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The National Center for Complementary and Integrative Health: Priorities for Cannabis and Cannabinoid Research [Special Section: Cannabinoid Signaling in Human Health and Disease-Commentary]

The National Center for Complementary and Integrative Health (NCCIH), which is part of the US National Institutes of Health (NIH), has a broad interest in studying the biologic activities of natural products, especially those for which compelling evidence from preclinical research suggests biologic activities that may be beneficial to health or have a potential role in disease treatment, as well as products used extensively by the American public. As of 2023, use of cannabis for medical purposes is legal in 38 states and Washington, D.C. Such use continues to climb generally without sufficient knowledge regarding risks and benefits. In keeping with NCCIH’s natural product research priorities and recognizing this gap in knowledge, NCCIH formally launched a research program in 2019 to expand research on the possible benefits for pain management of certain substances found in cannabis: minor cannabinoids and terpenes. This Viewpoint provides additional details and the rationale for this research priority at NCCIH. In addition, NCCIH’s efforts and initiatives to facilitate and coordinate an NIH research agenda focused on cannabis and cannabinoid research are described.

SIGNIFICANCE STATEMENT

Use of cannabis for purported medical purposes continues to increase despite insufficient knowledge regarding risks and benefits. Research is needed to help health professionals and patients make knowledgeable decisions about using cannabis and cannabinoids for medical purposes. The National Center for Complementary and Integrative Health, along with other NIH Institutes, Centers, and Offices, is expanding study on the safety, efficacy, and harms of cannabis—a complex mixture of phytochemicals that needs to be studied alone and in combination.




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Cannabis and Cannabinoid Signaling: Research Gaps and Opportunities [Special Section: Cannabinoid Signaling in Human Health and Disease-Commentary]

Cannabis and its products have been used for centuries for both medicinal and recreational purposes. The recent widespread legalization of cannabis has vastly expanded its use in the United States across all demographics except for adolescents. Meanwhile, decades of research have advanced our knowledge of cannabis pharmacology and particularly of the endocannabinoid system with which the components of cannabis interact. This research has revealed multiple targets and approaches for manipulating the system for therapeutic use and to ameliorate cannabis toxicity or cannabis use disorder. Research has also led to new questions that underscore the potential risks of its widespread use, particularly the enduring consequences of exposure during critical windows of brain development or for consumption of large daily doses of cannabis with high content 9-tetrahydrocannabinol. This article highlights current neuroscience research on cannabis that has shed light on therapeutic opportunities and potential adverse consequences of misuse and points to gaps in knowledge that can guide future research.

SIGNIFICANCE STATEMENT

Cannabis use has escalated with its increased availability. Here, the authors highlight the challenges of cannabis research and the gaps in our knowledge of cannabis pharmacology and of the endocannabinoid system that it targets. Future research that addresses these gaps is needed so that the endocannabinoid system can be leveraged for safe and effective use.




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Preoperative Assessment of Meningioma Consistency Using a Combination of MR Elastography and DTI [RESEARCH]

BACKGROUND AND PURPOSE:

Preoperative assessment of meningioma consistency is beneficial for optimizing surgical strategy and prognosis of patients. We aim to develop a noninvasive prediction model for meningioma consistency utilizing MR elastography and DTI.

MATERIALS AND METHODS:

Ninety-four patients (52 ± 22 years old, 69 women, 25 men) diagnosed with meningioma were recruited in the study. Each patient underwent preoperative T1WI, T2WI, DTI, and MR elastography. Combined MR elastography–DTI model was developed based on multiple logistic regression. Intraoperative tumor descriptions served as clinical criteria for evaluating meningioma consistency. The diagnostic efficacy in determining meningioma consistency was evaluated by using a receiver operating characteristic curve. Further validation was conducted in 27 stereotactic biopsies by using indentation tests and underlying mechanism was investigated by histologic analysis.

RESULTS:

Among all the imaging modalities, MR elastography demonstrated the highest efficacy with the shear modulus magnitude (|G*|) achieving an area under the curve (AUC) of 0.81 (95% CI: 0.699–0.929). When combined with DTI, the diagnostic accuracy further increased (AUC: 0.88, 95% CI: 0.784–0.971), surpassing any technique alone. Indentation measurement based on stereotactic biopsies further demonstrated that the MR elastography–DTI model was suitable for predicting intratumor consistency. Histologic analysis suggested that meningioma consistency may be correlated with tumor cell density and fibrous content.

CONCLUSIONS:

The MR elastography–DTI combined model is effective in noninvasive prediction of meningioma consistency.




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Neuroimaging Correlates with Clinical Severity in Wilson Disease: A Multiparametric Quantitative Brain MRI [RESEARCH]

BACKGROUND AND PURPOSE:

Previous studies have reported metal accumulation and microstructure changes in deep gray nuclei (DGN) in Wilson disease (WD). However, there are limited studies that investigate whether there is metal accumulation and microstructure changes in DGN of patients with WD with normal-appearing routine MRI. This study aimed to evaluate multiparametric changes in DGN of WD and whether the findings correlate with clinical severity in patients with WD.

MATERIALS AND METHODS:

The study enrolled 28 patients with WD (19 with neurologic symptoms) and 25 controls. Fractional anisotropy (FA), mean diffusivity (MD), and magnetic susceptibility in globus pallidus, pontine tegmentum, dentate nucleus, red nucleus, head of caudate nucleus, putamen, substantia nigra, and thalamus were extracted. Correlations between imaging data and the Unified Wilson’s Disease Rating Scale (UWDRS) neurologic subitems were explored.

RESULTS:

FA, MD, and susceptibility values were higher in multiple DGN of patients with WD than controls (P < .05). Patients with WD without abnormal signals in DGN on routine MRI also had higher FA, MD, and susceptibility values than controls (P < .017). We found that UWDRS neurologic subscores correlated with FA and susceptibility values of DGN (P < .05). In addition, we also found that FA and susceptibility values in specific structures correlated with specific neurologic symptoms of WD (ie, tremor, parkinsonism, dysarthria, dystonia, and ataxia) (P < .05).

CONCLUSIONS:

Patients with WD have increased FA, MD, and susceptibility values even before the lesion is morphologically apparent on routine MRI. The increased FA and susceptibility values correlate with clinical severity of WD.




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Automated Volumetric Software in Dementia: Help or Hindrance to the Neuroradiologist? [RESEARCH]

BACKGROUND AND PURPOSE:

Brain atrophy occurs in the late stage of dementia, yet structural MRI is widely used in the work-up. Atrophy patterns can suggest a diagnosis of Alzheimer disease (AD) or frontotemporal dementia (FTD) but are difficult to assess visually. We hypothesized that the availability of a quantitative volumetric brain MRI report would increase neuroradiologists’ accuracy in diagnosing AD, FTD, or healthy controls compared with visual assessment.

