There is substantial evidence that the “Western” dietary pattern, a diet defined as being relatively high in red and processed meat, total fat, refined/processed foods, and relatively lacking in vegetables and fruits, is associated with increased intestinal inflammation, which in turn is implicated in the pathophysiology of disease states such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). Conversely, there is accumulating evidence suggesting that plant-based foods that contain whole grains, dietary fiber, antioxidant vitamins, and phytochemicals, have anti-inflammatory effects in the gut. However, there is a paucity of research investigating the anti-inflammatory effects of a dietary pattern that eliminates all animal products (typical of a Western dietary pattern) and is instead entirely plant-based. Such a pattern, which eliminates all animal products (including meat, eggs, and dairy), eliminates the foods associated with intestinal inflammation and instead replaces them with plant-based foods, many of which have been found to be anti-inflammatory. The proposed study is a prospective study that will use fecal calprotectin to quantify the levels of intestinal inflammation in healthy participants before and after shifting them from a predominantly Western dietary pattern to an entirely plant-based dietary pattern. This study will help determine whether substituting a plant-based dietary pattern for Western dietary pattern decreases intestinal inflammation, thereby supporting its use as a potential treatment modality for those with IBD (in conjunction with or in place of pharmaceutical treatment regimens) and as an intervention for primary prevention of IBD and CRC.

RATIONALE: Alcohol use disorder (AUD) is a devastating neurologic condition that affects millions of people every year. Despite its prevalence, there is still a lack of knowledge and effective treatment options available to alleviate aversive withdrawal symptoms. One such symptom is mechanical allodynia which is the development of a pain response following innocuous tactile stimuli and is found in many chronic pain disorders. The adrenergic system has been previously shown to play a role in modulating ethanol drinking behavior and withdrawal symptoms, but has also been demonstrated to impact nociception. The alpha2-adrenoceptor, in particular, exerts an inhibitory effect on adrenergic and non-adrenergic neurons, and systemically administered agonists have produced reductions in drinking behavior and antinociception. Though this receptor system has been extensively studied, there has yet to be an investigation of the role of alpha2-adrenoceptor agonsim in regards to alcohol withdrawal-induced mechanical allodynia. OBJECTIVES: The objectives of this study were to determine the extent that the alpha2-adrenoceptor agonist, clonidine, could reduce drinking behavior and withdrawal associated mechanical allodynia in C57B1/6J mice chronically exposed to ethanol. METHODS: We employed a series of behavioral tests to examine ethanol actions in adult male and female mice following the administration of varying doses of clonidine (0-160 µg/kg). To investigate the effect on ethanol drinking behavior, we subjected mice to a two-bottle choice, intermittent access paradigm with 24hr access to 20% (v/v) ethanol solutions every other day (Monday, Wednesday and Friday)(MWF group). After stabilization of intake, mice were intraperitoneally administered with vehicle or clonidine, and their actions on the intake of food water and ethanol were determined. Nociceptive threshold was determined following 72hrs of alcohol abstinence using an electronic von Frey device. MWF mice were compared to water drinking control animals following vehicle treatment and again after a 30 minute pretreatment with clonidine. In a separate experiment, alcohol-naïve mice were subjected to the same two-bottle choice schedule, except the ethanol was replaced with 1.15% (w/v) sucrose solutions. Mice were then treated with clonidine and its actions on sucrose, water and food intake were determined. RESULTS: Systemic injection of clonidine decreased ethanol intake during both short and long periods of ethanol intake, decreased allodynia following prolonged abstinence from alcohol and had no effect on the consumption of naturally-reinforcing substances such as sucrose. CONCLUSION: Our results indicate that alpha2-adrenoceptor agonsim leads to a reduction in ethanol drinking behaviors in mice and is sufficient in reversing the changes to pain threshold following prolonged alcohol withdrawal. / 2020-07-03T00:00:00Z

