Optimizing pharmacogenomic decision-making by data science.

Healthcare systems have made rapid progress towards combining data science with precision medicine, particularly in pharmacogenomics. With the lack of predictability in medication effectiveness from patient to patient, acquiring the specifics of their genotype would be highly advantageous for patient treatment. Genotype-guided dosing adjustment improves clinical decision-making and helps optimize doses to deliver medications with greater efficacy and within safe margins. Current databases demand extensive effort to locate relevant genetic dosing information. To address this problem, Patient Optimization Pharmacogenomics (POPGx) was constructed. The objective of this paper is to describe the development of POPGx, a tool to simplify the approach for healthcare providers to determine pharmacogenomic dosing recommendations for patients taking multiple medications. Additionally, this tool educates patients on how their allele variations may impact gene function in case they need further healthcare consultations. POPGx was created on Konstanz Information Miner (KNIME). KNIME is a modular environment that allows users to conduct code-free data analysis. The POPGx workflow can access Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines and subsequently be able to present relevant dosing and counseling information. A KNIME representational state transfer (REST) application program interface (API) node was established to retrieve information from CPIC and drugs that are exclusively metabolized through CYP450, and these drugs were processed simultaneously to demonstrate competency of the workflow. The POPGx program provides a time-efficient method for users to retrieve relevant, patient-specific medication selection and dosing recommendations. Users input metabolizer gene, genetic allele data, and medication list to retrieve clear dosing information. The program is automated to display current guideline recommendations from CPIC. The integration of this program into healthcare systems has the potential to revolutionize patient care by giving healthcare practitioners an easy way to prescribe medications with greater efficacy and safety by utilizing the latest advancements in the field of pharmacogenomics.

Efficacy, safety, and correlative biomarkers of bintrafusp alfa in recurrent or metastatic nasopharyngeal cancer patients: a phase II clinical trial.

Background: The strategy of dual blockade of TGF-ß and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients. Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFß1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR. Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning. Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.

Curriculum mapping of accredited pharmacy programs in the United States.

INTRODUCTION: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US). METHODS: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates. RESULTS: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate. CONCLUSIONS: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula.

Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson's Model.

Previous work revealed an inverse correlation between tobacco smoking and Parkinson's disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.

Mental Health Challenges Among First Nations Adolescents Living Off-Reserve in Ontario, Canada.

Limited data exist on the mental health challenges facing First Nations adolescents and the factors that modify these difficulties. The current study compared levels of common mental health challenges among 112 off-reserve First Nations and 3334 non-First Nations adolescents (12-17 years old) and examined the impact of maternal psychological distress on these mental health challenges. First Nations adolescents self-reported higher symptoms of conduct, oppositional-defiant, attention-deficit hyperactivity, major depressive, social phobia, generalized anxiety, and separation anxiety disorders and all associations remained statistically significant after adjusting for covariates. Moderation analyses found that increasing levels of maternal distress were associated more strongly with symptoms of oppositional defiant, attention-deficit hyperactivity, major depressive, and generalized anxiety disorders in First Nations adolescents. Future work aimed at improving the mental health of First Nations youth that focus on supporting these adolescents, and their mothers in particular, could result in substantial benefits.

Finding Your Identity and Partner in a Trade Mark? Consumption, Innovation and the Law.

Trade marks are not traditionally considered to be central to innovation because they do not need to be innovative to be protected. Instead, trade marks are used to indicate the source of products and services. Of course, if consumers could not determine the source, this would reduce the incentive for traders to compete through innovative products and services. Here, we argue that trade marks implicate innovation in yet another way. Namely, because consumption can be based on identity characteristics and personality traits of trade marks, which can result in consumer-brand relationships that are either or both identity-related and/or partner-like, companies have incentives to innovate in accordance with the identity characteristics and personality traits. Failure to do so can result in negative reactions from consumers and relationship break-ups, which impacts innovation selection and hence societal good. We explore the implications of this for trade mark law theory and practice.

Changes in Youth Mental Health, Psychological Wellbeing, and Substance Use During the COVID-19 Pandemic: A Rapid Review.

