Teaching Bleeding Control and Building Trust With a Community Affected by Firearm Injuries.

This survey study evaluates a program for increasing bystander bleeding control skills, improving self-efficacy for bleeding control, and building trust between community participants and first responders in a Somali community in the US affected by firearm-related deaths.

The Effect of Power Grip on Ulnar Variance A Computed Tomography Study of the Wrist and Elbow.

Although an increase in ulnar variance with power grip is well documented in the medical literature, there is a paucity of information concerning its mechanism. This concept was examined in five healthy individuals using computed tomography of their wrists and elbows. Images were obtained of both joints in the resting position and with maximum power grip. Ulnar variance at the wrist increased an average of 0.64 mm (range: 0.3 to 1.2 mm). While the ulnohumeral joint remained unchanged, the radiocapitellar distance shortened an average of 0.62 mm (range: 0.3 to 1.0 mm; p = 0.03), which correlated directly with the change at the wrist. Our study showed that the increase in ulnar variance with grip was due to proximal shift of the radius and not to any distal migration of the ulna, which may have clinical implications in reconstruction or arthroplasty of the elbow.

An unscheduled switch to endocycles induces a reversible senescent arrest that impairs growth of the Drosophila wing disc.

A programmed developmental switch to G / S endocycles results in tissue growth through an increase in cell size. Unscheduled, induced endocycling cells (iECs) promote wound healing but also contribute to cancer. Much remains unknown, however, about how these iECs affect tissue growth. Using the D. melanogaster wing disc as model, we find that populations of iECs initially increase in size but then subsequently undergo a heterogenous arrest that causes severe tissue undergrowth. iECs acquired DNA damage and activated a Jun N-terminal kinase (JNK) pathway, but, unlike other stressed cells, were apoptosis-resistant and not eliminated from the epithelium. Instead, iECs entered a JNK-dependent and reversible senescent-like arrest. Senescent iECs promoted division of diploid neighbors, but this compensatory proliferation did not rescue tissue growth. Our study has uncovered unique attributes of iECs and their effects on tissue growth that have important implications for understanding their roles in wound healing and cancer.

The benefits (or detriments) of adapting to demand disruptions in a hospital pharmacy with supply chain disruptions.

Supply chain disruptions and demand disruptions make it challenging for hospital pharmacy managers to determine how much inventory to have on-hand. Having insufficient inventory leads to drug shortages, while having excess inventory leads to drug waste. To mitigate drug shortages and waste, hospital pharmacy managers can implement inventory policies that account for supply chain disruptions and adapt these inventory policies over time to respond to demand disruptions. Demand disruptions were prevalent during the Covid-19 pandemic. However, it remains unclear how a drug's shortage-waste weighting (i.e., concern for shortages versus concern for waste) as well as the duration of and time between supply chain disruptions influence the benefits (or detriments) of adapting to demand disruptions. We develop an adaptive inventory system (i.e., inventory policies change over time) and conduct an extensive numerical analysis using real-world demand data from the University of Michigan's Central Pharmacy to address this research question. For a fixed mean duration of and mean time between supply chain disruptions, we find a drug's shortage-waste weighting dictates the magnitude of the benefits (or detriments) of adaptive inventory policies. We create a ranking procedure that provides a way of discerning which drugs are of most concern and illustrates which policies to update given that a limited number of inventory policies can be updated. When applying our framework to over 300 drugs, we find a decision-maker needs to update a very small proportion of drugs (e.g., < 5 % ) at any point in time to get the greatest benefits of adaptive inventory policies.

Vesicular Stomatitis Virus Detected in Biting Midges and Black Flies during the 2023 Outbreak in Southern California.