BACKGROUND: It is a commonly held view in the ophthalmologic community that eyes with sufficiently low calculated postoperative corneal keratometry, less than 35 diopters, should not undergo corrective refractive laser surgery (CRLS) due to the increased risk of best corrected visual acuity (BCVA) loss. Typical CRLS include Laser In-Situ Keratomileusis (LASIK), Photorefractive Keratectomy (PRK), and Laser-Assisted Sub-Epithelial Keratectomy (LASEK). Evidence for this claim in currently available literature is sparse and inconsistent. PURPOSE: To further elucidate the relationship between calculated “flat” postoperative corneal keratometry and loss of BCVA. Additionally, to investigate the role of procedure type (LASIK, ASA, or LASEK) and degree of calculated postoperative corneal flatness on visual outcomes following CRLS. METHODS: 222 eyes (111 candidates and 111 controls) were retrospectively analyzed and matched based on calculated postoperative keratometry compared to control subgroups with calculated postoperative keratometries ≥38 D and further stratified into subgroups 1b (K=38-38.99 D), 2b (K=39-39.99 D), 3b (K=40-40.9 9D), and 4b (K≥41 D). All of the eyes had undergone LASIK, PRK, or LASEK between December 2008 and November 2016 at Boston Eye Group/Boston Laser in Brookline, MA. RESULTS: Statistical analyses showed no significant differences between candidates and controls in preoperative BCVA (p=0.650) and postoperative BCVA (p=0.081). Subgroup matching showed no significant differences in the amount of tissue ablated in 1a & 1b (p=0.946), 2a & 2b (p=0.694), 3a & 3b (p=0.989), and 4a & 4b (p=0.986). There was also no significant change between preoperative and postoperative BCVA in subgroups 1a (p=0.367), 2a (p=0.297), 3a (p=0.576), 4a (p=0.669), 1b (p=0.458), 2b (p=0.227), 3b (p=0.071), or 4b (p=0.703). 3 of 111 (2.70%) candidate eyes and 1 (0.90%) control eye lost 1+ lines of BCVA following surgery. There was no statistical difference in 1+ lines of BCVA lost between these groups (p=0.313). Similarly, the type of CRLS undergone did not affect the rate of BCVA line loss (p=0.793). CONCLUSION: Our evidence suggests that in a matched comparison of flat and normal mathematically predicted postoperative keratometries, there was no increase in BCVA lost due to flat keratometry.

Infertility affects nearly 10% of women globally, and many of these women seek Assisted Reproductive Technology (ART) therapies (Mascarenhas, Flaxman, Boerma, Vanderpoel, & Stevens, 2012). Despite the substantial clinical need for improvements in in vitro fertilization, embryo implantation, pregnancy and live birth rates following embryo transfer remain below 50% (CDC Division of Reproductive Health, 2017). This paper aims to review the driving factors behind IVF failures and the new technologies being utilized to improve IVF outcomes, while also outlining novel experimental approaches to address these challenges. While morphology, morphokinetics, time-lapse imaging, and embryo biopsy have all been studied to assess embryo quality, no method has proven to be uniquely effective in improving the outcomes of IVF treatments. Single-cell whole genome sequencing will be evaluated to determine if this alternative approach can provide better information about early embryonic events that may impede embryo viability in vivo. Conversion of human embryonic stem cells (hESCs) into human extended pluripotent stem cells (hEPS) will also be undertaken. Co-culture of hEPS cells with cells derived from human embryo trophectoderm biopsies will support further investigation of early embryonic events at the cellular level, as well as of culture conditions that could facilitate long-term culture of human embryonic trophectoderm cells. Ultimately, the results of both approaches will be used to improve outcomes for patients seeking successful IVF treatment and pregnancy.

BACKGROUND: Presently, there is very little research on the clinical validity of mental health smartphone application data, its relationship to brain biology, and its ability to inform clinical decisions. This paper seeks to explore these relationships within a sample of schizophrenic patients through the analysis of data collected on the mental health smartphone application Biewe. OBJECTIVES: To validate mental health smartphone applications and support their potential to augment clinical practice. METHODS: The application involved a series of 21 questions from several questionnaires including Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder-7 (GAD-7), Warning Signals Scale (WSS), Pittsburgh Sleep Quality Index, and the psychosis subscale of the Mini Mental State Examination. Data was collected over a period of 3 months, and patients attended a total of 4 clinic visits during this timeframe. Seven study participants also had brain scan data available from the BSNIP, PARDIP and Biceps studies currently in progress at MMHC which has been used for analysis. The structural MPRAGE T1 scans were processed using Free Surfer 6 in which thickness and volume measures were extracted. All statistical analyses on the data were carried out using R statistics software. RESULTS: Clinic and application responses within the same week were not significantly different from each other. The application answers, however, appeared to be more sensitive to structural abnormalities in the brain. Symptoms defined as a lack of normal emotional responses (i.e. negative symptoms of schizophrenia) were negatively correlated to home time and positively correlated to distance travelled, which was a counterintuitive result. CONCLUSIONS: The results show that mobile monitoring has the potential to be a valid and reliable method of data collection and that it may be able to augment clinical decision making.