MATERIALS AND METHODS:

Twenty-two patients with AD, 17 with FTD, and 21 cognitively healthy patients were identified from the electronic health systems record and a behavioral neurology clinic. Four neuroradiologists evaluated T1-weighted anatomic MRI studies with and without a volumetric report. Outcome measures were the proportion of correct diagnoses of neurodegenerative disease versus normal aging ("rough accuracy") and AD versus FTD ("exact accuracy"). Generalized linear mixed models were fit to assess whether the use of a volumetric report was associated with higher accuracy, accounting for random effects of within-rater and within-subject variability. Post hoc within-group analysis was performed with multiple comparisons correction. Residualized volumes were tested for an association with the diagnosis using ANOVA.

RESULTS:

There was no statistically significant effect of the report on overall correct diagnoses. The proportion of "exact" correct diagnoses was higher with the report versus without the report for AD (0.52 versus 0.38) and FTD (0.49 versus 0.32) and lower for cognitively healthy (0.75 versus 0.89). The proportion of "rough" correct diagnoses of neurodegenerative disease was higher with the report than without the report within the AD group (0.59 versus 0.41), and it was similar within the FTD group (0.66 versus 0.63). Post hoc within-group analysis suggested that the report increased the accuracy in AD (OR = 2.77) and decreased the accuracy in cognitively healthy (OR = 0.25). Residualized hippocampal volumes were smaller in AD (mean difference –1.8; multiple comparisons correction, –2.8 to –0.8; P < .001) and FTD (mean difference –1.2; multiple comparisons correction, –2.2 to –0.1; P = .02) compared with cognitively healthy.

CONCLUSIONS:

The availability of a brain volumetric report did not improve neuroradiologists’ accuracy over visual assessment in diagnosing AD or FTD in this limited sample. Post hoc analysis suggested that the report may have biased readers incorrectly toward a diagnosis of neurodegeneration in cognitively healthy adults.




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NeuroMix with MRA: A Fast MR Protocol to Reduce Head and Neck CTA for Patients with Acute Neurologic Presentations [RESEARCH]

BACKGROUND AND PURPOSE:

Overuse of CT-based cerebrovascular imaging in the emergency department and inpatient settings, notably CTA of the head and neck for minor and nonfocal neurologic presentations, stresses imaging services and exposes patients to radiation and contrast. Furthermore, such CT-based imaging is often insufficient for definitive diagnosis, necessitating additional MR imaging. Recent advances in fast MRI may allow timely assessment and a reduced need for head and neck CTA in select populations.

MATERIALS AND METHODS:

We identified inpatients or patients in the emergency department who underwent CTAHN (including noncontrast and postcontrast head CT, with or without CTP imaging) followed within 24 hours by a 3T MRI study that included a 2.5-minute unenhanced multicontrast sequence (NeuroMix) and a 5-minute intracranial time of flight MRA) during a 9-month period (April to December 2022). Cases were classified by 4 radiologists in consensus as to whether NeuroMix and NeuroMix + MRA detected equivalent findings, detected unique findings, or missed findings relative to CTAHN.

RESULTS:

One hundred seventy-four cases (mean age, 67 [SD, 16] years; 56% female) met the inclusion criteria. NeuroMix alone and NeuroMix + MRA protocols were determined to be equivalent or better compared with CTAHN in 71% and 95% of patients, respectively. NeuroMix always provided equivalent or better assessment of the brain parenchyma, with unique findings on NeuroMix and NeuroMix + MRA in 35% and 36% of cases, respectively, most commonly acute infarction or multiple microhemorrhages. In 8/174 cases (5%), CTAHN identified vascular abnormalities not seen on the NeuroMix + MRA protocol due to the wider coverage of the cervical arteries by CTAHN.

CONCLUSIONS:

A fast MR imaging protocol consisting of NeuroMix + MRA provided equivalent or better information compared with CTAHN in 95% of cases in our population of patients with an acute neurologic presentation. The findings provide a deeper understanding of the benefits and challenges of a fast unenhanced MR-first approach with NeuroMix + MRA, which could be used to design prospective trials in select patient groups, with the potential to reduce radiation dose, mitigate adverse contrast-related patient and environmental effects, and lessen the burden on radiologists and health care systems.




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Cyclic Aspiration in Mechanical Thrombectomy: Influencing Factors and Experimental Validation [RESEARCH]

BACKGROUND AND PURPOSE:

Mechanical thrombectomy is a fundamental intervention for acute ischemic stroke treatment. While conventional techniques are effective, cyclic aspiration (CyA) shows potential for better recanalization rates. We aim to investigate factors affecting CyA and compare them with static aspiration (StA).

MATERIALS AND METHODS:

StA setup consisted of an aspiration pump connected to pressure transducer. CyA was tested with 5 subsequent iterations: single solenoid valve with air plus saline (i1) or saline alone (i2) as aspiration medium; 2 solenoid valves with air plus saline (i3) as aspiration medium; complete air removal and saline feeding (i4); and pressurized saline feeding (i5). To assess the efficacy of clot ingestion, the pressure transducer was replaced with a distal aspiration catheter. Moderately stiff clot analogs (15 mm) were used to investigate the ingestion quantified as clot relative weight loss. Additionally, the aspiration flow rate was assessed for each setup.

RESULTS:

With CyA i1, the amplitude of the achieved negative pressure waves declined with increasing frequencies but progressively increased with each subsequent iteration, achieving a maximum amplitude of 81 kPa for i5 at 1 Hz. Relative clot weight loss was significantly higher with i5 at 5 Hz than with StA (100% versus 37.8%; P = .05). Aspiration flow rate was lower with CyA than with StA (i5 at 5 Hz: 199.8 mL/min versus StA: 311 mL/min; P < .01).

CONCLUSIONS:

CyA with the appropriate setup may represent an encouraging innovation in mechanical thrombectomy, offering a promising pathway for improving efficacy in clot ingestion and recanalization. The observed benefits warrant confirmation in a clinical setting.




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Intra-Aneurysmal High-Resolution 4D MR Flow Imaging for Hemodynamic Imaging Markers in Intracranial Aneurysm Instability [RESEARCH]

BACKGROUND AND PURPOSE:

Prediction of aneurysm instability is crucial to guide treatment decisions and to select appropriate patients with unruptured intracranial aneurysms (IAs) for preventive treatment. High-resolution 4D MR flow imaging and 3D quantification of aneurysm morphology could offer insights and new imaging markers for aneurysm instability. In this cross-sectional study, we aim to identify 4D MR flow imaging markers for aneurysm instability by relating hemodynamics in the aneurysm sac to 3D morphologic proxy parameters for aneurysm instability.