Vesicular stomatitis (VS) is a viral disease that affects horses, cattle, and swine that is transmitted by direct contact and hematophagous insects. In 2023, a multi-state outbreak of vesicular stomatitis New Jersey virus (VSNJV) occurred in California, Nevada, and Texas, infecting horses, cattle, and rhinoceros. To identify possible insect vectors, we conducted insect surveillance at various locations in San Diego County, CA, including at a wildlife park. CO2 baited traps set from mid-May to mid-August 2023 collected 2357 Culicoides biting midges and 1215 Simulium black flies, which are insect genera implicated in VSNJV transmission. Insects were pooled by species, location, and date, then tested for viral RNA. Nine RNA-positive pools of Culicoides spp. and sixteen RNA-positive pools of Simulium spp were detected. Infectious virus was detected by cytopathic effect in 96% of the RNA-positive pools. This is the first report of VSNJV in wild-caught C. bergi, C. freeborni, C. occidentalis, S. argus, S. hippovorum, and S. tescorum. The vector competency of these species for VSNJV has yet to be determined but warrants examination. Active vector surveillance and testing during disease outbreaks increases our understanding of the ecology and epidemiology of VS and informs vector control efforts.

Clinical outcomes and ctDNA correlates for CAPOX BETR: a phase II trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2+ gastroesophageal adenocarcinoma.

Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.

Ileo-Ileal Intussusception Secondary to Neuroendocrine Tumor in Adult Patient.

BACKGROUND Intussusception occurs when a proximal region of the intestine telescopes into a distal region. It is more common in the pediatric population, with only 5% of cases occurring in adults. The most frequent causes of adult intussusception are malignancy, polyps, or diverticula. A very rare cause is neuroendocrine tumor (NET). NETs are a diverse group of neoplasms that arise from endocrine cells throughout the body. Here, we present a case of a patient who presented with ileo-ileal intussusception due to a T3N1 NET, grade 1. CASE REPORT A 60-year-old man with a medical history of peptic ulcer disease presented for evaluation of lower abdominal pain, dark "maroon" colored stools, and hematemesis for the past 2 days. Computed tomography (CT) of the abdomen and pelvis showed ileo-ileal intussusception. Exploratory laparotomy revealed a small bowel mass approximately 30 cm from the ileocecal valve. After removal of 15 cm of small bowel and 13 lymph nodes, pathology confirmed the diagnosis of a T3N1 NET, grade 1. He was subsequently referred to the Oncology Department, where he was cleared, with no need for additional surveillance. CONCLUSIONS In adult patients presenting with nonspecific abdominal pain and concern for small bowel obstruction, a CT scan can be helpful in diagnosing intussusception. When dealing with adult intussusception, the etiology needs to be carefully investigated to search for an underlying malignancy. In rare occasions, small bowel NETs can be the cause of intussusception and can therefore be identified early, before they metastasize and present with carcinoid syndrome.

Preinjury and Event-Related Characteristics of Pediatric Firearm Injuries: The American College of Surgeons Firearm Study, United States, March 2021‒February 2022.

Objectives. To assess differences in contextual factors by intent among pediatric firearm injury patients and determine factors associated with data missingness. Methods. We retrospectively queried the American College of Surgeons Firearm Study database (March 1, 2021-February 28, 2022) for patients aged 18 years or younger. We stratified preinjury, firearm-related, and event-related factors by intent and compared them by using Fisher exact, χ2, or 1-way analysis of variance testing. Secondary analysis estimated the adjusted odds of missingness by using generalized linear modeling with binominal logit link. Results. Among 17 395 patients, 2974 (17.1%) were aged 18 years or younger; 1966 (66.1%) were injured by assault, 579 (19.5%) unintentionally, and 76 (2.6%) by self-inflicted means. Most contextual factors differed by intent, including proportion of youths with previous adverse childhood experiences, mental illness, and violent assaults or injury, firearm type and access, perpetrator relationship, and injury location. In adjusted analyses, age, trauma center designation, intent, and admission status were associated with missingness. Conclusions. Contextual factors related to pediatric firearm injury vary by intent. Specific predictors associated with missingness may inform improved future data collection. Public Health Implications. Contextual factors related to pediatric firearm injury can be obtained in a systematic manner nationally to inform targeted interventions. (Am J Public Health. 2024;114(10):1097-1109. https://doi.org/10.2105/AJPH.2024.307754).

