A blockchain-based framework to support pharmacogenetic data sharing.

The successful implementation of pharmacogenetics (PGx) into clinical practice requires patient genomic data to be shared between stakeholders in multiple settings. This creates a number of barriers to widespread adoption of PGx, including privacy concerns related to the storage and movement of identifiable genomic data. Informatic solutions that support secure and equitable data access for genomic data are therefore important to PGx. Here we propose a methodology that uses smart contracts implemented on a blockchain-based framework, PGxChain, to address this issue. The design requirements for PGxChain were identified through a systematic literature review, identifying technical challenges and barriers impeding the clinical implementation of pharmacogenomics. These requirements included security and privacy, accessibility, interoperability, traceability and legal compliance. A proof-of-concept implementation based on Ethereum was then developed that met the design requirements. PGxChain's performance was examined using Hyperledger Caliper for latency, throughput, and transaction success rate. The findings clearly indicate that blockchain technology offers considerable potential to advance pharmacogenetic data sharing, particularly with regard to PGx data security and privacy, large-scale accessibility of PGx data, PGx data interoperability between multiple health care providers and compliance with data-sharing laws and regulations.

Fifty-year history of the evolution of spinal metastatic disease management.

Spine metastases are a significant source of morbidity in oncology. Treatment of these spine metastases largely remains palliative, but advances over the past 50 years have improved the effectiveness of interventions for preserving functional status and obtaining local control while minimizing morbidity. While the field began with conventional external beam radiation as the primary treatment modality, a series of paradigm shifts and technological advances in the 2000s led to a change in treatment patterns. These advances allowed for an increased role of surgical decompression of neural elements, a shift in the stereotactic capabilities of radiation oncologists, and an improved understanding of the radiobiology of metastatic disease. The result was improved local control while minimizing treatment morbidity. These advances fit within the larger framework of metastatic spine tumor management known as the Neurologic, Oncologic, Mechanical, and Systemic disease decision framework. This dynamic framework takes into account the neurological function of the patient, the radiobiology of their tumor, their degree of mechanical instability, and their systemic disease control and treatment options to help determine appropriate interventions based on the individual patient. Herein, we describe the 50-year evolution of metastatic spine tumor management and the impact of various advances on the field.

The transformation of a gold standard in-person substance use assessment to a web-based, REDCap integrated data capture tool.

The adoption of computer systems for gathering, managing, and analyzing health data is resulting in the replacement of pen-and-paper methods for collecting data and managing health records by computerized methods. One classic "pen-and-paper" assessment in health and substance use research is the Timeline Follow-Back (TLFB), the gold standard in self-reported substance use developed in 1996 by Sobell et al. to assess alcohol consumption patterns and later other substances such as marijuana or tobacco over discreet timeframes [1-7]. The TLFB has been modified by some research groups for use as a web-based assessment [8-10], but not without significant limitations. As such, this paper describes the team-oriented, interdisciplinary process by which a new online TLFB (O-TLFB) was conceptualized, the technical details of development towards a dynamic data capture tool fully integrated with REDCap via application programming interface (API), and the potential for this optimized O-TLFB to be leveraged broadly across the domains of substance use, health, and behavioral research.

Genetics of mitochondrial dysfunction and infertility.

Increasingly, mitochondria are being recognized as having an important role in fertility. Indeed in assisted reproductive technologies mitochondrial function is a key indicator of sperm and oocyte quality. Here, we review the literature regarding mitochondrial genetics and infertility. In many multisystem disorders caused by mitochondrial dysfunction death occurs prior to sexual maturity, or the clinical features are so severe that infertility may be underreported. Interestingly, many of the genes linked to mitochondrial dysfunction and infertility have roles in the maintenance of mitochondrial DNA or in mitochondrial translation. Studies on populations with genetically uncharacterized infertility have highlighted an association with mitochondrial DNA deletions, whether this is causative or indicative of poor functioning mitochondria requires further examination. Studies on the impact of mitochondrial DNA variants present conflicting data but highlight POLG as a particularly interesting candidate gene for both male and female infertility.

Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome.

Perrault syndrome (PS) is a genetically heterogeneous disorder characterized by primary ovarian insufficiency (POI) in females and sensorineural hearing loss in males and females. In many PS subjects, causative variants have not been found in the five reported PS genes. The objective of this study was to identify the genetic cause of PS in an extended consanguineous family with six deaf individuals. Whole exome sequencing (WES) was completed on four affected members of a large family, and variants and co-segregation was confirmed by Sanger sequencing. All hearing impaired individuals, including the proband, are homozygous for a pathogenic variant of CLDN14, but this only explains the deafness. The PS proband is also homozygous for a frameshift variant (c.1453_1454delGA, p.(Glu485Lysfs*5)) in exon 7 of SGO2 encoding shugoshin 2, which is the likely cause of her concurrent ovarian insufficiency. In mouse, Sgol2a encoding shugoshin-like 2a is necessary during meiosis in both sexes to maintain the integrity of the cohesin complex that tethers sister chromatids. Human SGO2 has not previously been implicated in any disorder, but in this case of POI and perhaps others, it is a candidate for unexplained infertility.

Expanding the genotypic spectrum of Perrault syndrome.

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome.

DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation.

Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.(Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 (DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development.

Detection of nitroaromatics in the solid, solution, and vapor phases using silicon quantum dot sensors.

Silicon quantum dots (Si-QDs) represent a well-known QD fluorophore that can emit throughout the visible spectrum depending on the interface structure and surface functional group. Detection of nitroaromatic compounds by monitoring the luminescence response of the sensor material (typically fluorescent polymers) currently forms the basis of new explosives sensing technologies. Freestanding silicon QDs may represent a benign alternative with a high degree of chemical and physical versatility. Here, we investigate dodecyl and amine-terminated Si-QD luminescence response to the presence of nitrobenzene and dinitrotoluene (DNT) in various solid, solution, and vapor forms. For dinitrotoluene vapor the 3σ detection limit was 6 ppb for monomer-terminated QDs. For nitroaromatics dissolved in toluene the detection limit was on the order of 400 nM, corresponding to ∼100 pg of material distributed over ∼1 cm(2) on the sensor surface. Solid traces of nitroaromatics were also easily detectable via a simple 'touch test'. The samples showed minimal interference effects from common contaminants such as water, ethanol, and acetonitrile. The sensor can be as simple and inexpensive as a small circle of filter paper dipped into a QD solution, with a single vial of QDs able to make hundreds of these sensors. Additionally, a trial fiber-optic sensor device was tested by applying the QDs to one end of a 2 × 2 fiber coupler and exposing them to controlled DNT vapor. Finally, the quenching mechanism was explored via luminescence dynamics measurements and is different for blue (amine) and red (dodecyl) fluorescent silicon QDs.

The BRCA2 polymorphic stop codon: stuff or nonsense?

BACKGROUND: Despite classification of the BRCA2c.9976A>T, p.(Lys3326Ter) variant as a polymorphism, it has been associated with increased risks of pancreatic, lung, oesophageal and breast cancer. METHODS: We have noticed multiple co-occurrences of the BRCA2 c.9976A>T variant with the pathogenic BRCA2c.6275_6276delTT frameshift mutation p.(Leu2092ProfsTer7) and using a cohort study have assessed if this might account for these tumour risk associations. RESULTS: We identified 52 families with BRCA2c.6275_6276delTT, all of which occur in cis with the BRCA2c.9976A>T variant allele as demonstrated by co-segregation in all family members tested. Of 3245 breast/ovarian cancer samples sequenced for BRCA2, only 43/3245 (1.3%) carried BRCA2 c.9976A>T alone, after excluding individuals with BRCA2c.6275_6276delTT (n=22) or other BRCA1 (n=3) or BRCA2 (n=2) pathogenic mutations. The resultant frequency (1.3%) after removal of co-occurring mutations is lower than the 1.7% and 1.67% frequencies from two control populations for BRCA2 c.9976A>T, but similar to the 1.39% seen in the Exome Aggregation Consortium database. We did not identify increased frequencies of oesophageal, pancreatic or lung cancer in families with just BRCA2 c.9976A>T using person-years at risk analysis. CONCLUSIONS: It is likely that the previous associations of increased cancer risks due to BRCA2c.9976A>T represent reporting bias and are contributed to because the variant is in LD with BRCA2c.6275_6276delTT.