MATERIALS AND METHODS:

In 35 patients with 37 unruptured IAs, a 3T MRA and a 7T 4D MRI flow scan were performed. Five hemodynamic parameters—peak-systolic wall shear stress (WSSMAX) and time-averaged wall shear stress (WSSMEAN), oscillatory shear index (OSI), mean velocity, and velocity pulsatility index—were correlated to 6 3D morphology proxy parameters of aneurysm instability—major axis length, volume, surface area (all 3 size parameters), flatness, shape index, and curvedness—by Pearson correlation with 95% CI. Scatterplots of hemodynamic parameters that correlated with IA size (major axis length) were created.

RESULTS:

WSSMAX and WSSMEAN correlated negatively with all 3 size parameters (strongest for WSSMEAN with volume (r = –0.70, 95% CI –0.83 to –0.49) and OSI positively (strongest with major axis length [r = 0.87, 95% CI 0.76–0.93]). WSSMAX and WSSMEAN correlated positively with shape index (r = 0.61, 95% CI 0.36–0.78 and r = 0.49, 95% CI 0.20–0.70, respectively) and OSI negatively (r = –0.82, 95% CI –0.9 to –0.68). WSSMEAN and mean velocity correlated negatively with flatness (r = –0.35, 95% CI –0.61 to –0.029 and r = –0.33, 95% CI –0.59 to 0.007, respectively) and OSI positively (r = 0.54, 95% CI 0.26–0.74). Velocity pulsatility index did not show any statistically relevant correlation.

CONCLUSIONS:

Out of the 5 included hemodynamic parameters, WSSMAX, WSSMEAN, and OSI showed the strongest correlation with morphologic 3D proxy parameters of aneurysm instability. Future studies should assess these promising new imaging marker parameters for predicting aneurysm instability in longitudinal cohorts of patients with IA.




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Artificial Intelligence Efficacy as a Function of Trainee Interpreter Proficiency: Lessons from a Randomized Controlled Trial [RESEARCH]

BACKGROUND AND PURPOSE:

Recently, artificial intelligence tools have been deployed with increasing speed in educational and clinical settings. However, the use of artificial intelligence by trainees across different levels of experience has not been well-studied. This study investigates the impact of artificial intelligence assistance on the diagnostic accuracy for intracranial hemorrhage and large-vessel occlusion by medical students and resident trainees.

MATERIALS AND METHODS:

This prospective study was conducted between March 2023 and October 2023. Medical students and resident trainees were asked to identify intracranial hemorrhage and large-vessel occlusion in 100 noncontrast head CTs and 100 head CTAs, respectively. One group received diagnostic aid simulating artificial intelligence for intracranial hemorrhage only (n = 26); the other, for large-vessel occlusion only (n = 28). Primary outcomes included accuracy, sensitivity, and specificity for intracranial hemorrhage/large-vessel occlusion detection without and with aid. Study interpretation time was a secondary outcome. Individual responses were pooled and analyzed with the t test; differences in continuous variables were assessed with ANOVA.

RESULTS:

Forty-eight participants completed the study, generating 10,779 intracranial hemorrhage or large-vessel occlusion interpretations. With diagnostic aid, medical student accuracy improved 11.0 points (P < .001) and resident trainee accuracy showed no significant change. Intracranial hemorrhage interpretation time increased with diagnostic aid for both groups (P < .001), while large-vessel occlusion interpretation time decreased for medical students (P < .001). Despite worse performance in the detection of the smallest-versus-largest hemorrhages at baseline, medical students were not more likely to accept a true-positive artificial intelligence result for these more difficult tasks. Both groups were considerably less accurate when disagreeing with the artificial intelligence or when supplied with an incorrect artificial intelligence result.

CONCLUSIONS:

This study demonstrated greater improvement in diagnostic accuracy with artificial intelligence for medical students compared with resident trainees. However, medical students were less likely than resident trainees to overrule incorrect artificial intelligence interpretations and were less accurate, even with diagnostic aid, than the artificial intelligence was by itself.




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Pericarotid Fat as a Marker of Cerebrovascular Risk [RESEARCH]

SUMMARY:

Vascular inflammation is widely recognized as an important factor in the atherosclerotic process, particularly in terms of plaque development and progression. Conventional tests, such as measuring circulating inflammatory biomarkers, lack the precision to identify specific areas of vascular inflammation. In this context, noninvasive imaging modalities can detect perivascular fat changes, serving as a marker of vascular inflammation. This review aims to provide a comprehensive overview of the key concepts related to perivascular carotid fat and its pathophysiology. Additionally, we examine the existing literature on the association of pericarotid fat with features of plaque vulnerability and cerebrovascular events. Finally, we scrutinize the advantages and limitations of the noninvasive assessment of pericarotid fat.




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The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature [RESEARCH REPORT]

Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS. Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies. This case study documents the diagnostic journey of an 18-yr-old patient with DHP deficiency, highlighting features at the severe end of the clinical spectrum. Notably, our patient exhibited previously unreported skeletal features that positively responded to bisphosphonate treatment, contributing valuable insights to the clinical characterization of DHP deficiency. Additionally, a novel DPYS variant was identified and confirmed pathogenicity through metabolic testing, further expanding the variant spectrum of the gene. Our case emphasizes the importance of a comprehensive diagnostic approach using genetic sequencing and metabolic testing for accurate diagnosis.




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PD-L1+ diffuse large B-cell lymphoma with extremely high mutational burden and microsatellite instability due to acquired PMS2 mutation [RESEARCH REPORT]

We present a unique case of a single patient presenting with two mutationally distinct, PD-L1+ diffuse large B-cell lymphomas (DLBCLs). One of these DLBCLs demonstrated exceptionally high mutational burden (eight disease-associated variants and 41 variants of undetermined significance) with microsatellite instability (MSI) and an acquired PMS2 mutation with loss of PMS2 protein expression, detected postchemotherapy. This report, while highlighting the extent of possible tumor heterogeneity across separate clonal expansions as well as possible syndromic B-cell neoplasia, supports the notion that, although rare, PD-L1 expression and associated states permissive of high mutational burden (such as mismatch repair gene loss of function/MSI) should be more routinely considered in DLBCLs. Appropriate testing may be predictive of outcome and inform the utility of targeted therapy in these genetically diverse and historically treatment-refractory malignancies.




