A Qualitative Exploration of Oncology Clinician's Needs for PGT-M Discussions in Clinical Practice.

Purpose: Oncology clinicians are appropriately positioned to facilitate discussions of assisted reproductive technologies including preimplantation genetic testing for monogenic disease (PGT-M), in the context of cancer treatment or surveillance. Yet, reproductive services, including PGT-M, remain one of the least implemented services in oncology. No studies to date have explored which practice resources the clinicians need to increase knowledge of PGT-M. The objective of this study was to explore the specific needs of oncology clinicians to help maximize the reproductive potential of young adult patients with hereditary cancers. Methods: Participants were recruited through notices circulated on social media platforms and snowball sampling. Participants completed a brief online survey to confirm eligibility. Eligible participants completed a virtual, semi-structured interview. Interviews focused on clinician experiences with PGT-M and initiating referrals to fertility specialists. Thematic analysis was conducted using a constant comparative approach to identify current clinical practices. Results: This study found that PGT-M discussions are not necessarily within the scope of responsibilities for oncology clinicians owing to prioritization of cancer treatment and overall lack of knowledge. Participants need accessible resources and timely support for reproductive planning in the context of cancer treatment. Participants desire a streamlined referral pathway to professionals trained in oncofertility to help address their patient's reproductive needs. Conclusion: Our study identified that educational and referral resources to reproductive specialists are needed to maximize reproductive potential across the cancer continuum. These findings provide a foundation for larger studies that can inform standard-of-care recommendations in the emerging field of oncofertility.

CDK activity at the centrosome regulates the cell cycle.

In human cells and yeast, an intact "hydrophobic patch" substrate docking site is needed for mitotic cyclin centrosomal localization. A hydrophobic patch mutant (HPM) of the fission yeast mitotic cyclin Cdc13 cannot enter mitosis, but whether this is due to defective centrosomal localization or defective cyclin-substrate docking more widely is unknown. Here, we show that artificially restoring Cdc13-HPM centrosomal localization promotes mitotic entry and increases CDK (cyclin-dependent kinase) substrate phosphorylation at the centrosome and in the cytoplasm. We also show that the S-phase B-cyclin hydrophobic patch is required for centrosomal localization but not for S phase. We propose that the hydrophobic patch is essential for mitosis due to its requirement for the local concentration of cyclin-CDK with CDK substrates and regulators at the centrosome. Our findings emphasize the central importance of the centrosome as a hub coordinating cell-cycle control and explain why the cyclin hydrophobic patch is essential for mitosis.

RNA polymerase II dynamics and mRNA stability feedback scale mRNA amounts with cell size.

A fundamental feature of cellular growth is that total protein and RNA amounts increase with cell size to keep concentrations approximately constant. A key component of this is that global transcription rates increase in larger cells. Here, we identify RNA polymerase II (RNAPII) as the limiting factor scaling mRNA transcription with cell size in budding yeast, as transcription is highly sensitive to the dosage of RNAPII but not to other components of the transcriptional machinery. Our experiments support a dynamic equilibrium model where global RNAPII transcription at a given size is set by the mass action recruitment kinetics of unengaged nucleoplasmic RNAPII to the genome. However, this only drives a sub-linear increase in transcription with size, which is then partially compensated for by a decrease in mRNA decay rates as cells enlarge. Thus, limiting RNAPII and feedback on mRNA stability work in concert to scale mRNA amounts with cell size.

Results of a Pilot Study for a Pharmacy Discharge Review in Neurosurgical Patients: A Quality-Safety Initiative.

