Healthcare resource utilization following ustekinumab initiation among bio-naïve Canadian patients with moderately-to-severely active Crohn's disease.

BACKGROUND/AIMS: Real-world healthcare resource utilization (HCRU) of bio-naïve patients with Crohn's disease (CD) receiving ustekinumab was assessed. METHODS: A multicentre, retrospective chart review study of bio-naïve Canadian adult patients with moderately-to-severely active CD treated with ustekinumab was conducted. CD-related HCRU (i.e., surgery, hospitalization, or emergency room [ER] visits) was evaluated at Months 4, 6, and 12 post-ustekinumab initiation, and associated costs were sourced from a provincial database. Proportion of patients with HCRU events and ustekinumab persistence were summarized at each timepoint. Paired analysis compared HCRU events and associated costs incurred by the same patient whilst in remission vs. when not in remission. RESULTS: By Month 12, 11.1 % (17/153) of patients had record(s) of any CD-related HCRU event, with ER visits being the most common (7.7 %; 12/155). Hospitalization had the highest average cost (CAD $436.10; SD $2,089.25) across all patients, accounting for 82.2 % of the mean total annual cost/patient (CAD $530.47; SD $2,229.92). While in remission, ≤5 % of patients experienced some healthcare encounter, compared with 7 % when not in remission (P = 0.289). Finally, 93.5 % of patients persisted on ustekinumab at Month 12. CONCLUSIONS: HCRU rates and associated total annual costs were lower for bio-naïve CD patients receiving ustekinumab, and when patients were in remission. Most patients continued with ustekinumab at Month 12.

Real-World Treatment Patterns and Clinical Outcomes among Patients Receiving CDK4/6 Inhibitors for Metastatic Breast Cancer in a Canadian Setting Using AI-Extracted Data.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are widely used in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced/metastatic breast cancer (ABC/MBC) in first line (1L), but little is known about their real-world use and clinical outcomes long-term, in Canada. This study used Pentavere's previously validated artificial intelligence (AI) to extract real-world data on the treatment patterns and outcomes of patients receiving CDK4/6i+endocrine therapy (ET) for HR+/HER2- ABC/MBC at Sinai Health in Toronto, Canada. Between 1 January 2016 and 1 July 2021, 48 patients were diagnosed with HR+/HER2- ABC/MBC and received CDK4/6i + ET. A total of 38 out of 48 patients received CDK4/6i + ET in 1L, of which 34 of the 38 (89.5%) received palbociclib + ET. In 2L, 12 of the 21 (57.1%) patients received CDK4/6i + ET, of which 58.3% received abemaciclib. In 3L, most patients received chemotherapy (10/12, 83.3%). For the patients receiving CDK4/6i in 1L, the median (95% CI) time to the next treatment was 42.3 (41.2, NA) months. The median (95% CI) time to chemotherapy was 46.5 (41.4, NA) months. The two-year overall survival (95% CI) was 97.4% (92.4, 100.0), and the median (range) follow-up was 28.7 (3.4-67.6) months. Despite the limitations inherent in real-world studies and a limited number of patients, these AI-extracted data complement previous studies, demonstrating the effectiveness of CDK4/6i + ET in the Canadian real-world 1L, with most patients receiving palbociclib as CDK4/6i in 1L.

The Role of Demographic and Clinical Factors in Germline Mutation Testing for Patients with Primary Hyperparathyroidism.

INTRODUCTION: Guidelines recommending genetic counseling in primary hyperparathyroidism (PHPT) vary. To further delineate current recommendations, this study examined genetic counseling referral patterns and rates of mutations in surgical patients with PHPT. PATIENTS AND METHODS: A single-institution review was performed of adult patients who underwent parathyroidectomy for presumed sporadic PHPT. Genetic testing indications of hypercalcemia onset ≤ 40 years, multigland disease (MGD), family history (FHx) of PHPT, or other clinical indications suspicious for a PHPT-related endocrinopathy were examined by demographics and mutation detection rates. RESULTS: Genetic counseling was performed in 237 (37.9%) of 625 patients. Counseling was discussed but not performed in 121 (19.4%) patients. No evidence was noted of genetic referral discussion in the remaining 267 (42.7%). Of these groups, patients who received genetic counseling were youngest, p < 0.001 [median age 55.3 (IQR 43.2, 66.7) years]. The majority of patients with indications of age ≤ 40 years (65.7%), FHx (78.0%), and other clinical indications (70.7%) underwent genetic counseling, while most with MGD (57.0%) did not. Eight mutations were detected in 227 patients (3.5%). Mutations included: MEN1 (n = 2), CDC-73 (n = 4), and CASR (n = 2). Detection was most common in patients with FHx (4/71, 5.6%), then age ≤ 40 years (3/66, 4.5%), and other clinical indications (3/80, 3.8%). No mutations were identified in 48 patients tested solely for MGD. CONCLUSIONS: Most patients with onset of hypercalcemia age ≤ 40 years, positive FHx, or other clinical concerns underwent genetic counseling, while most with MGD did not. As no germline mutations were identified in patients with MGD alone, further investigation of MGD as a sole indication for genetic counseling may be warranted.