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Common clonal origin of three distinct hematopoietic neoplasms in a single patient: B-cell lymphoma, T-cell lymphoma, and polycythemia vera [RESEARCH ARTICLE]

The potential for more than one distinct hematolymphoid neoplasm to arise from a common mutated stem or precursor cell has been proposed based on findings in primary human malignancies. Particularly, angioimmunoblastic T-cell lymphoma (AITL), which shares a somatic mutation profile in common with other hematopoietic malignancies, has been reported to occur alongside myeloid neoplasms or clonal B-cell proliferations, with identical mutations occurring in more than one cell lineage. Here we report such a case of an elderly woman who was diagnosed over a period of 8 years with diffuse large B-cell lymphoma, polycythemia vera, and AITL, each harboring identical somatic mutations in multiple genes. Overall, at least five identical nucleotide mutations were shared across multiple specimens, with two identical mutations co-occurring at variable variant allele frequencies in all three specimen types. These findings lend credence to the theory that a common mutated stem cell could give rise to multiple neoplasms through parallel hematopoietic differentiation pathways.




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Deep molecular tracking over the 12-yr development of endometrial cancer from hyperplasia in a single patient [RESEARCH REPORT]

Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes, APC, ARID1A, CTNNB1, CDKN2A, KRAS, PTEN, and TP53, were identified. A PTEN nonsense mutation p.W111* was present in all samples analyzed except histologically normal endometrium. Apart from this PTEN mutation, the only other recurrent mutation was KRAS G12D, which was present in six biopsy samplings, including histologically normal tissue obtained at the patient's first visit but not detectable in the cancer. The PTEN p.W111* mutant allele fractions were lowest in benign, inactive endometrial glands (0.7%), highest in adenocarcinoma (36.9%), and, notably, were always markedly reduced following progesterone treatment. To our knowledge, this report provides the first molecular characterization of EndoCA development in a single patient. A single PTEN mutation was present throughout the 12 years of cancer development. Importantly, and with potential significance toward medical and nonsurgical management of EndoCA, progesterone treatments were consistently noted to markedly decrease PTEN mutant allele fractions to precancerous levels.




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Pazopanib elicits remarkable response in metastatic porocarcinoma: a functional precision medicine approach [RESEARCH REPORT]

Metastatic porocarcinomas (PCs) are vanishingly rare, highly aggressive skin adnexal tumors with mortality rates exceeding 70%. Their rarity has precluded the understanding of their disease pathogenesis, let alone the conduct of clinical trials to evaluate treatment strategies. There are no effective agents for unresectable PCs. Here, we successfully demonstrate how functional precision medicine was implemented in the clinic for a metastatic PC with no known systemic treatment options. Comprehensive genomic profiling of the tumor specimen did not yield any actionable genomic aberrations. However, ex vivo drug testing predicted pazopanib efficacy, and indeed, administration of pazopanib elicited remarkable clinicoradiological response. Pazopanib and its class of drugs should be evaluated for efficacy in other cases of PC, and the rationale for efficacy should be determined when PC tumor models become available. A functional precision medicine approach could be useful to derive effective treatment options for rare cancers.




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ITPR1-associated spinocerebellar ataxia with craniofacial features--additional evidence for germline mosaicism [RESEARCH ARTICLE]

Inositol 1,4,5-triphosphate receptor type 1 (ITPR1) is an endoplasmic reticulum–bound intracellular inositol triphosphate receptor involved in the regulation of intracellular calcium. Pathogenic variants in ITPR1 are associated with spinocerebellar ataxia (SCA) types 15/16 and 29 and have recently been implicated in a facial microsomia syndrome. In this report, we present a family with three affected individuals found to have a heterozygous missense c.800C > T (predicted p.Thr267Met) who present clinically with a SCA29-like syndrome. All three individuals presented with varying degrees of ataxia, developmental delay, and apparent intellectual disability, as well as craniofacial involvement—an uncommon finding in patients with SCA29. The variant was identified using clinical exome sequencing and validated with Sanger sequencing. It is presumed to be inherited via parental germline mosaicism. We present our findings to provide additional evidence for germline mosaic inheritance of SCA29, as well as to expand the clinical phenotype of the syndrome.




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Prostate cancer patient stratification by molecular signatures in the Veterans Precision Oncology Data Commons [RESEARCH REPORT]

Veterans are at an increased risk for prostate cancer, a disease with extraordinary clinical and molecular heterogeneity, compared with the general population. However, little is known about the underlying molecular heterogeneity within the veteran population and its impact on patient management and treatment. Using clinical and targeted tumor sequencing data from the National Veterans Affairs health system, we conducted a retrospective cohort study on 45 patients with advanced prostate cancer in the Veterans Precision Oncology Data Commons (VPODC), most of whom were metastatic castration-resistant. We characterized the mutational burden in this cohort and conducted unsupervised clustering analysis to stratify patients by molecular alterations. Veterans with prostate cancer exhibited a mutational landscape broadly similar to prior studies, including KMT2A and NOTCH1 mutations associated with neuroendocrine prostate cancer phenotype, previously reported to be enriched in veterans. We also identified several potential novel mutations in PTEN, MSH6, VHL, SMO, and ABL1. Hierarchical clustering analysis revealed two subgroups containing therapeutically targetable molecular features with novel mutational signatures distinct from those reported in the Catalogue of Somatic Mutations in Cancer database. The clustering approach presented in this study can potentially be used to clinically stratify patients based on their distinct mutational profiles and identify actionable somatic mutations for precision oncology.




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Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment [RESEARCH REPORT]

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol–cytochrome c reductase, are particularly rare in humans. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here, we describe a girl who presented at 3 yr of age with lactic acidosis, hyperammonemia, and hypoglycemia but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole-exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.




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De novo TRPM3 missense variant associated with neurodevelopmental delay and manifestations of cerebral palsy [RESEARCH ARTICLE]

We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease–associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).




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Rapid genome diagnosis of alveolar capillary dysplasia leading to treatment in a child with respiratory and cardiac failure [RESEARCH REPORT]

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.




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Clinical and functional analysis of the germline TP53 p.K164E acetylation site variant [RESEARCH ARTICLE]

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.




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Leukemic presentation and progressive genomic alterations of MCD/C5 diffuse large B-cell lymphoma (DLBCL) [RESEARCH ARTICLE]

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of CD79B, MyD88, TP53, TBL1XR1, and PIM1 genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of TP53 heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as PRDM1 loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of BTK and FOXO1 mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.