Objective A multidisciplinary collaboration between the neurosurgical team and the pharmacy was established to conduct a pilot study in which discharged neurosurgical patients from a community hospital would receive medication reconciliation services and counseling by a pharmacy specialist to determine the impact on patient safety, readmission rates, and medication compliance. Methods Pharmacists reviewed discharge medication reconciliations of neurosurgical patients to address any discrepancies with the nurse practitioners or physicians prior to discharge and provided discharge medication counseling to the patient/families at the bedside. The service was provided on weekdays during the eight-hour pharmacist shift in addition to other daily responsibilities. Data were analyzed by type and the total number of pharmacy interventions encountered during the discharge medication reconciliation process, time to complete services, and readmission rates. Lastly, the discharged neurosurgical patients that were not seen by pharmacists during the one-month pilot study were reviewed retrospectively to determine potential interventions. Results A total of 48 neurosurgical patients were discharged during the one-month pilot study; 27 patients received discharge medication reconciliation services and counseling from the pharmacy specialists. Sixty-three pharmacy interventions were accepted with prevention of medication errors/adverse drug reactions (21%, n=21) and addition of missing medication (21%, n=21) being the most common intervention types. The mean time to complete the services was 27 minutes and there was one non-medication-related readmission of the 27 patients seen. Twenty-one neurosurgical patients who were discharged without receiving services were reviewed retrospectively. It was determined that there was a potential for another 64 pharmacy interventions in which clarification of indication (33%, n=21) was the most common intervention type, followed by prevention of medication errors/adverse drug reactions (25%, n=16) and addition of missing medication (22%, n=14). There was a total of one medication-related readmission of the 21 patients not seen by the pharmacist during the pilot study. Conclusion The collaboration of pharmacists in the discharge process benefits neurosurgical patients by reducing the number of discrepancies when transitioning home and provides an additional layer of safety to reduce medication errors and/or prevent adverse events.

Core control principles of the eukaryotic cell cycle.

Cyclin-dependent kinases (CDKs) lie at the heart of eukaryotic cell cycle control, with different cyclin-CDK complexes initiating DNA replication (S-CDKs) and mitosis (M-CDKs)1,2. However, the principles on which cyclin-CDK complexes organize the temporal order of cell cycle events are contentious3. One model proposes that S-CDKs and M-CDKs are functionally specialized, with substantially different substrate specificities to execute different cell cycle events4-6. A second model proposes that S-CDKs and M-CDKs are redundant with each other, with both acting as sources of overall CDK activity7,8. In this model, increasing CDK activity, rather than CDK substrate specificity, orders cell cycle events9,10. Here we reconcile these two views of core cell cycle control. Using phosphoproteomic assays of in vivo CDK activity in fission yeast, we find that S-CDK and M-CDK substrate specificities are remarkably similar, showing that S-CDKs and M-CDKs are not completely specialized for S phase and mitosis alone. Normally, S-CDK cannot drive mitosis but can do so when protein phosphatase 1 is removed from the centrosome. Thus, increasing S-CDK activity in vivo is sufficient to overcome substrate specificity differences between S-CDK and M-CDK, and allows S-CDK to carry out M-CDK function. Therefore, we unite the two opposing views of cell cycle control, showing that the core cell cycle engine is largely based on a quantitative increase in CDK activity through the cell cycle, combined with minor and surmountable qualitative differences in catalytic specialization of S-CDKs and M-CDKs.

Analytical Validation of a Deep Neural Network Algorithm for the Detection of Ovarian Cancer.

PURPOSE: Early detection of ovarian cancer, the deadliest gynecologic cancer, is crucial for reducing mortality. Current noninvasive risk assessment measures include protein biomarkers in combination with other clinical factors, which vary in their accuracy. Machine learning can be applied to optimizing the combination of these features, leading to more accurate assessment of malignancy. However, the low prevalence of the disease can make rigorous validation of these tests challenging and can result in unbalanced performance. METHODS: MIA3G is a deep feedforward neural network for ovarian cancer risk assessment, using seven protein biomarkers along with age and menopausal status as input features. The algorithm was developed on a heterogenous data set of 1,067 serum specimens from women with adnexal masses (prevalence = 31.8%). It was subsequently validated on a cohort almost twice that size (N = 2,000). RESULTS: In the analytical validation data set (prevalence = 4.9%), MIA3G demonstrated a sensitivity of 89.8% and a specificity of 84.02%. The positive predictive value was 22.45%, and the negative predictive value was 99.38%. When stratified by cancer type and stage, MIA3G achieved sensitivities of 94.94% for epithelial ovarian cancer, 76.92% for early-stage cancer, and 98.04% for late-stage cancer. CONCLUSION: The balanced performance of MIA3G leads to a high sensitivity and high specificity, a combination that may be clinically useful for providers in evaluating the appropriate management strategy for their patients. Limitations of this work include the largely retrospective nature of the data set and the unequal, albeit random, assignment of histologic subtypes between the training and validation data sets. Future directions may include the addition of new biomarkers or other modalities to strengthen the performance of the algorithm.