Since the onset of the COVID-19 pandemic, researchers around the world have made efforts to assess its impact on youth mental health; however, the breadth of this topic has impeded a clear assessment of pandemic outcomes. This study aimed to address this gap by reviewing changes in youth (age ≤ 25) mental health, psychological wellbeing, substance use, and the use or delivery of relevant services during the pandemic. PubMed and Embase were searched in May 2021 to conduct a rapid review of the literature. The results encompass 156 primary publications and are reported using a narrative synthesis. Studies of mental health (n = 122) and psychological wellbeing (n = 28) generally indicated poor outcomes in many settings. Publications regarding substance use (n = 41) noted overall declines or unchanged patterns. Studies of service delivery (n = 12) indicated a generally positive reception for helplines and telehealth, although some youth experienced difficulties accessing services. The findings indicate negative impacts of the pandemic on youth mental health, with mixed results for substance use. Services must support marginalized youth who lack access to telehealth. Supplementary Information: The online version contains supplementary material available at 10.1007/s40894-022-00185-6.

Induction chemotherapy followed by radical chemoradiotherapy for patients with stage IV non-metastatic nasopharyngeal carcinoma: 11-Year Experience in a tertiary centre.

INTRODUCTION: T4 nasopharyngeal carcinoma (NPC) with close proximity to critical organs at risk (OARs) is usually underdosed during radiotherapy in order to respect radiation constraints. N3 disease has high risk of distant metastasis. Induction chemotherapy (IC) provides advantages of sparing of OARs during subsequent chemoradiotherapy (CCRT) and early eradication of micrometastasis. However, factors predicting successes of IC in this patient group are not well-studied. METHODS: 104 T4 or N3 NPC patients were retrospectively reviewed during 2007-2018. They were planned for IC followed by CCRT using intensity-modulated radiotherapy. RESULTS: In the whole group, five-year failure-free survival (FFS), locoregional failure-free survival (LRFS), distant failure-free survival (DFFS) and overall survival (OS) were 40.9%, 45.7%, 46.9% and 53.6% respectively. Isolated marginal failure rate was 5% (4/80) among patients with primary tumours located close to critical OARs. Pre-IC gross tumour volume primary (GTVp) total volume > 110 cm3 correlated with worse five-year LRFS (OR 6.37, P = 0.008), DFFS (OR 8.89, P = 0.003) and OS (OR 50.12, P < 0.001). In the T4 subgroup, IC improved D100% GTVp from 61.39 Gy to 64.71 Gy (P < 0.001) and V100% GTVp from 98.78% to 99.28% (P < 0.001). CONCLUSION: Our study demonstrated improved dosimetric parameters and low isolated marginal failure rate. It supported the use of IC and CCRT for tumours located close to critical OARs. Further research is warranted to compare predictive roles of pre- and post-IC tumour volumes. For high-risk patients being defined by pre-IC volume or other prognostic models, treatment escalation should be considered.

Second primary cancer after intensity-modulated radiotherapy for nasopharyngeal carcinoma: A territory-wide study by HKNPCSG.

OBJECTIVES: Long-term risk of second primary cancer (SPC) after definitive intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) remains unclear. This study aims to evaluate the risk, predictive factors and survival impact of SPC in a large territory-wide cohort of NPC survivors in an endemic region. MATERIALS AND METHODS: In this multicenter study, consecutive NPC patients (n = 3166) who underwent definitive IMRT in all six public oncology centers in Hong Kong between 2001 and 2010 were included. SPC risks were quantified by standardized incidence ratios (SIRs) and absolute excess risks (AERs) estimated from corresponding age-, sex-, and calendar year-specific population cancer incidence data from the Hong Kong Cancer Registry. Predictive factors and SPC-specific mortality were analyzed. RESULTS: Over a median follow-up period of 10.8 years, 290 cases of SPC were observed with a crude incidence of 9.2%. Cancer risk in NPC survivors was 90% higher than that in general population [SIR, 1.9; 95% confidence interval (CI), 1.7-2.2], with an AER of 52.1 (95% CI, 36.8-67.3) per 10,000 person-years at risk. Significant excess cancer risks were observed for oral cavity, sarcoma, oropharynx, paranasal sinus, salivary gland, thyroid, skin and lung. Advanced age, smoking, hepatitis B status, and re-irradiation were independent predictive factors. SPC accounted for 9.4% of all deaths among NPC survivors during the study period, and 10-year SPC-specific mortality was 3.4%. CONCLUSIONS: Second cancer risk after IMRT was substantial among NPC patients. SPC impairs long-term survival, and close surveillance is warranted as part of survivorship care.

Dose volume effects of re-irradiation for locally recurrent nasopharyngeal carcinoma.