Dysregulation of Neuropilin-2 Expression in Inhibitory Neurons Impairs Hippocampal Circuit Development Leading to Autism-Epilepsy Phenotype.

Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and epilepsy has not been tested. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.

Balancing act of small GTPases downstream of plexin-A4 signaling motifs promotes dendrite elaboration in mammalian cortical neurons.

The precise development of neuronal morphologies is crucial to the establishment of synaptic circuits and, ultimately, proper brain function. Signaling by the axon guidance cue semaphorin 3A (Sema3A) and its receptor complex of neuropilin-1 and plexin-A4 has multifunctional outcomes in neuronal morphogenesis. Downstream activation of the RhoGEF FARP2 through interaction with the lysine-arginine-lysine motif of plexin-A4 and consequent activation of the small GTPase Rac1 promotes dendrite arborization, but this pathway is dispensable for axon repulsion. Here, we investigated the interplay of small GTPase signaling mechanisms underlying Sema3A-mediated dendritic elaboration in mouse layer V cortical neurons in vitro and in vivo. Sema3A promoted the binding of the small GTPase Rnd1 to the amino acid motif lysine-valine-serine (LVS) in the cytoplasmic domain of plexin-A4. Rnd1 inhibited the activity of the small GTPase RhoA and the kinase ROCK, thus supporting the activity of the GTPase Rac1, which permitted the growth and branching of dendrites. Overexpression of a dominant-negative RhoA, a constitutively active Rac1, or the pharmacological inhibition of ROCK activity rescued defects in dendritic elaboration in neurons expressing a plexin-A4 mutant lacking the LVS motif. Our findings provide insights into the previously unappreciated balancing act between Rho and Rac signaling downstream of specific motifs in plexin-A4 to mediate Sema3A-dependent dendritic elaboration in mammalian cortical neuron development.

Racial and Ethnic Disparities in the Diagnosis and Treatment of Thyroid Disease.

CONTEXT: There are differences in diagnosis, treatment, and outcomes for thyroid between racial and ethnic groups that contribute to disparities. Identifying these differences and their causes are the key to understanding and reducing disparities in presentation and outcomes in endocrine disorders. EVIDENCE ACQUISITION: The present study reviews original studies identifying and exploring differences between benign and malignant thyroid diseases. A PubMed, Web of Science, and Scopus search was conducted for English-language studies using the terms "thyroid," "thyroid disease," "thyroid cancer," "race," "ethnicity," and "disparities" from inception to December 31, 2022. EVIDENCE SYNTHESIS: Many racial and ethnic disparities in the diagnosis, presentation, treatment, and outcomes of thyroid disease were found. Non-White patients are more likely to have a later time to referral, to present with more advanced disease, to have more aggressive forms of thyroid cancer, and are less likely to receive the appropriate treatment than White patients. Overall and disease-specific survival rates are lower in Black and Hispanic populations when compared to White patients. CONCLUSIONS: Extensive disparities exist in thyroid disease diagnosis, treatment, and outcomes that may have been overlooked. Further work is needed to identify the causes of these disparities to begin to work toward equity in the care of thyroid disease.

Real-world effectiveness and safety of ustekinumab in bio-naive patients with moderate-to-severe Crohn's disease: A Canadian multi-center study.