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PBRNs: Past, Present, and Future: A NAPCRG Report on the Practice-Based Research Network Conference. [Family Medicine Updates]




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The Odyssey of HOMER: Comparative Effectiveness Research on Medication for Opioid Use Disorder During the COVID-19 Pandemic [Special Report]

The usual challenges of conducting primary care research, including randomized trials, have been exacerbated, and new ones identified, during the COVID-19 pandemic. HOMER (Home versus Office for Medication Enhanced Recovery; subsequently, Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) is a pragmatic, comparative-effectiveness research trial that aims to answer a key question from patients and clinicians: What is the best setting in which to start treatment with buprenorphine for opioid use disorder for this patient at this time? In this article, we describe the difficult journey to find the answer. The HOMER study began as a randomized trial comparing treatment outcomes in patients starting treatment with buprenorphine via induction at home (unobserved) vs in the office (observed, synchronous). The study aimed to enroll 1,000 participants from 100 diverse primary care practices associated with the State Networks of Colorado Ambulatory Practices and Partners and the American Academy of Family Physicians National Research Network. The research team faced unexpected challenges related to the COVID-19 pandemic and dramatic changes in the opioid epidemic. These challenges required changes to the study design, protocol, recruitment intensity, and funding conversations, as well as patience. As this is a participatory research study, we sought, documented, and responded to practice and patient requests for adaptations. Changes included adding a third study arm using telehealth induction (observed via telephone or video, synchronous) and switching to a comprehensive cohort design to answer meaningful patient-centered research questions. Using a narrative approach based on the Greek myth of Homer, we describe here the challenges and adaptations that have provided the opportunity for HOMER to thrive and find the way home. These clinical trial strategies may apply to other studies faced with similar cultural and extreme circumstances.




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Self-Reported PrEP Use and Risk of Bacterial STIs Among Ontarian Men Who Are Gay or Bisexual or Have Sex With Men [Original Research]

PURPOSE

HIV pre-exposure prophylaxis (PrEP) may increase rates of bacterial sexually transmitted infections (STIs) among gay, bisexual, and other men who have sex with men (GBM) through risk compensation (eg, an increase in condomless sex or number of partners); however, longitudinal studies exploring the time-dependent nature of PrEP uptake and bacterial STIs are limited. We used marginal structural models to estimate the effect of PrEP uptake on STI incidence.

METHODS

We analyzed data from the iCruise study, an online longitudinal study of 535 Ontarian GBM from July 2017 to April 2018, to estimate the effects of PrEP uptake on incidence of self-reported bacterial STIs (chlamydia, gonorrhea, and syphilis) collected with 12 weekly diaries. The incidence rate was calculated as the number of infections per 100 person-months, with evaluation of the STIs overall and individually. We used marginal structural models to account for time-varying confounding and quantitative bias analysis to evaluate the sensitivity of estimates to nondifferential outcome misclassification.

RESULTS

Participating GBM were followed up for a total of 1,623.5 person-months. Overall, 70 participants (13.1%) took PrEP during the study period. Relative to no uptake, PrEP uptake was associated with an increased incidence rate of gonorrhea (incidence rate ratio = 4.00; 95% CI, 1.67-9.58), but not of chlamydia or syphilis, and not of any bacterial STI overall. Accounting for misclassification, the median incidence rate ratio for gonorrhea was 2.36 (95% simulation interval, 1.08-5.06).

CONCLUSIONS

We observed an increased incidence rate of gonorrhea associated with PrEP uptake among Ontarian GBM that was robust to misclassification. Although our findings support current guidelines for integrating gonorrhea screening with PrEP services, additional research should consider the long-term impact of PrEP among this population.

Annals Early Access article




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Lack of Knowledge of Antibiotic Risks Contributes to Primary Care Patients Expectations of Antibiotics for Common Symptoms [Research Briefs]

Patient expectations of receiving antibiotics for common symptoms can trigger unnecessary use. We conducted a survey (n = 564) between January 2020 to June 2021 in public and private primary care clinics in Texas to study the prevalence and predictors of patients’ antibiotic expectations for common symptoms/illnesses. We surveyed Black patients (33%) and Hispanic/Latine patients (47%), and over 93% expected to receive an antibiotic for at least 1 of the 5 pre-defined symptoms/illnesses. Public clinic patients were nearly twice as likely to expect antibiotics for sore throat, diarrhea, and cold/flu than private clinic patients. Lack of knowledge of potential risks of antibiotic use was associated with increased antibiotic expectations for diarrhea (odds ratio [OR] = 1.6; 95% CI, 1.1-2.4) and cold/flu symptoms (OR = 2.9; 95% CI, 2.0-4.4). Lower education and inadequate health literacy were predictors of antibiotic expectations for diarrhea. Future antibiotic stewardship interventions should tailor patient education materials to include information on antibiotic risks and guidance on appropriate antibiotic indications.




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Evaluation of the Importance of Capsule Transparency in Dry Powder Inhalation Devices [Research Briefs]

The aim of this work is to test whether the use of a transparent capsule affects the residual capsule weight after inhalation as a surrogate of the inhaled delivered dose for patients with non-reversible chronic airway disease. Researchers conducted an observational cross-sectional study with patients using a single-dose dry powder inhaler. The weight of the capsule was measured with a precision microbalance before and after inhalation. Ninety-one patients were included, of whom 63 (69.2%) used a transparent capsule. Inhalation with a transparent capsule achieved a weight decrease of 30.1% vs 8.6% for devices with an opaque capsule (P <0.001). These data reinforce the need to provide patients with mechanisms that verify the correct inhalation technique.




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Digital Innovation to Grow Quality Care Through an Interprofessional Care Team (DIG IT) Among Underserved Patients With Hypertension [Original Research]

PURPOSE

The impact of digital health on medically underserved patients is unclear. This study aimed to determine the early impact of a digital innovation to grow quality care through an interprofessional care team (DIG IT) on the blood pressure (BP) and 10-year atherosclerotic cardiovascular disease (ASCVD) risk score of medically underserved patients.

METHODS

This was a 3-month, prospective intervention study that included patients aged 40 years or more with BP of 140/90 mmHg or higher who received care from DIG IT from August through December 2021. Sociodemographic and clinical outcomes of DIG IT were compared with historical controls (controls) whose data were randomly extracted by the University of California Data Warehouse and matched 1:1 based on age, ethnicity, and baseline BP of the DIG IT arm. Multiple linear regression was performed to adjust for potential confounding factors.

RESULTS

A total of 140 patients (70 DIG IT, 70 controls) were included. Both arms were similar with an average age (SD) of 62.8 (9.7) years. The population was dominated by Latinx (79.3%) persons, with baseline mean BP of 163/81 mmHg, and mean ASCVD risk score of 23.9%. The mean (SD) reduction in systolic BP at 3 months in the DIG IT arm was twice that of the controls (30.8 [17.3] mmHg vs 15.2 [21.2] mmHg; P <.001). The mean (SD) ASCVD risk score reduction in the DIG IT arm was also twice that of the controls (6.4% [7.4%] vs 3.1% [5.1%]; P = .003).

CONCLUSIONS

The DIG IT was more effective than controls (receiving usual care). Twofold improvement in the BP readings and ASCVD scores in medically underserved patients were achieved with DIG IT.