AlphaFold predictions of fold-switched conformations are driven by structure memorization.

Recent work suggests that AlphaFold (AF)-a deep learning-based model that can accurately infer protein structure from sequence-may discern important features of folded protein energy landscapes, defined by the diversity and frequency of different conformations in the folded state. Here, we test the limits of its predictive power on fold-switching proteins, which assume two structures with regions of distinct secondary and/or tertiary structure. We find that (1) AF is a weak predictor of fold switching and (2) some of its successes result from memorization of training-set structures rather than learned protein energetics. Combining >280,000 models from several implementations of AF2 and AF3, a 35% success rate was achieved for fold switchers likely in AF's training sets. AF2's confidence metrics selected against models consistent with experimentally determined fold-switching structures and failed to discriminate between low and high energy conformations. Further, AF captured only one out of seven experimentally confirmed fold switchers outside of its training sets despite extensive sampling of an additional ~280,000 models. Several observations indicate that AF2 has memorized structural information during training, and AF3 misassigns coevolutionary restraints. These limitations constrain the scope of successful predictions, highlighting the need for physically based methods that readily predict multiple protein conformations.

Acculturative stress and identity challenges undermine the successful reintegration of Australian veterans.

Reintegration into civilian society following military separation is a challenging process. There is a dearth of research into the impact of these factors on Australian veteran reintegration. The purpose of this phenomenological study was to explore the lived experience of Australian veterans during reintegration, through the lens of acculturative stress and identity. Ten interviews were conducted with ex-serving members of the Australian Defence Force. Post-1990 veterans of all genders, who were at least 18 years of age, from all service branches were eligible for the study. Thematic analysis revealed two overarching themes each with three main themes; acculturative stress (assimilation, societal issues, social isolation), and integrated identity (acceptance, integrated communities, and adapting to the civilian world). Each main theme contained two subthemes illustrating their significance. Difficulty integrating civilian and veteran identities was a key barrier to successful reintegration and negative separation experiences undermined integration of civilian and veteran identities. Acculturative stressors identified were poor understanding by family, community, and clinicians of the incompatibility between military and civilian cultures. Education is needed for clinicians, the community, and families about military culture and difficulties for veterans when reintegrating into civilian society. Support for reintegration should be tailored to the needs of veterans encompassing personally meaningful activities, use of military skills in civilian contexts, ongoing membership of the military community and engagement with other veterans. This will ultimately foster integration of veteran and civilian identities, enabling veterans to retain their veteran identity in a manner that is adaptive for the civilian context. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Predicting Nerve Course Variations to Prevent Iatrogenic Lesions: A Surgical Perspective on Sural Nerve Variations.

Background: There are several documented variations of the sural nerve noted within the literature. This cadaveric study was conducted to provide a surgical perspective to either directly addressing the sural nerve, or avoiding it depending on the injury or pathology being surgically addressed. Methods: Twenty-five preserved cadaveric limbs were dissected from the popliteal fossa to the foot. Three locations of the course of the sural nerve data were analyzed. The first location (M1) was from the head of the fibula to the sural nerve. The second location (M3) was from 2.54 cm proximal to the distal tip of the lateral malleolus to the sural nerve. The third location (M2) was from the shaft of the fibula at the halfway point between measurements 1 and 2 to the course of the sural nerve. The types of variations were noted as well, compared to previous studies, highlighting the abundance of sural nerve variations in the lower limb that clinicians and surgeons need to be aware of and ready to address. Results: The sural nerve courses 4.6 cm posterior from the fibula at the proximal fibula and mid fibula and 4.5 cm at the distal fibula. The 25 sural nerve variations are not reflective of what has been previously published in the literature. Conclusion: The data can be utilized in preoperative planning in addressing or avoiding the sural nerve involving the posterior superficial compartment of the leg.

Proton therapy toxicity outcomes for localized prostate cancer: Long-term results at a comprehensive cancer center.