BACKGROUND: Clinical practice guidelines recommend ustekinumab as a first-line biological treatment option for moderately-to-severely active Crohn's disease (CD). However, there is limited real-world effectiveness and safety data in bio-naïve patients. AIMS: To assess ustekinumab effectiveness and safety in bio-naïve CD patients. METHODS: Medical charts were reviewed retrospectively at seven Canadian centers. The primary outcome was the proportion of patients achieving clinical remission at Month 6 following ustekinumab initiation. Secondary outcomes included clinical, biochemical, and endoscopic response, and remission at Months 4, 6 and 12. Ustekinumab safety was assessed over the one-year follow-up period. RESULTS: 158 charts were reviewed. Clinical remission was achieved by 50.0% (36/72), 67.7% (105/155), and 73.7% (84/114) of patients at Months 4, 6, and 12, respectively. At these study timepoints, biochemical remission was observed in 65.2% (43/66), 71.6% (63/88), and 73.9% (68/92) of patients. At Months 6 and 12, endoscopic remission was observed in 40.5% (15/37) and 56.3% (27/48) of patients, respectively. Most participants (93.5%; 145/155) persisted on ustekinumab through Month 12. No serious adverse drug reactions were reported. CONCLUSION: In this real-world study, ustekinumab presents as an effective first-line biologic for induction and maintenance of remission among bio-naïve Canadian patients with moderately-to-severely active CD.

A reappraisal of ovarian stimulation strategies used in assisted reproductive technology.

Ovarian stimulation is a fundamental step in assisted reproductive technology (ART) with the intention of inducing ovarian follicle development prior to timed intercourse or intra-uterine insemination and facilitating the retrieval of multiple oocytes during a single in vitro fertilization (IVF) cycle. The basis of ovarian stimulation includes the administration of exogenous gonadotropins, with or without pre-treatment with oral hormonal therapy. Gonadotropin-releasing hormone agonist or antagonist is given in addition to the gonadotropins to prevent a premature rise of endogenous luteinizing hormone that would in turn lead to premature ovulation. With the advancement in technology, various stimulation protocols have been devised to cater for different patient needs. However, ovarian hyperstimulation syndrome and its serious complications may occur following ovarian stimulation. It is also evident that suboptimal ovarian stimulation strategies may have a negative impact on oogenesis, embryo quality, endometrial receptivity, and reproductive outcomes over recent years. This review describes the various forms of pre-treatment for ovarian stimulation and stimulation protocols, and aims to provide clinicians with the latest available evidence.

Older Patients With Asymptomatic Primary Hyperparathyroidism: Should Criteria for Surgery Be Expanded?

Context: Patients with primary hyperparathyroidism (PHPT) can present with variable signs, symptoms, and end-organ effects. Clinical practice guidelines influence referral for consideration of parathyroidectomy. Objective: This study compared the demographic, biochemical, and symptom profile and examine indications for surgery in patients older than 50 years who underwent parathyroidectomy to determine how changes to current guidelines may affect recommendations for parathyroidectomy. Methods: A retrospective review was conducted of patients age 50 years or older who underwent initial parathyroidectomy for sporadic PHPT from 2012 to 2020. Patients were classified by indications for surgery per guideline criteria (classic, asymptomatic, and no criteria met) and age group (AG): 50 to 59 years; 60 to 69 years; 70 years or older. Patients were treated at a high-volume tertiary medical center by endocrine surgeons. Results: Of 1182 patients, 367 (31%) classic and 660 (56%) asymptomatic patients met the criteria for surgery. The most common indications for surgery were extent of hypercalcemia (51%), osteoporosis (28%), and nephrolithiasis (27%). Of the 155 (13%) patients who did not meet the criteria, neurocognitive symptoms (AG1: 88% vs AG2: 81% vs AG3: 70%; P = .14) and osteopenia (AG1: 53% vs AG2: 68% vs AG3: 68%; P = .43) were frequently observed regardless of patient age. If the age threshold of younger than 50 years was expanded to 60, 65, or 70 years, an additional 61 (5%), 99 (8%), and 124 (10%) patients in the entire cohort would have met the guideline criteria for surgery, respectively. Conclusion: Expanding current guidelines for PHPT to include a broader age range, osteopenia, and neurocognitive symptoms may allow for earlier surgical referral and evaluation for definitive treatment.

Relative thoracic changes from supine to upright patient position: A proton collaborative group study.

This study presents position changes of a few radiotherapy-relevant thoracic organs between upright and typical supine patient orientations. Using tools in a commercial treatment planning system (TPS), key anatomical distances were measured for four-dimensional CT data sets and analyzed for the two patient orientations. The uncertainty was calculated as the 95% confidence interval (CI) on the relative difference for each of the four analyzed changes for upright relative to supine, as follows: the distance of the bottom of the heart to the top of the sternum, it changed +2.6% or +4 mm (95% CI [+0.30%,+4.9%]); the distance of the center of the C3 vertebra to the backrest, it changed +29% (95% CI [+22%,+36%]); the contoured left and right lungs increased their volumes respectively: +17% (95% CI [+12%,+21%]) for the left, and +9.9% (95% CI [+4.1%,+16%]); and lastly, the distance from the top of the sternum to the top of the liver, but its uncertainty far exceeded the average change by a factor of two. This last result is therefore inconclusive, the others show that with 95% confidence that a change in internal positions is observed for lung volumes and heart position that could be important for upright treatments.