Risk of contracting SARS-CoV-2 (COVID-19) from hospital admission and the impact of protection efforts on acute stroke treatment.

BACKGROUND: It is unclear how interventions designed to restrict community and in-hospital exposure to the SARS-CoV-2 (COVID-19) virus influenced stroke care for patients seeking acute treatment. Therefore, we aimed to determine how these COVID-19 interventions impacted acute stroke treatment times and to assess the risk of contracting COVID-19 due to their stay in our medical center. METHODS: Retrospective, single center, two-phase study evaluating hospital and community trends from 12/2019 - 04/2020 compared to the previous year and pre/post (n = 156/93) intervention implementation. Phase I assessed stroke treatment times, delay to hospital arrival, and witnessed stroke volume. Phase II, a post-implementation telephone survey, assessed risk of developing symptoms or testing positive for COVID-19. RESULTS: Stroke volume declined by 29% (p < .05) from April to March compared to the previous year. However, no significant delays in seeking medical care (pre Mdn=112, post Mdn=95, p = .34) was observed. Witnessed stroke volume decreased 11% (p < .001) compared to the pre-implementation group, but no significant delay in IV alteplase (pre Mdn=22 mins; post Mdn=26 mins, p = .08) nor endovascular treatment (pre Mdn=60 mins; post Mdn=80 mins, p = .45) was observed. In Phase II, 63 patients participated, two tested (3%) COVID-19 positive during admission and four (6%) within two weeks of discharge. COVID-19 contraction risk during and after hospitalization remained similar to the general population (RR=1.75, 95%CI: 0.79-3.63). Overall results indicated a marked decrease in stroke volume, no significant delays to either seek or provide acute stroke care were evident, and COVID-19 contraction risk was low. CONCLUSIONS: Seeking acute stroke medical care outweighs the risk of COVID-19 exposure.

Opicapone: A third generation COMT inhibitor.

Objective: To provide a drug review of the newly FDA approved catechol-O-methyl transferase (COMT) inhibitor, opicapone, for the use of end-of-motor motor fluctuation in adults with Parkinson's disease. Data sources: A literature search of Pubmed was performed till May 2020 using the following key terms: opicapone, Ongentys, and BIA 9-1067. Review articles, clinical trials, and drug monographs were reviewed. Study selection and data extraction: Relevant English-language monographs and studies conducted in humans were considered. Data synthesis: Opicapone was FDA approved for the treatment of end-of-motor motor fluctuation in adults with Parkinson's disease in April 2020 based on two published randomized clinical trials that were 14 to 15 weeks in duration called BIPARK I and BIPARK II. Based on the clinical trials, 50 mg of opicapone once daily was shown to be noninferior to entacapone and reduced the mean off time by about 50 min when compared to placebo. Most common treatment-emergent adverse events were dyskinesia, falls, insomnia, and elevated blood creatine phosphokinase levels. Relevance to patient care and clinical practice: Opicapone overcomes the limitations associated with other COMT inhibitors since it is dosed once daily, well tolerated, and has not been associated with the risk of hepatic failure. When switching from entacapone to opicapone a reduction in "off" time of -39.3 min was also seen. Conclusions: Opicapone is a once daily 3rd generation COMT inhibitor that has the potential to benefit patients with Parkinson's disease who are experiencing end-of-motor fluctuations.

Lumateperone: A Novel Antipsychotic for Schizophrenia.

