Investigating the effectiveness of oral ketamine on pain, mood and quality of life in treatment resistant chronic pain.

Introduction: Chronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketamine within a tertiary chronic pain management clinic. Methods: This study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale. Results: 73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased (p < 0.0001) on both numerical scores (41.6% decrease) and BPI scoring (mean decrease 2.61). Mood improved (p < 0.0001) across both PHQ-9 and BPI measurements. Patients also reported less difficulty with daily activities and improved QoL. The most common adverse reaction was drowsiness (21.9%), with 30.1% reporting no adverse reactions from Ketamine. Discussion: This work adds to the growing body of evidence that under the supervision of a pain specialist, oral ketamine therapy may be a safe, tolerable and effective treatment for chronic pain conditions which have not responded to other management options. Further research is required to produce a more accurate understanding of its chronic use. Key message: This real-world study shows that patients being treated with oral ketamine for chronic pain report decreased severity of pain, improved mood and increased quality of life across all conditions.

A comparison of MVP and MSVT performance among a diverse clinical pediatric sample.

The Memory Validity Profile (MVP) and Medical Symptom Validity Test (MSVT) are performance validity tests (PVTs) used to identify potential noncredible test performance during psychological evaluations. This study sought to examine the agreement between MVP and MSVT pass rates, as well as to determine if there are differences in MVP pass rates when using the cutoff score in the MVP professional manual compared with the experimental cutoff score of <31. Via retrospective review of records, 106 clients at a private neuropsychological clinic who had been given the MVP and the MSVT were identified. Results indicated that only one client met the manual cutoff scores, compared to 20 clients who failed the MSVT, raising concerns regarding the sensitivity of the MVP. Utilizing the receiver operator characteristic (ROC), curve analyses indicated fair discriminability of the MVP for the 106 participants (AUC = .717) with acceptable sensitivity (.50) and specificity (.92) for an MVP total score cutoff of <31. These findings support the utility of the experimental cut score in improving the sensitivity while maintaining adequate specificity in a clinically mixed population.

Is paternal age associated with transfer day, developmental stage, morphology, and initial hCG-rise of the competent blastocyst leading to live birth? A multicenter cohort study.

In this study we investigated whether age of men undergoing assisted reproductive technology (ART) treatment was associated with day of transfer, stage, morphology, and initial hCG-rise of the competent blastocyst leading to a live birth? The design was a multicenter historical cohort study based on exposure (age) and outcome data (blastocyst stage and morphology and initial hCG-rise) from men whose partner underwent single blastocyst transfer resulting in singleton pregnancy/birth. The ART treatments were carried out at sixteen private and university-based public fertility clinics. We included 7246 men and women, who between 2014 and 2018 underwent controlled ovarian stimulation (COS) or Frozen-thawed Embryo Transfer (FET) with a single blastocyst transfer resulting in singleton pregnancy were identified. 4842 men with a partner giving birth were included, by linking data to the Danish Medical Birth Registry. We showed that the adjusted association between paternal age and transfer day in COS treatments was OR 1.06, 95% CI (1.00;1.13). Meaning that for every increase of one year, men had a 6% increased probability that the competent blastocyst was transferred on day 6 compared to day 5. Further we showed that the mean difference in hCG values when comparing paternal age group 30-34, 35-39 and 40-45 with the age group 25-29 in those receiving COS treatment, all showed significantly lower adjusted values for older men. In conclusion we hypothesize that the later transfer (day 6) in female partners of older men may be due to longer time spent by the oocyte to repair fragmented DNA of the sperm cells, which should be a focus of future research in men.

Blame it on the pump.

Although intrathecal pumps may lead to spinal symptoms that are likely related to the pump itself, the case presented herein underscores the importance of casting a broad differential diagnosis at the time of initial presentation.

Association between women's age and stage, morphology, and implantation of the competent blastocyst: a multicenter cohort study.