Background: Proton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database. Methods: We reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 117]. Descriptive statistics and Kaplan-Meier estimates assessed toxicity and freedom from biochemical relapse (FFBR). Results: Median follow-up was 7.0 years. The median dose was 78 Gy(RBE)(range: 72-79.2 Gy) in 2.0 Gy(RBE) fractions; 63 % of patients received 78 Gy(RBE) in 39 fractions, and 29 % received 76 Gy(RBE) in 38 fractions. Overall rates of late grade ≥3 GU and GI toxicity were 0.87 % and 1.01 %, respectively. Two patients developed grade 4 late GU toxicity and seven patients with grade 4 late GI toxicity. All patients experiencing severe late grade 4 toxicities were treated to 78 Gy(RBE) in 39 fractions with 80 Gy(RBE) dose to the anterior rectal wall and/or bladder neck. The 10-year FFBR rates for patients with LR to U-IR disease were compared between those treated with 76 and 78 Gy(RBE); the rates were 94.5 % (95 % confidence interval [CI] 92.4-96.0 %) and 93.2 % (95 % CI 91.3-95.7 %), respectively (log-rank p = 0.22). Conclusions: Proton therapy is associated with low rates of late grade ≥3 GU and GI toxicity. While rare, late grade 4 toxicities occurred in nine (0.3 %) patients. De-escalation to a total dose of 76 Gy(RBE) yields excellent clinical outcomes for patients with LR to U-IR disease with the potential for significant reductions in grade ≥3 late toxicity.

Health and social care experience and research perception of different ethnic minority populations in the East Midlands, United Kingdom (REPRESENT study).

INTRODUCTION: Ethnic minority populations experience significant health and social care disparities; despite experiencing a greater burden of diseases, these groups are underrepresented in health and social care research. Consequently, related research can be less applicable to these population groups. The REPRESENT study aims to explore the health and social care experiences of ethnic minorities and other minoritised populations, their research interests and appropriate research practices. METHODS: Focus groups and semistructured interviews were conducted between May and September 2022 with members of a number of ethnic minority communities in England. Data were audio recorded, transcribed and thematically coded using NVivo 12. Rigour was determined through extensive sampling, iterative data collection and analysis. FINDINGS: Fifty-two ethnic minority members were engaged in group interviews and one-to-one interviews. Participants included representatives of the following groups: African Caribbean, Eastern European, Gypsy Travellers, Lesbian, Gay, Bisexual, Transgender, Queer, Intersex and Asexual+, Refugee/Asylum Seekers, Somali and South Asian communities. Interviews were also conducted with ethnic minority healthcare providers and researchers. Three overarching categories were identified: health information, medical service experiences, health and social care concerns and health research. Health and social care services challenges were mostly attributed to discrimination, delayed services, poor cultural relevance and language and cultural barriers. The most influential information sources were local community organisations and word-of-mouth. The main health and social care concerns were chronic long-term health conditions, mental health, maternal health and child development. Recommendations for research involved understanding the motivations for participation, improving communication and empowering communities. Top research priorities were long-term health conditions, health promotion and education, early care interventions and understanding community needs. INTERPRETATION: Discrimination and bias in health and social care provision have severe implications for worsening ethnic health inequalities. Healthcare commissioning authorities and policymakers can leverage the preference of ethnic minority groups for pharmacy services and community organisations to improve access to care. Improving research interest and engagement requires understanding individual community needs, community sensitivity, research relevance and cultural appropriateness. PATIENT OR PUBLIC CONTRIBUTION: Members of ethnic minority Patient and Public Involvement and Engagement group and Community Advisory Board supported the REPRESENT study design, conceptualisation and report development.

Inequalities in accelerated cognitive decline: Resolving observational window bias using nested non-linear regression.