BACKGROUND: This study analyzed the dose volume effects of re-irradiation for locally recurrent nasopharyngeal carcinoma (NPC) and attempts to determine the optimal dose for the best survival. METHODS: Ninety-one patients were studied. The local control, fatal complication, and overall survival were analyzed against the dose (in Equivalent Dose at 2 Gy/fractions) and recurrent gross tumor volume (GTV). RESULTS: The local control and fatal complication rate appear to increase with prescribed dose. The overall survival peaks at around 60 Gy10 . Local control decreases significantly with increasing GTV (P < .001) while overall survival shows similar trend (P = .06). No correlation was observed between the fatal complication rate and GTV volume. The dose response of local control appears to be stronger for smaller tumors. CONCLUSION: GTV volume plays a significant role in local control. A 60 Gy10 appears to be optimal for the best survival outcome; higher doses might be considered for small tumors.

Patterns of care and treatment outcomes for local recurrence of NPC after definite IMRT-A study by the HKNPCSG.

BACKGROUND: This study evaluates the contemporary care for patients with locally recurrent nasopharyngeal carcinoma after failure of the primary course of intensity modulated radiotherapy. METHODS: Eligible patients were identified through the Hong Kong Cancer Registry database. Patterns of care and treatment outcomes were analyzed. RESULTS: Two hundred seventy-two patients with locally recurrent tumors were identified. Of them, 30.9% received surgery, whereas 35.7% received re-irradiation (re-RT). The 5-year overall survival (OS) for the whole group was 30.2%. Old age and advanced rT classification were adverse prognostic factors, whereas surgery (mainly in resectable recurrence) was associated with favorable survival outcome. The 5-year OS rates for patients who received surgery and re-RT were 56.3% and 21.8%, respectively. CONCLUSIONS: Early detection of resectable recurrence is of paramount importance as surgery for resectable tumors offers the potential to achieve excellent outcomes. Re-RT could be considered in selected patients with unresectable disease and favorable prognostic features.

Modular organization of the multipartite central pattern generator for turtle rostral scratch: knee-related interneurons during deletions.

Central pattern generators (CPGs) are neuronal networks in the spinal cord that generate rhythmic patterns of motor activity in the absence of movement-related sensory feedback. For many vertebrate rhythmic behaviors, CPGs generate normal patterns of motor neuron activities as well as variations of the normal patterns, termed deletions, in which bursts in one or more motor nerves are absent from one or more cycles of the rhythm. Prior work with hip-extensor deletions during turtle rostral scratch supports hypotheses of hip-extensor interneurons in a hip-extensor module and of hip-flexor interneurons in a hip-flexor module. We present here single-unit interneuronal recording data that support hypotheses of knee-extensor interneurons in a knee-extensor module and of knee-flexor interneurons in a knee-flexor module. Members of knee-related modules are not members of hip-related modules and vice versa. These results in turtle provide experimental support at the single-unit interneuronal level for the organizational concept that the rostral-scratch CPG for the turtle hindlimb is multipartite, that is, composed of more than two modules. This work, when combined with experimental and computational work in other vertebrates, does not support the classical view that the vertebrate limb CPG is bipartite with only two modules, one controlling all the flexors of the limb and the other controlling all the extensors of the limb. Instead, these results support the general principle that spinal CPGs are multipartite.

Sociodemographic characteristics, risk factors and psychobehavioral disorders associated to alcohol consumption in adolescents of Veneto.

BACKGROUND: This study aims to estimate the alcohol consumption in a large student population in Veneto (North Italy) and to identify possible psychosocial factors associated, with particular attention to the relationship between alcohol consumption and psychopathological vulnerability. METHODS: Two semi-structured questionnaires were administered: the Questionnaire for Adolescents' Saturday evening, ad hoc designed for the study, which investigates the habits and alcohol consumption patterns, and the Youth Self Report which assesses the possible presence of psychic and behavioral problems. We recruited 10,465 students attending secondary and high schools in two Venetian provinces (age range 11-19 years). Frequency and amount of alcohol consumption were analyzed in relation to socio-demographic characteristics, habits, and vulnerability to psycho-behavioral problems. RESULTS: Data confirmed the high occurrence of alcohol consumption among young people (36.5%), with a higher prevalence among males (58,0%); the frequency of consumption and the amount of alcohol in taking increase with age, in greater measure after the transition to higher education level (10.4% in secondary school, 36,% in first year till 50% in third year of high school). Alcohol misuse was associated with: pubs and clubs attendance, coming back home late, a greater availability of money and externalizing behavioral problems. CONCLUSIONS: Results from this study confirmed the worrying data about the prevalence of alcohol misuse among young people, pointing out some protective and risk factors to be taken into account in planning of preventive interventions.

Importance of a personal history of breast cancer as a risk factor for the development of subsequent breast cancer: results from screening breast MRI.