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Family Medicine Resident Scholarly Activity Infrastructure, Output, and Dissemination: A CERA Survey [Original Research]

PURPOSE

Meeting scholarly activity requirements continues to be a challenge in many family medicine (FM) residency programs. Studies comprehensively describing FM resident scholarship have been limited. We sought to identify institutional factors associated with increased scholarly output and meeting requirements of the Accreditation Council for Graduate Medical Education (ACGME).

OBJECTIVES

Our goals were to: (1) describe scholarly activity experiences among FM residents compared with ACGME requirements; (2) classify experiences by Boyer’s domains of scholarship; and (3) associate experiences with residency program characteristics and scholarly activity infrastructure.

METHODS

This was a cross-sectional survey. The survey questions were part of an omnibus survey to FM residency program directors conducted by the Council of Academic Family Medicine Educational Research Alliance (CERA). All ACGME-accredited US FM residency program directors, identified by the Association of Family Medicine Residency Directors, were sampled.

RESULTS

Of the 691 eligible program directors, 298 (43%) completed the survey. The respondents reported that 25% or more residents exceeded ACGME minimum output, 17% reported that 25% or more residents published their work, and 50% reported that 25% or more residents delivered conference presentations. Programs exceeding ACGME scholarship requirements exhibit robust infrastructure characterized by access to faculty mentorship, scholarly activity curricula, Institutional Review Board, medical librarian, and statistician.

CONCLUSIONS

These findings suggest the need for codified ACGME requirements for scholarly activity infrastructure to ensure access to resources in FM residency programs. By fostering FM resident engagement in scholarly activity, programs help to create a culture of inquiry, and address discrepancies in funding and output among FM residency programs.




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A Cluster-Randomized Study of Technology-Assisted Health Coaching for Weight Management in Primary Care [Original Research]

PURPOSE

We undertook a trial to test the efficacy of a technology-assisted health coaching intervention for weight management, called Goals for Eating and Moving (GEM), within primary care.

METHODS

This cluster-randomized controlled trial enrolled 19 primary care teams with 63 clinicians; 9 teams were randomized to GEM and 10 to enhanced usual care (EUC). The GEM intervention included 1 in-person and up to 12 telephone-delivered coaching sessions. Coaches supported goal setting and engagement with weight management programs, facilitated by a software tool. Patients in the EUC arm received educational handouts. We enrolled patients who spoke English or Spanish, were aged 18 to 69 years, and either were overweight (body mass index 25-29 kg/m2) with a weight-related comorbidity or had obesity (body mass index ≥30 kg/m2). The primary outcome (weight change at 12 months) and exploratory outcomes (eg, program attendance, diet, physical activity) were analyzed according to intention to treat.

RESULTS

We enrolled 489 patients (220 in the GEM arm, 269 in the EUC arm). Their mean (SD) age was 49.8 (12.1) years; 44% were male, 41% Hispanic, and 44% non-Hispanic Black. At 12 months, the mean adjusted weight change (standard error) was –1.4 (0.8) kg in the GEM arm vs –0.8 (1.6) kg in the EUC arm, a nonsignificant difference (P = .48). There were no statistically significant differences in secondary outcomes. Exploratory analyses showed that the GEM arm had a greater change than the EUC arm in mean number of weekly minutes of moderate to vigorous physical activity other than walking, a finding that may warrant further exploration.

CONCLUSIONS

The GEM intervention did not achieve clinically important weight loss in primary care. Although this was a negative study possibly affected by health system resource limitations and disruptions, its findings can guide the development of similar interventions. Future studies could explore the efficacy of higher-intensity interventions and interventions that include medication and bariatric surgery options, in addition to lifestyle modification.




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A Few Doctors Will See Some of You: The Critical Role of Underrepresented in Medicine (URiM) Family Physicians in the Care of Medicaid Beneficiaries [Original Research]

PURPOSE

Despite being key to better health outcomes for patients from racial and ethnic minority groups, the proportion of underrepresented in medicine (URiM) physicians remains low in the US health care system. This study linked a nationally representative sample of family physicians (FPs) with Medicaid claims data to explore the relative contributions to care of Medicaid populations by FP race and ethnicity.

METHODS

This descriptive cross-sectional study used 2016 Medicaid claims data from the Transformed Medicaid Statistical Information System and from 2016-2017 American Board of Family Medicine certification questionnaire responses to examine the diversity and Medicaid participation of FPs. We explored the diversity of FP Medicaid patient panels and whether they saw ≥150 beneficiaries in 2016. Using logistic regression models, we controlled for FP demographics, practice characteristics, and characteristics of the communities in which they practiced.

RESULTS

Of 13,096 FPs, Latine, Hispanic, or of Spanish Origin (LHS) FPs and non-LHS Black FPs saw more Medicaid beneficiaries compared with non-LHS White and non-LHS Asian FPs. The patient panels of URiM FPs had a much greater proportion of Medicaid beneficiaries from racial and ethnic minority groups. Overall, non-LHS Black and LHS FPs had greater odds of seeing ≥150 Medicaid beneficiaries in 2016.

CONCLUSIONS

These findings clearly show the critical role URiM FPs play in caring for Medicaid beneficiaries, suggesting physician race and ethnicity are correlated with Medicaid participation. Diversity in the health care workforce is essential for addressing racial health inequities. Policies need to address problems in pathways to medical education, including failures to recruit, nurture, and retain URiM students.




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Family Medicine Presence on Labor and Delivery: Effect on Safety Culture and Cesarean Delivery [Original Research]

PURPOSE

Currently, 40% of counties in the United States do not have an obstetrician or midwife, and in rural areas the likelihood of childbirth being attended to by a family medicine (FM) physician is increasing. We sought to characterize the effect of the FM presence on unit culture and a key perinatal quality metric in Iowa hospital intrapartum units.

METHODS

Using a cross-sectional design, we surveyed Iowa physicians, nurses, and midwives delivering intrapartum care at hospitals participating in a quality improvement initiative to decrease the incidence of cesarean delivery. We linked respondents with their hospital characteristics and outcomes data. The primary outcome was the association between FM physician, obstetrician (OB), or both disciplines’ presence on labor and delivery and hospital low-risk, primary cesarean delivery rate. Unit culture was compared by hospital type (FM-only, OB-only, or Both).

RESULTS

A total of 849 clinicians from 39 hospitals completed the survey; 13 FM-only, 11 OB-only, and 15 hospitals with both. FM-only hospitals were all rural, with <1,000 annual births. Among hospitals with <1,000 annual births, births at FM-only hospitals had an adjusted 34.3% lower risk of cesarean delivery (adjusted incident rate ratio = 0.66; 95% CI, 0.52-.0.98) compared with hospitals with both. Nurses endorsed unit norms more supportive of vaginal birth and stronger safety culture at FM-only hospitals (P <.05).