Real-World Persistence of Ustekinumab in the Treatment of Inflammatory Bowel Disease.

INTRODUCTION: There is an urgent need to understand the long-term real-world effectiveness of ustekinumab (UST) in the treatment of Crohn's disease (CD), fistulizing CD (FCD), and ulcerative colitis (UC). Persistence on treatment is commonly used as a surrogate measure of real-world treatment response. This study aims to estimate the long-term real-world persistence of UST in adult patients with CD, FCD, and UC. METHODS: A retrospective study was conducted in patients with CD, FCD, and UC treated with UST through a national patient support program in Canada. Treatment persistence was described using the Kaplan-Meier method, and the impact of patient characteristics on persistence was explored through stratified analyses and multivariable Cox proportional hazards models. RESULTS: Persistence rates for 8724 patients with CD were 82.9%, 71.4%, 64.1%, and 59.7% at 1, 2, 3, and 4 years, respectively. Similarly, persistence rates for 276 patients with FCD were 84.1%, 70.9%, 64.9%, and 63.1% at 1, 2, 3, and 4 years, respectively. Persistence rates for 1291 patients with UC were 76.5% at 1 year and 69.5% at 1.5 years. When stratified by prior IBD-indicated biologic experience, persistence was numerically higher in biologic-naïve patients across all disease cohorts. A Cox proportional hazards model confirmed that this difference was significant in patients with CD (hazard ratio: 0.72; confidence interval: [0.65-0.79]). CONCLUSIONS: This study estimated long-term persistence in a large population of patients with IBD. At 1 year, over three-fourths of patients remained on UST treatment in all disease cohorts, and over half of patients remained on treatment at 4 years in CD and FCD patients. Biologic-naïve status was significantly associated with higher persistence in patients with CD.

Inflammatory bowel disease is a term that refers to a group of disorders where the tissues of the gastrointestinal tract are chronically inflamed and may become damaged; it includes Crohn's disease and ulcerative colitis. While there is no cure, treatments are available to help patients manage their disease. Patients must typically continue treatment to ensure ongoing control. As such, the length of time a patient continues using a specific treatment can be suggestive of its success in the real-world. Ustekinumab is a biologic therapy that is used to treat both Crohn's disease and ulcerative colitis. Although ustekinumab has been evaluated in clinical trials, understanding how patients respond to treatment in the real world is valuable to physicians. This study was able to look at patients with inflammatory bowel disease who received treatment with ustekinumab through a patient support program in Canada and assess the length of time they continued treatment. After 1 year, over three-fourths of all patients with inflammatory bowel disease were still using ustekinumab; and after 4 years, more than half of patients with Crohn's disease were still using ustekinumab. This study was also able to look at whether certain factors affected the likelihood of a patient continuing treatment with ustekinumab. Patients that had never received a biologic therapy before were more likely to continue ustekinumab treatment than those who had received a different biologic therapy beforehand.

Anatomical changes in the male pelvis between the supine and upright positions-A feasibility study for prostate treatments in the upright position.

Treating and imaging patients in the upright orientation is gaining acceptance in radiation oncology and radiology and has distinct advantages over the recumbent position. An IRB approved study to investigate the positions and orientations of the male pelvic organs between the supine and upright positions was conducted. The study comprised of scanning 15 male volunteers (aged 55-75 years) on a 0.6 T Fonar MRI scanner in the supine and upright positions with a full bladder and in the upright position with an empty bladder. The Pelvic study revealed that in the upright position the 1. Position and shape of the prostate are not impacted significantly by bladder fill. 2. Distance between the sacrum and the anterior bladder wall is significantly smaller. 3. Anterior-Posterior length and the bladder width is significantly larger. 4. Seminal vesicles are pushed down by the bladder. 5. Top of the penile bulb is further away from the apex of the prostate. These observed differences could positively impact upright prostate treatments by 1. Reducing the risk of small bowel approximating the treatment volume. 2. Prostate treatments can be done with a reduced focus on bladder fill. 3. Radiation beams for treating intermediate risk prostrate can be made smaller or a larger portion of the seminal vesicles can be treated with the same beam size than typically used for supine treatments. 4. Reducing the average dose to the penile bulb.