Compliance With Federal Price Transparency Rules and Cost Estimation at United States Hospitals With Neurosurgical Training Programs.

BACKGROUND AND OBJECTIVES: The Centers for Medicare & Medicaid Services implemented federal requirements on January 1, 2021, under the Public Health Service Act that require hospitals to provide a list of payer-negotiated prices or "standard charges" in a machine-readable file and in a patient-friendly online estimator for standard services. We sought to assess compliance by United States hospitals associated with neurosurgical training programs with these federal requirements for 11 common neurosurgical procedures. METHODS: We performed a cross-sectional analysis in March 2023 of 116 United States hospitals associated with a neurosurgical training program to assess compliance with the new federal requirements to have a machine-readable, downloadable file with standard charges and a patient-friendly online estimator for two spinal procedures. RESULTS: A total of 110/114 (96.5%) hospitals were compliant with the requirement for a machine-readable file with payer-negotiated prices. A total of 47/110 hospitals (42.7%) were compliant with downloadable machine-readable files and reported at least one payer-negotiated price for 1 of the 11 common neurosurgical procedures. A total of 45/110 (40.9%) used bundled Diagnosis-Related Group codes, and 18/110 (16.4%) did not contain any price information for neurosurgical procedures. For neurosurgical procedures, the percent difference between the average negotiated private insurance and Medicare price per procedure ranged from 17.5% to 77.6%. Medicare and private insurance data for each procedure were available on average for 10.3 states (SD = 3.8) and 15.6 states (SD = 4.8), respectively. CONCLUSION: While hospital compliance with federal requirements for machine-readable files with payer-negotiated prices was high, availability of payer-negotiated prices for 4 major insurance types across 11 common neurosurgical procedures based on Current Procedural Terminology codes was sparce. Consequently, meaningful conclusions on procedure-related charges for elective procedures are difficult for patients to make because of the unintelligible format of data and a lack of reporting of charges per Current Procedural Terminology code in a comprehensive manner.

Streamlining the Journey of Research Into Clinical Practice: Making Your Patients and Practice Flourish Understanding and Setting Treatment Expectations for Patients With Metastatic Spine Tumors.

STUDY DESIGN: Literature review with clinical recommendation. OBJECTIVE: A concise curation of the latest spine literature exploring the relationship between expectations and satisfaction for patients with metastatic spinal disease (MSD). Deliver recommendations to practicing clinicians regarding interpretation and utilisation of this evidence. METHODS: The latest spine literature in the topic of factors affecting the expectations of patients with MSD was reviewed and clinical recommendations were formulated. Recommendations are graded as strong or Conditional. RESULTS: 5 articles were selected. Article 1: risk factors for the development of dissatisfaction from a cohort of 362 MSD patients. Strong recommendation to incorporate risk factor assessment when considering treatment. Article 2: systematic review assessing the relationship between pre-operative patient expectations and subsequent satisfaction in allied disciplines. Conditional recommendation to optimize patient expectation to positively modify patient satisfaction. Article 3: qualitative study of how clinicians, from different specialties, counsel patients with MSD pre-treatment. Strong recommendation to use a multidisciplinary approach. Article 4 qualitative study of how MSD patients experience their pre-treatment counselling and how that affected their appreciation of treatment success. Conditional recommendation to furnish patients with tailored, expected outcomes in the context of systemic progression. Article 5 Design and validation of a pre-treatment questionnaire specific to MSD. A conditional recommendation to incorporate this questionnaire in clinical and research MSD practice. CONCLUSION: Patients with MSD are approaching end of life care and high levels of treatment satisfaction are crucial at this juncture. The role of expectation management and comprehensive counselling is critical.