OBJECTIVE: To study if the age of women undergoing assisted reproductive technology treatment associates with stage, morphology, and implantation of the competent blastocyst. DESIGN: Multicenter historical cohort study based on exposure (age) and outcome data (blastocyst stage and morphology and initial human chorionic gonadotrophin [hCG] rise) from women undergoing single blastocyst transfer resulting in singleton pregnancy/birth. SETTING: Sixteen private and university-based facilities. PATIENT(S): In this study, 7,246 women who, between 2014 and 2018, underwent controlled ovarian stimulation (COS) or frozen-thawed embryo transfer (FET) with a single blastocyst transfer resulting in singleton pregnancy were identified. Linking data to the Danish Medical Birth Registry resulted in a total of 4,842 women with a live birth being included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The competent blastocyst development stage (1-6), inner cell mass (A, B, C), trophectoderm (A, B, C), and initial serum hCG value. RESULT(S): Adjusted analysis of age and stage in COS treatments showed that for every 1-year increase in age there was a 5% reduced probability of the competent blastocyst assessed as being in a high stage at transfer. Comparison between hCG values in women 18-24 years and 25-29 years in both COS and FET showed significantly lower levels in the youngest women. CONCLUSION(S): The initial hCG rise was influenced by the age of the woman, with an identical pattern for hCG values in COS and FET treatments. In COS, the competent blastocyst had a reduced stage with increasing women's age.

A review of performance and symptom validity testing with pediatric populations.

Growing recognition and concerns of non-credible performance in pediatric populations have led clinicians to investigate the utility of performance and symptom validity tests (PVT/SVTs) among children and adolescents. Yet current research has indicated that a minority of clinicians routinely utilize a free-standing PVT in pediatric neuropsychological evaluations. The current article investigates the rationale for using PVT/SVTs, and the impact that failure of such exams have on other neurocognitive tests. A review of common adult PVTs and their appropriateness for use with specific pediatric clinical populations is presented, as well as empirical evidence for evaluating embedded validity indicators. The limited literature on SVTs with youth is also reviewed and provides additional insight into symptom exaggeration. There are various reasons children would provide noncredible performance, many of which are different from adults. A review of how the clinician should handle this behavior in pediatric evaluations is provided and what patient populations may present with a higher base rate of failure. Finally, various approaches are offered on how to explain these results to children and their caregivers.

Aging at Home: A Portrait of Home-Based Primary Care Across Canada.

Older adults and their families often struggle in navigating an increasingly fragmented healthcare system when it becomes increasingly difficult to receive care beyond their homes in the face of advanced illness, frailty and complex care needs. The provision of integrated home-based primary care has demonstrated improved patient and caregiver experiences and reduced healthcare costs when primary care providers collaborate in delivering care as part of larger interprofessional teams. In this trans-Canada portrait of five urban home-based primary care programs, their core features are highlighted to provide a roadmap on how to integrate this form of care into a Patient's Medical Home in partnership with acute and home-care providers.

Inductive Spikes in the Crab Nebula: A Theory of γ-Ray Flares.

We show that the mysterious, rapidly variable emission at ∼400 MeV observed from the Crab Nebula by the AGILE and Fermi satellites could be the result of a sudden drop in the mass loading of the pulsar wind. The current required to maintain wave activity in the wind is then carried by very few particles of a high Lorentz factor. On impacting the nebula, these particles produce a tightly beamed, high-luminosity burst of hard gamma rays, similar to those observed. This implies that (i) the emission is synchrotron radiation in the toroidal field of the nebula and, therefore, linearly polarized and (ii) this mechanism potentially contributes to the gamma-ray emission from other powerful pulsars, such as the Magellanic Cloud objects J0537-6910 and B0540-69.

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. RESULTS: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations. TRIAL REGISTRATION NUMBER: NCT00925301; Pre-results.

The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat.

PURPOSE: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity. METHODS: A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. RESULTS: Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. CONCLUSION: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.Genet Med 19 4, 430-438.

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat.

BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

Patient Relationships and the Personal Physician in Tomorrow's Health System: A Perspective from the Keystone IV Conference.

