionnaire are displayed in Table 1. BR23 results (% quite a bit/very much) one month after chemotherapyBR23 ItemsTreatment Success % (95% CI)Treatment Failure % (95% CI)Felt physically less attractive18.5% (9.0%, 27.9%)52.2% (31.8%, 72.6%)Felt less feminine15.4% (6.6%, 24.2%)29.1% (19.2%, 59.1%)Found it difficult to see themselves naked13.8% (5.5%, 22.2%)21.7% (4.9%, 38.6%)Felt dissatisfied with their body12.3% (4.3%, 20.3%)26.1% (8.1%, 44.0%) Conclusions: Women with breast cancer using scalp cooling during chemotherapy who had hair preservation experienced improved quality of life, according to self-assessment of body image, compared to women who had significant hair loss. Citation Format: Cigler T, Melin SA, Klein P, Hurvitz SA, Melisko M, Moore A, Park GD, Bageman E, Ver Hoeve ES, Rugo HS. Body image in women with breast cancer using a scalp cooling system to reduce chemotherapy induced alopecia [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-17.