INTRODUCTION: Limited observational windows lead to conflicting results in studies examining educational differences in Alzheimer's disease and related dementias (ADRD) risk, due to observational window bias relative to onset of accelerated cognitive decline. This study tested a novel model to address observational window bias and tested for the presence and sources of disparities in accelerated cognitive declines due to ADRD. METHODS: The sample examined 167,314 cognitive assessments from 32,441 Health and Retirement Study participants. We implemented a parametric non-linear nested longitudinal regression and reported multivariable-adjusted nodal incidence ratios (aNIR). RESULTS: University degrees were associated with lower incidence (aNIR = 0.253, 95% confidence interval [CI] = [0.221 to 0.289], p < 0.001), while black participants had a higher incidence (aNIR = 1.995, [1.858 to 2.141], p < 0.001) of accelerated cognitive decline, adjusting for demographic, sociobehavioral, and medical risk factors. Sex-stratified analyses identified diminished educational returns for women and increased incidence among minoritized women. DISCUSSION: Addressing observational window bias reveals large social inequalities in the onset of accelerated cognitive declines indicative of ADRD. HIGHLIGHTS: This study identifies observational window bias as a source of conflicting results among previous studies of educational achievement in Alzheimer's disease and related dementias (ADRD) disparities. The study locates preclinical accelerated cognitive decline, which is indicative of ADRD while occurring 10+ years prior to symptom onset, as a site to study ADRD disparities that mitigates observational window bias. A novel method, nested non-linear regression, is developed to test for differences in the onset of accelerated cognitive decline. Educational and racial/ethnic disparities are demonstrated in the onset of accelerated cognitive decline, as are their intersecting differences with sex/gender.

Nonendoscopic Screening for Barrett's Esophagus and Esophageal Adenocarcinoma in At-Risk Veterans.

INTRODUCTION: Although rates of esophageal adenocarcinoma (EAC) in the United States continue to rise, many patients at risk of disease are not screened. EsoCheck (EC), a nonendoscopic esophageal balloon sampling device coupled with EsoGuard (EG), a DNA-based screening assay, is an US Food and Drug Administration-approved minimally invasive alternative to the traditional screening method of upper endoscopy. The objective of this study was to prospectively determine the diagnostic accuracy, tolerance, and acceptability of the EC/EG test in a screening population. METHODS: We recruited veterans who met the American College of Gastroenterology Guideline criteria for endoscopic Barrett's esophagus (BE) and EAC screening at the Louis Stokes Cleveland Veterans Affairs Medical Center. All study participants completed unsedated EC-guided distal esophageal sampling followed by a sedated esophagogastroduodenoscopy (EGD). Diagnostic yield of the EG assay and EGD was recorded and used in calculation of sensitivity and specificity of EC/EG in prospective screening. The abbreviated Spielberger State-Trait Anxiety Inventory questionnaire was administered before and after completion of EC. Overall tolerance of EC sampling was evaluated on a 10-point Likert scale. RESULTS: Esophageal cancer screening was accepted by 130 of 782 eligible veterans (16.6%), and we analyzed results of those who completed both screening tests (N = 124). Prevalence of BE/EAC among studied veterans was 12.9% (16/124), based on EGD. Sensitivity and specificity of EC/EG for EGD-detected BE/EAC were 92.9% (95% confidence interval [CI] 66.1-99.8) and 72.2% (95% CI 62.1-80.8), respectively. Positive and negative predictive values were 32.5% (95% CI 18.6-49.1) and 98.6% (95% CI 92.4-100), respectively. Baseline Spielberger State-Trait Anxiety Inventory-6 scores were reflective of notable levels of anxiety among veterans in the periprocedural setting. The mean postprocedure acceptability score for the EC test was 7.23 (SD 2.45). DISCUSSION: Our data suggest excellent sensitivity and negative predictive value of EC/EG in a screening population of veterans, making this modality a powerful screening tool for BE and EAC.

Neural population dynamics in songbird RA and HVC during learned motor-vocal behavior.