OBJECTIVE: To provide a concise review of the new Food and Drug Administration (FDA)-approved antipsychotic, lumateperone, for use in schizophrenia. DATA SOURCES: A literature search of PubMed was performed (January 2000 to May 2020) using the following key terms: lumateperone, Caplyta, and ITI-007. Abstracts from conferences, review articles, clinical trials, and drug monographs were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language monographs and studies conducted in humans were considered. DATA SYNTHESIS: Lumateperone was FDA approved for the treatment of schizophrenia in December 2019 based on 2 published randomized, double-blind, placebo-controlled trials. Lumateperone's pharmacology is consistent with that of other second-generation antipsychotics in that it has a higher affinity for the serotonin (5-HT2A) receptors compared with dopamine (D2) receptors but with lower affinities for α-1 and histaminergic receptors. In addition, it serves as a presynaptic dopamine partial agonist, serotonin reuptake inhibitor, and an indirect modulator of glutamatergic systems. Based on the 4-week clinical trials, lumateperone was well tolerated. Most common treatment-emergent adverse events were headache, somnolence, and dizziness. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: At this time, lumateperone had a statistically significant reduction in Positive and Negative Syndrome Scale when compared with placebo and was not significantly associated with the extrapyramidal symptoms (EPS) and metabolic adverse effects commonly seen with other antipsychotics. CONCLUSIONS: Lumateperone has the potential to benefit individuals with schizophrenia who are intolerant to the EPSs or metabolic adverse effects of other antipsychotics. However, further head-to-head trials with commercially available antipsychotics are still required to assist in establishing its role in treatment.

Fission yeast telosomes: non-canonical histone-containing chromatin structures dependent on shelterin and RNA.

Despite the prime importance of telomeres in chromosome stability, significant mysteries surround the architecture of telomeric chromatin. Through micrococcal nuclease mapping, we show that fission yeast chromosome ends are assembled into distinct protected structures ('telosomes') encompassing the telomeric DNA repeats and over half a kilobase of subtelomeric DNA. Telosome formation depends on the conserved telomeric proteins Taz1 and Rap1, and surprisingly, RNA. Although yeast telomeres have long been thought to be free of histones, we show that this is not the case; telomere repeats contain histones. While telomeric histone H3 bears the heterochromatic lys9-methyl mark, we show that this mark is dispensable for telosome formation. Therefore, telomeric chromatin is organized at an architectural level, in which telomere-binding proteins and RNAs impose a unique nucleosome arrangement, and a second level, in which histone modifications are superimposed upon the higher order architecture.

Genome-wide screen for cell growth regulators in fission yeast.

Cellular growth control is important for all living organisms, but experimental investigation into this problem is difficult because of the complex range of growth regulatory mechanisms. Here, we have used the fission yeast Schizosaccharomyces pombe to identify potential master regulators of growth. At the restrictive temperature, the S. pombe pat1ts mei4Δ strain enters the meiotic developmental program, but arrests in meiotic G2 phase as mei4+ is essential for meiotic progression. These cells do not grow, even in an abundance of nutrients. To identify regulators of growth that can reverse this growth arrest, we introduced an ORFeome plasmid library into the pat1tsmei4Δ strain. Overexpression of eight genes promoted cell growth; two of these were core RNA polymerase subunits, and one was sck2+ , an S6 kinase thought to contribute to TORC1 signalling. Sck2 had the greatest effect on cell growth, and we also show that it significantly increases the cellular transcription rate. These findings indicate, for the first time, that global transcriptional control mediated through S6 kinase signalling is central to cellular growth control.

Perampanel (Fycompa): A Review of Clinical Efficacy and Safety in Epilepsy.

Perampanel (Fycompa): a review of clinical efficacy and safety in epilepsy.

Factors related to HPV vaccine uptake and 3-dose completion among women in a low vaccination region of the USA: an observational study.

BACKGROUND: To assess the demographic and attitudinal factors associated with HPV vaccine initiation and completion among 18-26 year old women in Utah. METHOD: Between January 2013 and December 2013, we surveyed 325 women from the University of Utah Community Clinics about their HPV vaccine related beliefs and behaviors. Odds ratios (ORs) were estimated from logistic regression models to identify variables related to HPV vaccine initiation and series completion. RESULTS: Of the 325 participants, 204 (62.8 %) had initiated the vaccine and 159 (48.9 %) had completed the 3-dose series. The variables associated with HPV vaccine initiation were lower age (OR = 1.18 per year); being unmarried (OR = 3.62); not practicing organized religion (OR = 2.40); knowing how HPV spreads (OR = 6.29); knowing the connection between HPV and cervical cancer (OR = 3.90); a belief in the importance of preventive vaccination (OR = 2.45 per scale unit); strength of doctor recommendation (OR = 1.86 per scale unit); and whether a doctor's recommendation was influential (OR = 1.70 per scale unit). These variables were also significantly associated with HPV vaccine completion. CONCLUSION: The implications of these findings may help inform policies and interventions focused on increasing HPV vaccination rates among young women. For example, without this information, programs might focus on HPV awareness; however, the results of this study illustrate that awareness is already high (near saturation) in target populations and other factors, such as strong and consistent physician recommendations, are more pivotal in increasing likelihood of vaccination. Additionally, our findings indicate the need for discussions of risk assessment be tailored to the young adult population.