CONCLUSIONS

Birthing hospitals staffed exclusively by FM physicians were more likely to have lower cesarean rates and stronger nursing-rated safety culture. Both access and quality of care provide strong arguments for reinforcing the pipeline of FM physicians training in intrapartum care.




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Challenges in Receiving Care for Long COVID: A Qualitative Interview Study Among Primary Care Patients About Expectations and Experiences [Original Research]

BACKGROUND

For many patients with post–COVID-19 condition (long COVID), primary care is the first point of interaction with the health care system. In principle, primary care is well situated to manage long COVID. Beyond expressions of disempowerment, however, the patient’s perspective regarding the quality of long COVID care is lacking. Therefore, this study aimed to analyze the expectations and experiences of primary care patients seeking treatment for long COVID.

METHODS

A phenomenological approach guided this analysis. Using purposive sampling, we conducted semistructured interviews with English-speaking, adult primary care patients describing symptoms of long COVID. We deidentified and transcribed the recorded interviews. Transcripts were analyzed using inductive qualitative content analysis.

RESULTS

This article reports results from 19 interviews (53% female, mean age = 54 years). Patients expected their primary care practitioners (PCPs) to be knowledgeable about long COVID, attentive to their individual condition, and to engage in collaborative processes for treatment. Patients described 2 areas of experiences. First, interactions with clinicians were perceived as positive when clinicians were honest and validating, and negative when patients felt dismissed or discouraged. Second, patients described challenges navigating the fragmented US health care system when coordinating care, treatment and testing, and payment.

CONCLUSION

Primary care patients’ experiences seeking care for long COVID are incongruent with their expectations. Patients must overcome barriers at each level of the health care system and are frustrated by the constant challenges. PCPs and other health care professionals might increase congruence with expectations and experiences through listening, validating, and advocating for patients with long COVID.

Annals Early Access article




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New research to better understand the biological factors of suicidal behaviour

New research to better understand the biological factors of suicidal behaviour Researchers at the University of Glasgow are embarking on two new PhD projects to better understand the impact that biological factors may have on suicidal behaviour.




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MH370 search ends in two weeks

The hunt for missing flight MH370 will end in two weeks, Malaysia’s transport minister said yesterday.




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Search for alien transmissions in promising star system draws a blank

Astronomers listened for radio signals emanating from planets in the TRAPPIST-1 system, but found no evidence of any interplanetary communications




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NASA set to launch Europa probe to search for signs of habitability

A 6000-kilogram spacecraft will embark on a six-year journey to Jupiter to explore whether its icy moon Europa has the conditions to support life




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Boston Dynamics and Toyota Research Team Up on Robots



Today, Boston Dynamics and the Toyota Research Institute (TRI) announced a new partnership “to accelerate the development of general-purpose humanoid robots utilizing TRI’s Large Behavior Models and Boston Dynamics’ Atlas robot.” Committing to working towards a general purpose robot may make this partnership sound like a every other commercial humanoid company right now, but that’s not at all that’s going on here: BD and TRI are talking about fundamental robotics research, focusing on hard problems, and (most importantly) sharing the results.

The broader context here is that Boston Dynamics has an exceptionally capable humanoid platform capable of advanced and occasionally painful-looking whole-body motion behaviors along with some relatively basic and brute force-y manipulation. Meanwhile, TRI has been working for quite a while on developing AI-based learning techniques to tackle a variety of complicated manipulation challenges. TRI is working toward what they’re calling large behavior models (LBMs), which you can think of as analogous to large language models (LLMs), except for robots doing useful stuff in the physical world. The appeal of this partnership is pretty clear: Boston Dynamics gets new useful capabilities for Atlas, while TRI gets Atlas to explore new useful capabilities on.

Here’s a bit more from the press release:

The project is designed to leverage the strengths and expertise of each partner equally. The physical capabilities of the new electric Atlas robot, coupled with the ability to programmatically command and teleoperate a broad range of whole-body bimanual manipulation behaviors, will allow research teams to deploy the robot across a range of tasks and collect data on its performance. This data will, in turn, be used to support the training of advanced LBMs, utilizing rigorous hardware and simulation evaluation to demonstrate that large, pre-trained models can enable the rapid acquisition of new robust, dexterous, whole-body skills.

The joint team will also conduct research to answer fundamental training questions for humanoid robots, the ability of research models to leverage whole-body sensing, and understanding human-robot interaction and safety/assurance cases to support these new capabilities.

For more details, we spoke with Scott Kuindersma (Senior Director of Robotics Research at Boston Dynamics) and Russ Tedrake (VP of Robotics Research at TRI).

How did this partnership happen?

Russ Tedrake: We have a ton of respect for the Boston Dynamics team and what they’ve done, not only in terms of the hardware, but also the controller on Atlas. They’ve been growing their machine learning effort as we’ve been working more and more on the machine learning side. On TRI’s side, we’re seeing the limits of what you can do in tabletop manipulation, and we want to explore beyond that.

Scott Kuindersma: The combination skills and tools that TRI brings the table with the existing platform capabilities we have at Boston Dynamics, in addition to the machine learning teams we’ve been building up for the last couple years, put us in a really great position to hit the ground running together and do some pretty amazing stuff with Atlas.

What will your approach be to communicating your work, especially in the context of all the craziness around humanoids right now?

Tedrake: There’s a ton of pressure right now to do something new and incredible every six months or so. In some ways, it’s healthy for the field to have that much energy and enthusiasm and ambition. But I also think that there are people in the field that are coming around to appreciate the slightly longer and deeper view of understanding what works and what doesn’t, so we do have to balance that.

The other thing that I’d say is that there’s so much hype out there. I am incredibly excited about the promise of all this new capability; I just want to make sure that as we’re pushing the science forward, we’re being also honest and transparent about how well it’s working.

Kuindersma: It’s not lost on either of our organizations that this is maybe one of the most exciting points in the history of robotics, but there’s still a tremendous amount of work to do.

What are some of the challenges that your partnership will be uniquely capable of solving?

Kuindersma: One of the things that we’re both really excited about is the scope of behaviors that are possible with humanoids—a humanoid robot is much more than a pair of grippers on a mobile base. I think the opportunity to explore the full behavioral capability space of humanoids is probably something that we’re uniquely positioned to do right now because of the historical work that we’ve done at Boston Dynamics. Atlas is a very physically capable robot—the most capable humanoid we’ve ever built. And the platform software that we have allows for things like data collection for whole body manipulation to be about as easy as it is anywhere in the world.

