Program Evaluation of a Class Addressing Psychosocial Topics in Preparation for Hematopoietic Cell Transplantation: a Brief Report.

Patients undergoing hematopoietic cell transplantation (HCT) and their caregivers can experience psychosocial complications pre-, during, and post-transplant. To meet the needs of the most patients and caregivers, a class was developed to prepare patients and caregivers to prevent and manage common psychosocial challenges. We evaluated the feasibility and acceptability of the class over a 5-month pilot period. Attendance in this class became part of standard pre-transplant care. Attendees were invited to complete a questionnaire (Likert-scale and open-ended questions) to evaluate the feasibility and acceptability of this class. Data were collected over a 5-month period. Descriptive analysis was completed. Patients (n = 41) and caregivers (n = 40) were satisfied to very satisfied with the class. Patients (80%) and caregivers (65%) reported that the class met their expectations, with several describing it as worthwhile and informative. Information relating to finances and benefits were considered most helpful, followed by emotional support resources. Patients (73%) and caregivers (93%) reported that they would recommend the class to others. This education class should be provided as early as possible to ensure that psychosocial needs are addressed. Future research initiatives include further assessing the perspectives of patients, clinicians, and other stakeholders; evaluating delivery methods; and collaborating with other centers.

Psychological distress and resilience in first responders and health care workers during the COVID-19 pandemic.

During the COVID-19 pandemic, first responders and health care workers faced elevated virus-related risks through prolonged contacts with the public. Research suggests that these workers already experienced lower levels of psychological well-being linked to occupational risks. Thus, the pandemic's impact might have particularly affected mental health in these groups. This paper analysed data from a large-scale Welsh population study (N = 12,989) from June to July 2020. Levels of psychological distress were compared across various occupations, including police, fire and rescue, and NHS health care workers. Resilience was also indexed, and its role considered as a protective factor for psychological distress. Surprisingly, health care workers reported lower distress levels than the general population. Further, fire and rescue and police groups had lower distress than most groups and significantly higher resilience. Within police officers, higher resilience levels were protective for distress. Fire and rescue workers were half as likely as others to report distress, even accounting for demographic factors and resilience. The findings offer an optimistic view of psychological resilience in these critical occupations. They illustrate potential benefits to one's mental health of playing a crucial societal role during crises and reiterate the importance of enhancing resilience within groups who encounter high-risk situations daily. Practitioner points: Our findings provide evidence that health care workers and first responders showed lower levels of psychological distress than the general population during the first period of lockdown due to the COVID-19 pandemic in the United Kingdom. This may indicate that playing a critical role in society during an episode of crisis, and acting to help others, may be protective of one's own mental health.The research also provides an optimistic view of the psychological resilience of critical first responders and health care workers during a period early on in the COVID-19 pandemic (June-July 2020). This highlights the benefits of fostering resilience in those working within high-risk first responder and health care occupations.

Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4.

We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.

Assessing and Preparing Patients for Hematopoietic Stem Cell Transplant in Canada: An Environmental Scan of Psychosocial Care.

Recipients and caregivers of Hematopoietic Stem Cell Transplant (HCT) have extensive physical and psychosocial needs. HCT programs recognize the need to support psychosocial wellbeing. However, evidence-based guidance for pre-HCT psychosocial services is sparse. We conducted a qualitative environmental scan of programs across Canada to better understand how programs evaluate and support patients and caregivers prior to HCT. METHODS: HCT programs across Canada were contacted with a list of questions about their psychosocial assessment and preparation process with patients and caregivers. They could respond via email or participate in an interview over the phone. Descriptive qualitative content analysis was conducted, using steps outlined by Vaismoradi and colleagues (2013). RESULTS: Most participants were social workers from hospitals (64%). Four qualitative themes arose: (a) Psychosocial Team Composition. Psychosocial assessment for HCT patients was often provided by social workers, with limited availability of psychologists and psychiatrists. (b) Criteria for assessing select HCT patients. Participants prioritized psychosocial assessments for patients with higher perceived psychosocial needs or risk, and/or according to transplant type. Limited time and high psychosocial staff demands also played into decision-making. (c) Components and Practices of Pre-HCT Psychosocial Assessment. Common components and differences of assessments were identified, as well as a lack of standardized tools. (d) Patient Education Sessions. Many sites provided adjunct patient education sessions, of varying depth. CONCLUSION: Significant variation exists in the way programs across the country assess their patients' psychosocial pre-transplant needs and assist in preparing patients for the psychosocial aspects of HCT. This environmental scan identified several strategies used in diverse ways. Further in-depth research on program outcomes across Canada could help to identify which strategies are the most successful.

The Role of Hope and Resilience in Protecting Against Suicidal thoughts and Behaviors During the COVID-19 Pandemic.