Predictors Associated With Changes of Weight and Total Cholesterol Among Two Occupational Cohorts Over 10 Years.

OBJECTIVE: To ascertain worker health characteristics and psychosocial factors associated with changes in body weight and total cholesterol (TC) among two production operation populations. METHODS: We performed descriptive and predictive analysis of questionnaire data and biomedical measurements from two prospective cohort studies. Our key outcomes were changes in weight, and TC over 5 to 10 years between baseline and exit assessments. RESULTS: A total of 146 subjects were analyzed. Increases in weight were associated with belief in being overweight and baseline overweight and obesity. Increases in TC levels were associated with female sex, belief that TC levels were "not good," and feeling depressed. CONCLUSIONS: Most of the reported associations with increases in weight and TC levels are amenable to interventions and may be a target for workplace intervention programs.

Stages of weight change among an occupational cohort.

OBJECTIVE: To assess the readiness to change dietary intake and body weight among production workers. We also ascertained differences between self-perceived and measured body mass index. METHODS: This cross-sectional study queried physical activity, psychosocial factors, fruit and vegetable intake, and readiness to change based on the transtheoretical model. RESULTS: Sixty-three (28%) workers were overweight, and 114 (50%) were obese. Obese workers were in the following stages of weight change: precontemplation (4%), contemplation (45%), preparation (13%), action (21%), and (17%) maintenance. Ten percent of overweight workers erroneously reported their body mass index to be normal. CONCLUSIONS: About half of overweight/obese workers were in the precontemplation or contemplation stages for healthy dietary changes or weight loss. Recognizing the stages of change with regard to weight and the self-perception of weight status may help tailor workplace health promotion programs.

Two industrial cohorts: baseline characteristics and factors associated with obesity.

OBJECTIVE: To describe demographic and health characteristics, and factors associated with obesity among production workers. METHODS: This cross-sectional study analyzed baseline data from two occupational cohorts. Regression modeling was used to assess associations between worker characteristics and obesity. RESULTS: A total of 1974 subjects were included in these analyses. The mean body mass index was 29.5 kg/m (SD = 6.5). Having smoked in the past and currently smoking decreased the odds of being obese in the WISTAH Distal Upper Extremity cohort, whereas those feeling depressed had increased odds of being obese. Being a Pacific Islander/Native Hawaiian and married increased the odds of obesity in the BackWorks Low Back Pain cohort. CONCLUSIONS: Factors associated with obesity differed substantially between the two cohorts. Recognizing factors associated with obesity in specific work settings may provide opportunities for optimizing preventive workplace interventions.

The relationship between body esteem, exercise motivations, depression, and social support among female free clinic patients.

PURPOSE: Obesity is a significant public health problem in women's health. This study examined relationship between body esteem, exercise motivations, depression, and social support among female free clinic patients. Low-income women who are at risk for obesity and other health concerns would benefit from health education efforts. METHODS: We compared 299 female and 164 male free clinic patients 18 years or older using assessments for body esteem, motivation to exercise, depression, and social support. RESULTS: Although female participants reported lower levels of body esteem and higher levels of depression compared with male participants (p < .01), female participants were more motivated to exercise for weight-related reasons than male participants (p < .05). U.S.-born female participants reported lower exercise motivations compared with non-U.S.-born female participants (p < .01). Social support might be an important factor to increase exercise motivation among female free clinic patients (p < .05); depression lowers levels of body esteem (p < .01). CONCLUSIONS: The results of this study suggest that female free clinic patients should receive gender-specific interventions to promote positive body image and physical activity. It is important for health educators to engage a myriad of physical activity motives to increase the likelihood that clients will experience enjoyment and sustained adoption of exercise into their lifestyle. Future practice and research should warrant the implementation of body image and physical activity programs and the potential impact of using exercise to reducing depression among female patients at free clinics.