The use of image synthesis techniques in target and roi delineation in the upright position.

The use of multi-modality imaging technologies such as CT, MRI, and PET imaging is state of the art for radiation therapy treatment planning. Except for a limited number of low magnetic field MR scanners the majority of such imaging technologies can only image the patient in a recumbent position. Delivering radiation therapy treatments with the patient in an upright orientation has many benefits and several companies are now developing upright patient positioners combined with upright diagnostic helical CT scanners to facilitate upright radiation therapy treatments. Due to the directional changes in the gravitational forces on the patient's body, most structures and organs will change position and shape between the recumbent and upright positions. Detailed knowledge about such structures and organs are therefore often only available in the recumbent position. The problem statement is therefore well defined, that is, how do we know where such structures and organs, that is, the target or region at risk volumes, are in the upright position if those cannot be identified and or delineated accurately enough using the upright diagnostic quality CT images only? This paper outlines two methods based on synthetic CT or MR images to overcome this problem.

The Incidence of Graves' Hyperthyroidism Before and After COVID-19 Messenger RNA Vaccination.

OBJECTIVE: Case reports of postvaccine early-onset Graves' hyperthyroidism (PVGD) after the administration of COVID-19 vaccination have emerged. Our aim was to investigate whether the incidence of Graves' hyperthyroidism (GD) has increased after the introduction of COVID-19 vaccination. METHODS: We compared the incidence of new-onset GD at a single academic center during 2 periods: December 2017 to October 2019 and December 2020 to October 2022, ie, before and after the implementation of COVID-19 vaccinations. We defined PVGD as laboratory-confirmed hyperthyroidism and GD within 4 weeks after the vaccination or clear onset of symptoms of thyrotoxicosis within 4 weeks of vaccination with evidence of hyperthyroidism and GD within 3 months. RESULTS: During the prevaccination period, 803 patients carried diagnoses of GD, and of these, 131 were new. During the postvaccination period, 901 patients carried diagnoses of GD, and of these, 138 were new. There was no statistically significant difference in the incidence of GD (P = .52), age at onset, gender, or race between the 2 groups. Twenty-four of 138 newly diagnosed patients in the post-COVID-19 group met the criteria for PVGD. The median free T4 was higher, but this was not statistically significant (3.9 vs 2.5 ng/dL, P = .05). There were no differences in age, gender, race, antibody titers, or type of vaccination between PVGD and controls. CONCLUSION: There was no increase in new-onset GD after COVID-19 vaccination. Median free T4 was higher in patients with PVGD, but this was not statistically significant.

Adoption of Robotic Adrenalectomy: A Two-Institution Study of Surgeon Learning Curve.

BACKGROUND: Robotic adrenalectomy is feasible and safe, yet concerns over increased operative times and the learning curve (LC) for proficiency have limited its adoption. This study aimed to assess the LC for robotic adrenalectomy. METHODS: This is a two-institution retrospective review of consecutive unilateral minimally invasive adrenalectomies performed by four high-volume adrenal surgeons between 2007 and 2022. Two surgeons transitioned from laparoscopic to robotic adrenalectomy, and two surgeons adopted the approach, with proctoring, after completion of fellowship training without robotic experience. Operative time and complications were analyzed. Multivariable regression was used to identify factors associated with operative time. The number of cases required to overcome the LC was determined using the LC-cumulative-sum (LC-CUSUM) analysis. RESULTS: Of 457 adrenalectomies, 182 (40%) were laparoscopic and 275 (60%) robotic. The robotic approach was associated with shorter median operative time (106 vs 119 min; p = 0.002), fewer complications (6% vs 13%; p = 0.018), and fewer conversions to open adrenalectomy (1% vs 4%; p = 0.030), with no difference between the senior and junior surgeons. On adjusted analysis, factors associated with increased operative time were male sex (p < 0.001), BMI > 30 kg/m2 (p < 0.001), and higher gland weight (p < 0.001). The LC-CUSUM analysis showed proficiency after 8-29 procedures. Compared with the first 10 cases, there was a mean reduction in operative time of 14 min after 10-20 cases, 28 min after 20-30 cases, and 29 min after > 30 cases, regardless of surgeon experience. DISCUSSION: With dedicated teams and proctoring, robotic adrenalectomy can be safely adopted at high-volume centers with a minimal LC.