OBJECTIVE: The COVID-19 pandemic has impacted the mental health and wellbeing of populations across the world. This study aimed to examine: (1) which specific aspects of the COVID-19 pandemic were associated with the presence of suicidal thoughts and behaviors, and (2) the extent to which participants' hopelessness and resilience moderated the relationship between COVID-19 related stress and suicidal thoughts and behaviors. METHOD: We administered an online survey to 12,989 adult (16+) participants across Wales from the 9th June to the 13th July 2020. Participants completed a series of questionnaires measuring the stressors they had experienced during the COVID-19 pandemic, their levels of hopelessness over the past two weeks, their levels of resilience, and whether they had experienced suicidal thoughts or behaviors since the onset of the COVID-19 pandemic. RESULTS: Our findings revealed that: (1) food insecurity, domestic abuse, relationship problems, redundancy, social isolation and financial problems were the COVID-19 related stressors most strongly associated with suicidal thoughts and behaviors, and (2) that both hopelessness and resilience moderated the relationship between COVID-19 stress and suicidal thoughts, such that the relationship between COVID-19 stress and the presence of suicidal thoughts was much stronger for individuals with high hopelessness and low resilience. CONCLUSIONS: These results highlight the aspects of the COVID-19 pandemic that are closely related to suicidal thoughts and behaviors and demonstrate the important role that hope for the future and resilience play in protecting individuals against the negative effects of the COVID-19 pandemic.HighlightsStressors caused by the pandemic are linked to increased suicidal thoughts.Hope protects individuals against the negative impact of the COVID-19 pandemic.Resilience also protects people from the negative impact of the COVID-19 pandemic.

The Influence of the COVID-19 Pandemic on Mental Well-Being and Psychological Distress: Impact Upon a Single Country.

The COVID-19 pandemic is likely to have affected the psychological well-being and mental health of many people. Data on prevalence rates of mental health problems are needed for mental health service planning. Psychological well-being and prevalence of clinically significant mental distress were measured in a large sample from Wales 11-16 weeks into lockdown and compared to population-based data collected in 2019 before the COVID-19 pandemic. Data were collected using an online survey disseminated across Wales and open to adults (age 16+) from 9th June to 13th July 2020. Psychological well-being was indexed via the Warwick-Edinburgh Mental Well-being Scale, and psychological distress was indexed via the K10. Data from 12,989 people who took part in this study were compared to that from April 2018 - March 2019, gathered by the National Survey for Wales (N = 11,922). Well-being showed a large decrease from 2019 levels. Clinically significant psychological distress was found in around 50% of the population (men = 47.4%, women = 58.6%), with around 20% showing "severe" effects (men = 17.0%, women = 20.9%): a 3-4-fold increase in prevalence. Most affected were young people, women, and those in deprived areas. By June-July 2020 the COVID-19 pandemic had dramatic effects on the mental health of people living in Wales (and by implication those in the UK and beyond). The effects are larger than previous reports. This probably reflects that the current data were taken deeper into the lockdown period than previous evaluations. Mental health services need to prepare for this wave of mental health problems with an emphasis on younger adults, women, and in areas of greater deprivation.

The effect on medication errors of pharmacists charting medication in an emergency department.

OBJECTIVE: To determine the frequency and clinical significance of medication errors when (a) pharmacists elicit medication histories in the Emergency Department after medications have been prescribed by doctors and (b) pharmacists obtain and chart medication histories prior to doctors' approval. SETTING: The Queen Elizabeth Hospital, a 350 bed South Australian teaching hospital, serving the local adult community. METHOD: Emergency Department patients at risk of medication misadventure were recruited in two phases with a 'usual practice' arm (6 weeks) and a 'pharmacist medication charting' arm (5 weeks) reflecting an alternative intervention. In the 'usual care' arm, medication histories were compiled by a pharmacy researcher after a doctor had completed the medication chart. The researcher-elicited medication histories were compared with the doctors' medication charts and unintentional discrepancies were recorded. In the 'pharmacist medication charting' arm, the same process was followed except the researcher compiled the patients' medication histories at triage, prior to patients seeing a doctor. The medication history was then transcribed onto a medication chart for authorisation by a doctor. In addition, whether resolution of unintentional discrepancies for patients in the 'usual care' arm had occurred by discharge was determined by examining patients' medical records. Main outcome measure Frequency of unintentional discrepancies and medication errors. RESULTS: The study included 45 and 29 patients in the 'usual care' and intervention arms, respectively. In the 'usual care' arm, 75.6% of patients had one or more unintentional discrepancies compared with 3.3% in the 'pharmacist medication charting' arm. This resulted in an average of 2.35 missed doses per patient in the 'usual care' arm and 0.24 in the intervention arm. In addition, an average of 1.04 incorrect doses per patient were administered in the 'usual care' arm and none in the 'pharmacist medication charting' arm. The differences observed between the arms were statistically significant (P < 0.05) and deemed clinically significant by a multidisciplinary panel. CONCLUSION: This study provides evidence for pharmacists eliciting medication histories to prepare medication charts at the earliest possible opportunity following a patient's presentation to the Emergency Department.

Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265P Mutant Diffuse Large B Cell Lymphoma.

In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.

Tricyclic Indazoles-A Novel Class of Selective Estrogen Receptor Degrader Antagonists.

Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.

Benefits of positive relationship experiences for avoidantly attached individuals.

Attachment avoidance is characterized by discomfort with closeness and a reluctance to develop intimacy with romantic partners, which contribute to heightened general negativity and lower satisfaction and self-disclosure in and out of their relationships. Recent research, however, has begun to uncover circumstances in which romantic partners and positive relationships buffer more avoidantly attached individuals against deleterious individual and relationship outcomes. Across 3 studies, using a multimethod approach encompassing both experimental and dyadic longitudinal diary methods, we investigated the effects of positive, intimacy-related relationship experiences on more avoidant persons' positive and negative affect, relationship quality, self-disclosure, and attachment security immediately and over time. Results revealed that more avoidant individuals exhibit a reduction of general negative affect in particular (Studies 1-2) and report greater relationship quality (Studies 2-3) in response to positive relationship experiences, and, following intimacy-promoting activities with their partner, engage in greater self-disclosure over time and demonstrate decreased attachment avoidance 1 month later (Study 3). These findings identify novel circumstances in which more avoidant persons' negative expectations of relationships may be countered, and suggest that relatively simple techniques can have potentially important short- and long-term implications for more avoidant individuals and their relationships. (PsycINFO Database Record

Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma.

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.

Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat.

A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.

Registered Replication Report: Study 1 From Finkel, Rusbult, Kumashiro, & Hannon (2002).

Finkel, Rusbult, Kumashiro, and Hannon (2002, Study 1) demonstrated a causal link between subjective commitment to a relationship and how people responded to hypothetical betrayals of that relationship. Participants primed to think about their commitment to their partner (high commitment) reacted to the betrayals with reduced exit and neglect responses relative to those primed to think about their independence from their partner (low commitment). The priming manipulation did not affect constructive voice and loyalty responses. Although other studies have demonstrated a correlation between subjective commitment and responses to betrayal, this study provides the only experimental evidence that inducing changes to subjective commitment can causally affect forgiveness responses. This Registered Replication Report (RRR) meta-analytically combines the results of 16 new direct replications of the original study, all of which followed a standardized, vetted, and preregistered protocol. The results showed little effect of the priming manipulation on the forgiveness outcome measures, but it also did not observe an effect of priming on subjective commitment, so the manipulation did not work as it had in the original study. We discuss possible explanations for the discrepancy between the findings from this RRR and the original study.

Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators.

A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.

Synthesis of functionalized cyanopyrazoles via magnesium bases.

4-Alkyl- and 4-H-pyrazoles were sequentially metalated using TMPMgCl·LiCl, and their reaction with electrophiles afforded 3-aryl-4-alkyl-5-cyanopyrazoles.

Sustainability of a pharmacist-driven pathway for osteoporosis-related fractures on an orthopaedic unit after a 5-year period.

OBJECTIVES: Diagnosis and management of osteoporosis in hospitals are poor. Effective medications for reducing fracture risk are often underutilised in hospital settings. Studies have shown that improvements in secondary prevention of osteoporosis can occur with the implementation of clinical pathways and are effective in improving the prescription for osteoporosis medications. We aimed to assess the long-term sustainability of the benefit of the osteoporosis pathway implemented at The Queen Elizabeth Hospital, Adelaide, Australia, in 2003. METHODS: An audit was performed to review the rate of prescription for osteoporosis therapy 5 years after the implementation of a pharmacist-driven osteoporosis pathway in patients presented with a minimal trauma fracture and admitted to the Department of Orthopaedics at The Queen Elizabeth Hospital. KEY FINDINGS: Our review of a 5-year period shows that the rate of prescription for osteoporosis therapy in this patient group is 95%. CONCLUSIONS: The pharmacist-driven osteoporosis pathway at The Queen Elizabeth Hospital has sustained the rate of prescription for osteoporosis therapy over a prolonged period of time.

Diverse heterocyclic scaffolds as allosteric inhibitors of AKT.

Wide-ranging exploration of potential replacements for a quinoline-based inhibitor of activation of AKT kinase led to number of alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, and one such compound demonstrated pharmacodynamic knockdown of phosphorylation of AKT and downstream biomarkers in vivo and inhibition of tumor growth in a breast cancer xenograft model.

Protein-ligand crystal structures can guide the design of selective inhibitors of the FGFR tyrosine kinase.

The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.

Conformational preference in aromatic amides bearing chiral ortho substituents: its origin and application to relayed stereocontrol.

Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.