The relationship between diabetes attitudes and treatment among free clinic patients and volunteers.

Free clinics provide free primary care to the under or uninsured and have been playing an important role in serving the socio-economically disadvantaged. Free clinic patients represent a group of people who experience significant barriers to receiving diabetes prevention and intervention. This study examined diabetes attitudes among free clinic patients and volunteers. English or Spanish speaking patients and volunteers (N = 384), aged 18 years or older completed a self-administered survey. Diabetic patients and volunteers shared similar levels of diabetes attitudes compared to non-diabetic patients. Among patients, ethnicity, education level, diabetes education, and family history affected diabetes attitudes. Among volunteers, diabetes education was an important factor associated with positive diabetes attitudes. Whether the volunteer is a healthcare professional or student was related only to one aspect of diabetes attitudes, seriousness of type 2 diabetes. The results, indicating free clinic diabetic patients and volunteers shared similar levels of diabetes attitudes, were positive for maintaining and developing diabetes education programs at a free clinic. Unfortunately, the average length of volunteering at this free clinic was short and student volunteers likely leave the clinic upon graduation. Future research should examine issues of volunteer retention in free clinics. Diabetes education for patients may need to be diversified according to ethnicity, family history of diabetes, and educational level. Finally, non-healthcare professional volunteers could potentially be involved in diabetes education at a free clinic.

Health and diabetes self-efficacy: a study of diabetic and non-diabetic free clinic patients and family members.

Free clinics across the country provide free or reduced fee healthcare to individuals who lack access to primary care and are socio-economically disadvantaged. This study examined perceived health status among diabetic and non-diabetic free clinic patients and family members of the patients. Diabetes self-efficacy among diabetic free clinic patients was also investigated with the goal of developing appropriate diabetes health education programs to promote diabetes self-management. English or Spanish speaking patients and family members (N = 365) aged 18 years or older completed a self-administered survey. Physical and mental health and diabetes self-efficacy were measured using standardized instruments. Diabetic free clinic patients reported poorer physical and mental health and higher levels of dysfunction compared to non-diabetic free clinic patients and family members. Having a family history of diabetes and using emergency room or urgent care services were significant factors that affected health and dysfunction among diabetic and non-diabetes free clinic patients and family members. Diabetic free clinic patients need to receive services not only for diabetes, but also for overall health and dysfunction issues. Diabetes educational programs for free clinic patients should include a component to increase diabetes empowerment as well as the knowledge of treatment and management of diabetes. Non-diabetic patients and family members who have a family history of diabetes should also participate in diabetes education. Family members of free clinic patients need help to support a diabetic family member or with diabetes prevention.

Surveillance of human papilloma virus using reference laboratory data for the purpose of evaluating vaccine impact.

Nationwide positivity rates of high-risk human papillomavirus for the United States before and since the introduction of a Human Papillomavirus (HPV) vaccine in 2006 would provide insight into the population impact of HPV vaccination. Data for high-risk HPV testing results from January 1, 2004 to June 1, 2013 at a national reference laboratory were retrospectively analyzed to produce 757,761 patient records of women between the ages of 14 and 59. Generalized linear models and finite mixture models were utilized to eliminate sources of bias and establish a population undergoing standard gynecological screening. Unadjusted positivity rates for high-risk HPV were 27.2% for all age groups combined. Highest rates occurred in women aged 14 to 19. While the positivity rates decreased for all age groups from 2004 to 2013, the higher age categories showed less downward trend following vaccine introduction, and the two age categories 20 to 24 and 25 to 29 showed a significantly different downward trend between pre- and post-vaccine time periods (-0.1% per year to -1.5% per year, and 0.4% per year to -1.5% per year, respectively). All other age groups had rates of change that became less negative, indicating a slower rate of decline.