INTRODUCTION: Post-natal fractures are among some of the most common orthopedic injuries with up to 10% resulting in delayed or non-unions. Understanding the early mechanism of fracture repair via stem cell recruitment will allow for more specific therapeutics to be developed. Two post-natal bone formation models were used for this study, ectopic bone and fracture repair; both show primarily endochondral ossification. To investigate the role of stem cells during post-natal bone formation, two markers were selected, based on previous results, Prx1 and Pax7. The Prx1 gene is expressed by skeletal progenitor cells within the periosteal tissues while the Pax7 gene is expressed by skeletal muscle precursor cells. OBJECTIVES: The purpose of this study is to follow stem cell lineages that arise from Prx1 and Pax7 expressing cells in both ectopic bone growth and fracture repair models. METHODS: Prx1 CreER-GFP mice (Kawanami et al., 2010) and Pax7 CreER (Jackson Laboratories) mice were individually crossed with the RosaAi14 reporter (dTomato) animal. These animals were then crossed with immunodeficient Rag1 mice allowing for implantation of human demineralized bone matrix. Six different control groups were analyzed with multiple mice used for each. These groups included no injury with Tamoxifen followed by three days (short term), seventeen days (intermediate) or 28 days and onward (long term) harvest, oil injections followed by three days (short term) or 30 days (long term) harvest, no injections, and Cre negative. Two methods of post-natal bone formation were studied, ectopic bone growth and fracture repair. For ectopic bone growth, demineralized bone matrix (DBM) was implanted on either the periosteum surface or and within skeletal muscle of the upper hind-limb. Samples were then harvested on day 16 or day 31 post-surgery. For post-natal fracture repair, mice received a transverse stabilized fracture and samples were harvested on day 5 or day 23. All samples were then fixed, decalcified, and standard frozen histology was performed. Images were collected with a fluorescent microscope to detect the presence of dTomato tagged Prx1 and Pax7 derived cells. Ratios of positive cells were calculated using total number of nuclei within the regions of interest. RESULTS: Prx1 control animals that received no Tamoxifen injections showed about 4-16% positively labeled cells. Cre+ control that received Tamoxifen washout showed the highest percentage of cells, 10-20%. Control animals that receive oil pulse and oil washout showed similar results, about 6-20%. Interestingly, the Cre- control group showed a high number of labeled cells, about 6-12%. Prx1 positive cells were seen throughout the bone (16-30%) and callous (43-70%) in the fracture model and throughout the bone (43%) and implant (30-47%) in the ectopic bone development model. Pax7 control animals that received no tamoxifen injections and animals that received tamoxifen long term injections both showed the highest percentage of cells, 2% in the muscle. No response was seen in the bone or marrow for either of the control groups. No Pax7 derived cells were seen in the bone or callous in the fracture model or the bone and implant in the ectopic bone model. CONCLUSIONS: Previous research has shown Prx1 cells to be localized to the periosteum. This study confirmed those results and showed an increase in Prx1 derived cells in the callous in the fracture model. An increase in Prx1 was also seen in the implant in the ectopic bone growth model. However, at a later time point, the number of Prx1 cells decreased in both the inner callous and implant suggesting either the presence of bone remodeling or a different population of stem cells contributing at later in time. With regards to Pax7, previous research has suggested a role in postnatal bone formation. However, this study showed that no Pax7 derived cells were seen in bone or the fracture callous in the fracture model nor in the implant in the ectopic bone growth model. Therefore, it does not appear Pax7 has any role in postnatal bone formation.

Approximately 1 in 10,000 North Americans have an aneurysmal subarachnoid hemorrhage (aSAH) each year. It is a devastating disease with a combined morbidity and mortality greater than 50%. Subarachnoid hemorrhage (SAH) can lead to neuronal injury and can impair cognitive function by increasing pressure on the brain. For these reasons, it is crucial that effective therapies for patients suffering from SAH are found. This thesis will discuss the clinical characteristics of SAH, as well as possible targets for therapeutic intervention. Carbon monoxide (CO) is commonly known as an environmental pollutant and toxic diatomic gas, infamous for its extremely high affinity for hemoglobin. Research has shown that CO possesses many of the same functions of nitric oxide. These functions include vasodilation, inhibition of platelet aggregation, and anti-proliferative effects on smooth muscle. It is also known as an anti-inflammatory agent under specific concentrations and conditions. Heme oxygenase isozymes (HO-1 and HO-2) both generate CO in the brain following ischemic injury. In ischemic stroke, the function of CO is mediated by upregulation of Nuclear factor-erythroid 2-related factor 2 (Nrf2). Nrf2 plays a protective role in a variety of neurological and inflammatory disorders. Experiments have shown that exogenous CO administered to mice with middle cerebral artery occlusions results in smaller infarct sizes in the brain compared to mice without CO treatment. CO treatment was most effective in its protective role after a 1-hour delay in treatment versus a 3-hour delay. Thus, a therapeutic window of time in which CO treatment in ischemic stroke is most effective needs to be elucidated. The same is true for hemorrhagic stroke. The evidence suggests that CO could have a neuroprotective effect following subarachnoid hemorrhage by decreasing cerebral inflammation.