Tedrake: In my mind, we really have opened up a brand new science—there’s a new set of basic questions that need answering. Robotics has come into this era of big science where it takes a big team and a big budget and strong collaborators to basically build the massive data sets and train the models to be in a position to ask these fundamental questions.

Fundamental questions like what?

Tedrake: Nobody has the beginnings of an idea of what the right training mixture is for humanoids. Like, we want to do pre-training with language, that’s way better, but how early do we introduce vision? How early do we introduce actions? Nobody knows. What’s the right curriculum of tasks? Do we want some easy tasks where we get greater than zero performance right out of the box? Probably. Do we also want some really complicated tasks? Probably. We want to be just in the home? Just in the factory? What’s the right mixture? Do we want backflips? I don’t know. We have to figure it out.

There are more questions too, like whether we have enough data on the Internet to train robots, and how we could mix and transfer capabilities from Internet data sets into robotics. Is robot data fundamentally different than other data? Should we expect the same scaling laws? Should we expect the same long-term capabilities?

The other big one that you’ll hear the experts talk about is evaluation, which is a major bottleneck. If you look at some of these papers that show incredible results, the statistical strength of their results section is very weak and consequently we’re making a lot of claims about things that we don’t really have a lot of basis for. It will take a lot of engineering work to carefully build up empirical strength in our results. I think evaluation doesn’t get enough attention.

What has changed in robotics research in the last year or so that you think has enabled the kind of progress that you’re hoping to achieve?

Kuindersma: From my perspective, there are two high-level things that have changed how I’ve thought about work in this space. One is the convergence of the field around repeatable processes for training manipulation skills through demonstrations. The pioneering work of diffusion policy (which TRI was a big part of) is a really powerful thing—it takes the process of generating manipulation skills that previously were basically unfathomable, and turned it into something where you just collect a bunch of data, you train it on an architecture that’s more or less stable at this point, and you get a result.

The second thing is everything that’s happened in robotics-adjacent areas of AI showing that data scale and diversity are really the keys to generalizable behavior. We expect that to also be true for robotics. And so taking these two things together, it makes the path really clear, but I still think there are a ton of open research challenges and questions that we need to answer.

Do you think that simulation is an effective way of scaling data for robotics?

Tedrake: I think generally people underestimate simulation. The work we’ve been doing has made me very optimistic about the capabilities of simulation as long as you use it wisely. Focusing on a specific robot doing a specific task is asking the wrong question; you need to get the distribution of tasks and performance in simulation to be predictive of the distribution of tasks and performance in the real world. There are some things that are still hard to simulate well, but even when it comes to frictional contact and stuff like that, I think we’re getting pretty good at this point.

Is there a commercial future for this partnership that you’re able to talk about?

Kuindersma: For Boston Dynamics, clearly we think there’s long-term commercial value in this work, and that’s one of the main reasons why we want to invest in it. But the purpose of this collaboration is really about fundamental research—making sure that we do the work, advance the science, and do it in a rigorous enough way so that we actually understand and trust the results and we can communicate that out to the world. So yes, we see tremendous value in this commercially. Yes, we are commercializing Atlas, but this project is really about fundamental research.

What happens next?

Tedrake: There are questions at the intersection of things that BD has done and things that TRI has done that we need to do together to start, and that’ll get things going. And then we have big ambitions—getting a generalist capability that we’re calling LBM (large behavior models) running on Atlas is the goal. In the first year we’re trying to focus on these fundamental questions, push boundaries, and write and publish papers.

I want people to be excited about watching for our results, and I want people to trust our results when they see them. For me, that’s the most important message for the robotics community: Through this partnership we’re trying to take a longer view that balances our extreme optimism with being critical in our approach.




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Do Newfoundland's Tablelands hold the answer to life on Mars? This researcher is trying to find out

The Tablelands in Gros Morne National Park, a UNESCO World Heritage Site, is one of the most unique landscapes in the world — and its orange peridotite rocks could hold the secret to finding life on Mars.



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How a researcher hacked ChatGPT's memory to expose a major security flaw

OpenAI recently introduced a new memory feature for ChatGPT that enables it to remember information about people, including age, gender and beliefs.



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Canadian police need a search warrant to get your IP address: Supreme Court

How private is your internet address? Very, says the Supreme Court of Canada. Police can’t just walk into a company and demand a suspect’s IP address by saying a Canadian resident doesn’t have an expectation of privacy of that information, the court ruled today. An IP address is vital enough that every resident expects it […]

The post Canadian police need a search warrant to get your IP address: Supreme Court first appeared on ITBusiness.ca.




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Hashtag Trending Mar.4- Canadian police need a search warrant to access IP address; Musk sues OpenAI; World Server Throwing Competition too violent?

In Canada, your IP address has the right to remain silent. Elon Musk is suing OpenAI for not being Open. Apple faces a class action not allowing competitive access to backup services and the World Server Throwing Competition in March 2024 is accused of being too violent towards servers.   All this and more on the […]

The post Hashtag Trending Mar.4- Canadian police need a search warrant to access IP address; Musk sues OpenAI; World Server Throwing Competition too violent? first appeared on ITBusiness.ca.




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NASA spacecraft to scour Jupiter's icy moon in search of life-supporting conditions

A massive NASA spacecraft is ready to set sail for Jupiter and its moon Europa. The craft, named Europa Clipper, will determine if conditions there could support life.



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Body found in search for missing mum Jane Burton as police launch investigation



Greater Manchester Police launched a public appeal to help find Jane Burton on Tuesday morning but have paused the search after a body was found




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Planetary Researchers Examine Tidal Effects on Interiors of Planets and Their Moons

A team of scientists from the Lunar and Planetary Laboratory at the University of Arizona, TU Delft, and Caltech has developed a new method to compute how tides affect the interiors of planets and moons in the Solar System.

The post Planetary Researchers Examine Tidal Effects on Interiors of Planets and Their Moons appeared first on Sci.News: Breaking Science News.




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New Research Questions Standard Theory of How Galaxies Formed in Early Universe

The standard model predicted that the NASA/ESA/CSA James Webb Space Telescope would see dim signals from small, primitive galaxies.

The post New Research Questions Standard Theory of How Galaxies Formed in Early Universe appeared first on Sci.News: Breaking Science News.




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Dazzling images illuminate research on cardiovascular disease

The British Heart Foundation’s Reflections of Research competition showcases beautiful images captured by researchers studying heart and circulatory disease




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NASA Launches Europa Clipper to Search for Signs of Life on Jupiter’s Moon

The huge spacecraft is headed toward the icy moon Europa, where it will use an array of instruments to survey for geologic activity, magnetism and more




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After Decades of Searching, Are Physicists Closing In on Dark Matter?

With no conclusive laboratory results, researchers are turning to other methods to find the elusive substance