OBJECTIVE: The purposes of this study were to assess the importance of a personal history of breast cancer as a risk factor for patients referred for screening breast MRI and to evaluate the importance of this risk factor compared with family history. MATERIALS AND METHODS: A retrospective review of screening breast MRI performed from 2004 to 2012 included a total of 702 patients, 465 of whom had undergone annual MRI and 237 of whom had undergone MRI every 6 months as part of a research protocol. RESULTS: Of the patients screened, 208 had a personal history of breast cancer, and 345 had a family history as the sole risk factor. An additional 97 patients had both risk factors. The absolute risk for detection of breast cancer at screening MRI among patients with a personal history of cancer was 2.8% (95% CI, 0.6-5.2%). The absolute risk for patients with a strong family history of cancer was 2.0% (95% CI, 0.5-3.5%). The relative risk for detection of breast cancer given a personal history was 1.42 (95% CI, 0.48-4.17) compared with family history. The relative risk when both risk factors were present compared with having only a family history was 3.04 (95% CI, 1.05-8.86). CONCLUSION: A personal history of breast cancer is an important risk factor for the development of subsequent breast cancer. Given the results, consideration should be given to MRI screening of patients with a personal history of breast cancer.

Management of Fusarium keratitis and its associated fungal iris nodule with intracameral voriconazole and amphotericin B.

A retrospective case report on the management of a 56-year-old man who was diagnosed with Fusarium keratitis with an associated iris fungal nodule. He presented with persistent right ocular pain, redness, photophobia and reduced vision following an injury six weeks earlier. Conservative management with topical antibiotics and intracameral injections was successfully used to treat a rare case of Fusarium keratitis with an associated fungal iris nodule. The patient had complete resolution of his vision. Therefore, conservative management of the fungal nodule is a successful therapy without the risk of anterior chamber dissemination, which may occur with surgical resection.

Percutaneous thrombin injection in an infant to treat hepatic artery pseudoaneurysm after failed embolization.

Percutaneous thrombin injection has been described in case reports as an alternative to surgical intervention for the treatment of hepatic artery pseudoaneurysms associated with high-grade liver lacerations in adults. However, there is limited description in the literature of this technique being applied in children, particularly in preadolescents, and no published literature describes its use in infants. The procedure can be performed by pediatric radiologists and pediatric interventional radiologists skilled in ultrasound-guided aspiration techniques. We report successful application of percutaneous thrombin injection in an infant to treat a pseudoaneurysm of a left hepatic arterial branch in an 11-month-old girl with a grade IV liver laceration after superselective transcatheter arterial embolization failed to achieve thrombosis.

Adolescent insight within the working alliance: A bridge between diagnostic and psychotherapeutic processes.

In the literature it has been stressed how important it is during consultation interviews to evaluate an adolescent's insight with a view to starting psychotherapeutic work. Motivated adolescents bring to the therapeutic effort a real, interiorized request for help and can start moving towards a change. The aim of this study is to assess the insight of adolescents with mental disorders during the diagnostic process and to analyze how this relates to further therapeutic compliance and clinical evolution. The study included 55 adolescents, 35 males and 20 females aged between 11 and 19 years, who were advised to receive psychotherapeutic treatment after a diagnostic procedure. Patient insight was assessed at the beginning and end of the diagnostic process. Then, six months later, a clinical interview assessed their therapeutic compliance and clinical evolution. The findings suggest that insight is important when working with adolescents because it influences both therapeutic compliance and clinical outcome.

Psychological and behavioral disease during developmental age: the importance of the alliance with parents.

The aim of the study is to analyze the clinician's alliance with parents during the diagnostic process in relation to therapeutic compliance and clinical evolution of individuals aged 0-11 years. The sample was formed by 84 individuals aged 0 to 11 years (18 < 6 years, 66 aged 6 to 11 years; 62 males and 22 females) who came to the Neuropsychiatric Unit for Children and Adolescents for a consultation regarding psychorelational and behavioral problems. Neuropsychiatric consultation took place in five diagnostic interviews with child and parents, separately. The last session was devoted to communication of psychiatric diagnosis (according to ICD 10) and therapeutic suggestions, if any. The clinician's relationship with parents and patients' participation were evaluated in terms of collaboration and quality of interaction, on the basis of pre-established criteria. Data about patients' therapeutic compliance and clinical outcome were collected during a follow-up visit eight months after the last session. Results suggest that the better the alliance between parents and clinician, the higher the therapeutic compliance and the likelihood of a positive outcome for patients. Our data suggest that good communication with parents benefits child patients, both in terms of response to the parents' need to report their children's worrying behavior and as a response to the discomfort expressed by children when they come in for consultation.