A group of senior leaders from the early generation of academic family medicine reflect on the meaning of being a personal physician, based on their own clinical experiences and as teachers of residents and students in academic health centers. Recognizing that changes in clinical care and education at national and local systems levels have added extraordinary demands to the role of the personal physician, the senior group offers examples of how the discipline might go forward in changing times. Differently organized care such as the Family Health Team model in Ontario, Canada; value-based payment for populations in large health systems; and federal changes in reimbursement for populations can have positive effects on physician satisfaction. These changes and examples of changes in medical student and residency education also have the potential to positively affect the primary care workforce. The authors conclude that, without substantive educational and health system reform, the ability to truly serve as a personal physician and adhere to the values of continuity, responsibility, and accountability will continue to be threatened.

Utility of the test of memory malingering (TOMM) in children ages 4-7 years with and without ADHD.

There is growing consensus that assessment for non-credible performance is a necessary component of pediatric neuropsychological examination. The current study examined the utility and validity of the Test of Memory Malingering (TOMM) in children ages 4-7 years with and without Attention-deficit/Hyperactivity Disorder (ADHD); 66 children (30 controls, 36 ADHD) completed all three TOMM trials. There were no significant group differences in total score on any trial, or passing rate for Trial 2 or Retention. Four-year-olds with ADHD achieved "passing" score on Trial 1 less often than controls. Across groups, performance on Trial 2 and Retention improved with age, such that 85% of the sample achieved a passing score. Four-year-olds had greater difficulty and achieved a passing score significantly less often than children 5-7 years. Moreover, half of the 4-year-olds performed worse on Retention than Trial 2, calling into question the utility of the Retention trial at this age. Performance was associated with IQ only within the ADHD group on the Retention trial. Results suggest that the TOMM can be used with confidence in clinical groups as young as 5 years. Among 4-year-olds, performance appears dependent on severity of ADHD or disruptive behaviors, and may be associated with factors other than effort.

Limitations of a time-lapse blastocyst prediction model: a large multicentre outcome analysis.

The goal of embryo selection models is to select embryos with the highest reproductive potential, whilst minimizing the rejection of viable embryos. Ultimately, any embryo selection model must be tested on clinical outcome. We therefore retrospectively tested a published blastocyst prediction model on a large combined set of transferred embryos with known clinical outcome. The model was somewhat effective in that we found a relative increase of 30% for implantation in the model-selected group of embryos. There was, however, a concomitant large rejection of embryos from our test cohort, which actually resulted in pregnancy. This hypothetical experiment highlights the limitations of predicting blastulation only. Crucially, it illustrates that both sensitivity and specificity are important parameters when developing embryo selection models for prospective clinical use.

The effects of multiple mild traumatic brain injuries on acute injury presentation and neuropsychological recovery in children.

BACKGROUND: Although research focused on mild traumatic brain injury (mTBI) has proliferated in recent years, few studies have examined the significance of a previous history of mTBI in children. OBJECTIVE: To compare the acute injury presentation and neuropsychological recovery in a pediatric sample after mTBI. METHODS: Participants 8 to 16 years of age were divided into 4 groups: no previous injury history, history of 1 mTBI, history of 2 mTBIs, and history of ≥ 3 mTBIs. Participants were evaluated within 3 months of the most recent injury by clinical interview and an abbreviated neuropsychological test battery. RESULTS: After the index mTBI, the groups did not differ in their likelihood to display a loss of consciousness, nor did they differ on neuropsychological test performance. CONCLUSION: Overall, contrary to our hypotheses, we found no demonstrable difference between those children with a self-reported mTBI history and those without after an index mTBI.

The relationship between the self-report BASC-2 validity indicators and performance validity test failure after pediatric mild traumatic brain injury.

In adult populations, research on methodologies to identify noncredible performance and exaggerated symptoms during neuropsychological evaluations has grown exponentially in the past two decades. Far less work has focused on methods appropriate for children. Although several recent studies have used stand-alone performance validity tests with younger populations, a near absence of pediatric work has investigated other indices to identify response bias. The present study examined the relationship between the validity scales from the self-report Behavior Assessment System for Children, Second Edition (BASC-2) and performance on the Medical Symptom Validity Test (MSVT), a stand-alone performance validity test. The sample consisted of 274 clinically referred patients with mild traumatic brain injuries aged 8 through 17 years. Fifty patients failed the MSVT based on actuarial criteria. The majority of these patients (92%) provided valid self-report BASC-2 profiles, with only three patients (6%) producing an invalid profile due to an elevated F index. Analysis of valid/invalid self-report BASC-2 profiles and MSVT pass/fail did not reveal a significant relationship (p = 0.471, two-tailed Fisher's exact test). These findings suggest that performance validity tests like the MSVT provide substantively different information about the validity of a neuropsychological profile than that provided by the self-report validity scales of the BASC-2.