Obesity is a major health problem associated with a plethora of health risks and a high economic cost in the United States. While non-surgical treatment options exist, surgical treatments have been shown to provide better success with weight-loss long term. Despite its success, an early type of weight loss surgery (WLS) called Roux-en-Y Gastric Bypass (RYGB) has been linked to a higher risk of alcohol consumption post-operatively; however, the potential risk between the newer, more commonly performed surgery, sleeve gastrectomy, has yet to be explored. This pilot study conducted at the Bariatric Center at Beth Israel Deaconess Medical Center in Boston, Massachusetts, will provide preliminary data on high-risk alcohol use before and after sleeve gastrectomy (SG). Patients were interviewed regarding eating and drinking behaviors before and after SG using modified versions of the Three Factor Eating Questionnaire Revised-18 and the Alcohol Use Disorder Identification Test-C respectively. In this interim analysis, 37 of 70 eligible subjects underwent the baseline questionnaire (52.9% participation) and out of the 9 participants who had 3-month follow-ups, 8 participants completed their interview (88.9% retention). The overall prevalence of high-risk drinkers at baseline was 27%. Among the 8 participants who completed the 3-month follow-up, 1 reported high-risk drinking baseline and none reported high risk alcohol use at follow-up. In conclusion, although 27% of patients were high-risk drinkers at baseline, none of the patients were high-risk drinkers at the 3-month follow-up. Future studies investigating the change of alcohol use after longer-time periods after weight loss surgery are necessary in order to better assess if there is an increased alcohol use after sleeve gastrectomy.

BACKGROUND: Young women with cancer often worry about impaired fertility after treatment but can experience devastating consequences from an unplanned pregnancy during treatment. Contraception screening and referral appear to occur infrequently in cancer care. OBJECTIVES: We sought to understand oncologic providers’ current practices, perceptions of facilitators and barriers to screening for adequate contraception during cancer treatment, and to understand patient perspectives on these processes. METHODS: We interviewed 19 oncologic providers and 20 female reproductive-aged oncology patients stable on treatment or who had completed therapy within the last 24 months. We recruited participants from an urban, northeast medical center where they worked or received oncologic care. Semi-structured interview questions examined components of the Promoting Action on Research Implementation in Health Services (PARiHS) framework, and subsequent constant comparative analysis identified similar themes. FINDINGS: Providers vary significantly in their current contraception screening practices with many focusing on diagnosing pregnancy rather than prevention. Providers identified many institutional and organizational barriers, including lack of education and lack of clear provider responsibility. Providers also identified resources and supports that would assist with contraception screening and referral, including education and enhanced interdisciplinary collaboration with gynecologic providers. Patients infrequently recalled contraception conversations with oncology providers and expressed challenges determining the most appropriate provider with whom to discuss contraception. CONCLUSION: Cancer centers should address barriers to contraception screening and referral locally in future implementation of contraception screening and referral. National organizations should work to develop guidelines to inform and support this process in clinical practice. / 2019-10-23T00:00:00Z

BACKGROUND: Avoidable readmissions to the hospital present a significant challenge for health systems with an estimated $41.3 billion per year in additional healthcare spending attributed to unnecessary rehospitalization. Existing interventions targeting readmissions shows mixed evidence of effectiveness and context dependent success for certain strategies. This study is a pragmatic evaluation of the effectiveness of a hospital-wide readmission reduction initiative at Boston Medical Center (BMC), a large safety-net hospital, with the goal of advancing a Learning Health System model. METHODS: Adult patients admitted to BMC were risk stratified using a proprietary algorithm into one of four risk groups: Low Risk (LR), Moderate Risk (MR), High Risk (HR) and Super Utilizer (SU). The MR, HR and SU groups were each assigned to receive a different bundle of evidence-informed readmission reduction interventions. We used a quasi-experimental design combining principles of Regression Discontinuity and Difference-in-Difference to estimate the effect that each of the three bundles had on a 30-day readmission outcome. Patient visits from February 2015 to January 2016 were included in the pre-implementation period and visits from November 2016 to October 2017 in the post-implementation period. RESULTS: There were 18,634 patient visits included in the pre-intervention period and 10,714 observations in the post-implementation period. We found no significant effect for any of the three bundles of interventions with adjusted pre-post changes in 30-day readmission of 2.67% (95%CI: -1.27, 6.61) for the MR group, 1.02% (95%CI: -4.65, 6.68) for the HR group and 8.07% (95%CI: -4.33, 18.46) for the SU group. DISCUSSION: The interventions in the BMC readmissions reduction initiative were not successful in reducing readmission rates for any of the targeted risk groups. Further work is needed to identify specific factors in the design and implementation of the interventions that limited their effectiveness. However, the results of this evaluation can be used to guide iterative improvement for future readmission reduction efforts. Additionally, the analytic strategy used in this study provides a model for hospitals to develop Learning Health System capabilities that can be applied to targets beyond hospital readmissions. / 2020-10-23T00:00:00Z