Complex, learned motor behaviors involve the coordination of large-scale neural activity across multiple brain regions, but our understanding of the population-level dynamics within different regions tied to the same behavior remains limited. Here, we investigate the neural population dynamics underlying learned vocal production in awake-singing songbirds. We use Neuropixels probes to record the simultaneous extracellular activity of populations of neurons in two regions of the vocal motor pathway. In line with observations made in non-human primates during limb-based motor tasks, we show that the population-level activity in both the premotor nucleus HVC and the motor nucleus RA is organized on low-dimensional neural manifolds upon which coordinated neural activity is well described by temporally structured trajectories during singing behavior. Both the HVC and RA latent trajectories provide relevant information to predict vocal sequence transitions between song syllables. However, the dynamics of these latent trajectories differ between regions. Our state-space models suggest a unique and continuous-over-time correspondence between the latent space of RA and vocal output, whereas the corresponding relationship for HVC exhibits a higher degree of neural variability. We then demonstrate that comparable high-fidelity reconstruction of continuous vocal outputs can be achieved from HVC and RA neural latents and spiking activity. Unlike those that use spiking activity, however, decoding models using neural latents generalize to novel sub-populations in each region, consistent with the existence of preserved manifolds that confine vocal-motor activity in HVC and RA.

Total Synthesis of Homoseongomycin Enantiomers and Evaluation of Their Optical Rotation.

A total synthesis of each homoseongomycin enantiomer was accomplished in 17 total steps (longest linear sequence = 12 steps) and 10 chromatographic purifications. Several schemes were attempted to forge the key 5-membered ring, but only a Suzuki coupling-intramolecular Friedel-Crafts acylation sequence proved viable. Challenges encountered during the optical rotation characterization of the natural product left us with two important takeaways. First, highly colored compounds like homoseongomycin that absorb near/at the sodium d-line may require optical rotation measurements at other wavelengths. Second, high dilution of such compounds to obtain measurement at the sodium d-line could result in artificially large and incorrectly assigned specific rotations. To verify the optical rotation, electronic circular dichroism spectra were acquired for both homoseongomycin enantiomers and were transformed into optical rotary dispersions via the Kramers-Kronig transform. We note the wavelength dependency on rotation, and at the sodium d-line 589 nm, we reassign the optical rotation of L-homoseongomycin from (-) to (+).

Development and clinical implementation of a digital workflow utilizing 3D-printed oral stents for patients with head and neck cancer receiving radiotherapy.

OBJECTIVES: We describe the development of 3D-printed stents using our digital workflow and their effects on patients enrolled in the lead-in phase of a multi-center, randomized Phase-II trial. MATERIALS AND METHODS: Digital dental models were created for patients using intraoral scanning. Digital processes were implemented to develop the mouth-opening, tongue-depressing, and tongue-lateralizing stents using stereolithography. Time spent and material 3D-printing costs were measured. Physicians assessed mucositis using the Oral Mucositis Assessment Scale (OMAS) and collected MD Anderson Symptom Inventory (MDASI) reports and adverse events (AEs) from patients at various time points (TPs). OMAS and MDASI results were evaluated using paired t-test analysis. RESULTS: 18 patients enrolled into the lead-in phase across 6 independent clinical sites in the USA. 15 patients received stents (average design and fabrication time, 8 h; average material 3D-printing cost, 11 USD). 10 eligible patients with complete OMAS and MDASI reports across all TPs were assessed. OMAS increased significantly from baseline to week 3 of treatment (mean difference = 0.34; 95 % CI, 0.09-0.60; p = 0.01). MDASI increased significantly from baseline to week 3 of treatment (mean difference = 1.02; 95 % CI, 0.40-1.70; p = 0.005), and week 3 of treatment to end of treatment (mean difference = 1.90; 95 % CI, 0.90-2.92; p = 0.002). AEs (grades 1-3) were reported by patients across TPs. Mucositis and radiation dermatitis were primarily attributed to chemoradiation. CONCLUSIONS: 3D-printed stents were successfully fabricated and well tolerated by patients. As patients enroll in the randomized phase of this trial, data herein will establish a baseline for comparative analysis.