The use of the Rey 15-Item Test and recognition trial to evaluate noncredible effort after pediatric mild traumatic brain injury.

The Rey 15-Item Test (FIT) is a performance validity test commonly used in adult neuropsychological assessment. FIT classification statistics across studies have been variable, so a recognition trial was created to enhance the measure (Boone, K. B., Salazar, X., Lu, P., Warner-Chacon, K., & Razani, J. (2002). The Rey 15-Item recognition trial: A technique to enhance sensitivity of the Rey 15-Item Memorization Test. Journal of Clinical and Experimental Neuropsychology, 24(5), 561-573.). The current study assessed the utility of the FIT and recognition trial in a pediatric mild traumatic brain injury sample (N = 319, M = 14.57 years). All participants were administered the FIT and recognition trial as part of an abbreviated clinical neuropsychological evaluation. Failure on the Medical Symptom Validity Test was used as the criterion for noncredible effort. Fifteen percent of the sample met the criterion. The traditional adult cutoff score of <9 on the FIT recall trial yielded excellent specificity (98%), but very poor sensitivity (12%). When the recognition trial was utilized, a total score of <26 resulted in the best combined cutoff score (sensitivity = 55%, specificity = 91%). Results indicate that the FIT with recognition trial may be useful in the assessment of noncredible effort with children and adolescents, at least among relatively high-functioning populations.

Embedded performance validity indicators within the California Verbal Learning Test, Children's Version.

To date, few studies have examined the use of embedded performance validity indicators in pediatric populations. The present study examined the utility of variables within the California Verbal Learning Test, Children's Version (CVLT-C) in detecting noncredible effort among a pediatric mild traumatic brain injury sample. The sample consisted of 411 clinically referred patients aged 8-16 years. A total of 13% of the participants failed both the Medical Symptom Validity Test and at least one other performance validity measure. No demographic or injury-related variables differentiated the noncredible and adequate effort groups. The noncredible group performed significantly worse than the adequate effort group across a majority of CVLT-C variables. Logistic regression analysis revealed that the Recognition Discriminability (RD) score was the most robust in predicting noncredible effort. Among this relatively high-functioning sample, an RD cutoff z-score of -0.5 resulted in sensitivity of 55% and specificity of 91%. A more conservative RD cutoff z-score of -1.0 resulted in sensitivity of 41% and specificity of 97%. These findings are comparable to the classification statistics found for many embedded indicators in the adult literature. Although only moderately sensitive, the RD score on the CVLT-C appears to have good utility in identifying noncredible effort in a relatively high-functioning pediatric mTBI population.

Detecting performance invalidity in children: not quite as easy as A, B, C, 1, 2, 3 but automatized sequences appears promising.

In adult populations, embedded performance validity indicators are well established, as they are time efficient, resistant to coaching, and allow for more continuous monitoring of effort than standalone measures. Although several recent studies have demonstrated the appropriateness of using standalone validity tests with school-age children, a paucity of pediatric work has examined embedded indicators. The present study investigated the value of a simple automatized sequences task to detect performance invalidity in 439 clinically referred patients with mild head injury aged 8 through 17 years. Sixteen percent of the participants failed the Medical Symptom Validity Test (MSVT). Thirteen percent failed the MSVT and also performed below established cutoffs on either the Test of Memory Malingering or Wechsler Digit Span subtest. The group classified as providing invalid data performed significantly worse than the group passing the MSVT across all sequencing conditions. Sensitivity and specificity for the total time on the sequencing task compared favorably to data produced for many respected adult-based embedded indicators (i.e., sensitivity around 50% when specificity ≥ 90%). Classification statistics for any embedded performance validity test can be expected to be worse in more severely affected populations; however, the current sequencing task appears to have value in detecting invalid performance in relatively high-functioning older children and adolescents. The fact that the task takes less than a couple of minutes to administer makes it especially appealing.