Is multiple SNP testing in BRCA2 and BRCA1 female carriers ready for use in clinical practice? Results from a large Genetic Centre in the UK.

BRCA1 and BRCA2 are major breast cancer susceptibility genes. Nineteen single nucleotide polymorphisms (SNPs) at 18 loci have been associated with breast cancer. We aimed to determine whether these predict breast cancer incidence in women with BRCA1/BRCA2 mutations. BRCA1/2 mutation carriers identified through the Manchester genetics centre between 1996 and 2011 were included. Using published odds ratios (OR) and risk allele frequencies, we calculated an overall breast cancer risk SNP score (OBRS) for each woman. The relationship between OBRS and age at breast cancer onset was investigated using the Cox proportional hazards model, and predictive ability assessed using Harrell's C concordance statistic. In BRCA1 mutation carriers we found no association between OBRS and age at breast cancer onset: OR for the lowest risk quintile compared to the highest was 1.20 (95% CI 0.82-1.75, Harrell's C = 0.54), but in BRCA2 mutation carriers the association was significant (OR for the lowest risk quintile relative to the highest was 0.47 (95% CI 0.33-0.69, Harrell's C = 0.59). The 18 validated breast cancer SNPs differentiate breast cancer risks between women with BRCA2 mutations, but not BRCA1. It may now be appropriate to use these SNPs to help women with BRCA2 mutations make maximally informed decisions about management options.

The NOMS approach to metastatic tumors: Integrating new technologies to improve outcomes. / El enfoque de NOMS para los tumores metastásicos: integración de nuevas tecnologías para mejorar los resultados.

Treatment paradigms for patients with spine metastases have evolved significantly over the past two decades. The most transformative change to these paradigms has been the integration of spinal stereotactic radiosurgery (sSRS). sSRS allows for the delivery of tumoricidal radiation doses with sparing of nearby organs at risk, particularly the spinal cord. Evidence supports the safety and efficacy of radiosurgery as it currently offers durable local tumor control with low complication rates even for tumors previously considered radioresistant to conventional external beam radiation therapy. The role for surgical intervention remains consistent, but a trend has been observed toward less aggressive, often minimally invasive techniques. Using modern technologies and improved instrumentation, surgical outcomes continue to improve with reduced morbidity. Additionally, targeted agents such as biologics and checkpoint inhibitors have revolutionized cancer care by improving both local control and patient survival. These advances have brought forth a need for new prognostication tools and a more critical review of long-term outcomes. The complex nature of current treatment schemes necessitates a multidisciplinary approach including surgeons, medical oncologists, radiation oncologists, interventionalists and pain specialists. This review recapitulates the current state-of-the-art, evidence-based data on the treatment of spinal metastases and integrates these data into a decision framework, NOMS, which is based on four sentinel pillars of decision making in metastatic spine tumors: neurological status, Oocologic tumor behavior, mechanical stability and systemic disease burden and medical co-morbidities.

The NOMS approach to metastatic tumors: Integrating new technologies to improve outcomes.

Treatment paradigms for patients with spine metastases have evolved significantly over the past two decades. The most transformative change to these paradigms has been the integration of spinal stereotactic radiosurgery (sSRS). sSRS allows for the delivery of tumoricidal radiation doses with sparing of nearby organs at risk, particularly the spinal cord. Evidence supports the safety and efficacy of radiosurgery as it currently offers durable local tumor control with low complication rates even for tumors previously considered radioresistant to conventional external beam radiation therapy. The role for surgical intervention remains consistent, but a trend has been observed toward less aggressive, often minimally invasive techniques. Using modern technologies and improved instrumentation, surgical outcomes continue to improve with reduced morbidity. Additionally, targeted agents such as biologics and checkpoint inhibitors have revolutionized cancer care by improving both local control and patient survival. These advances have brought forth a need for new prognostication tools and a more critical review of long-term outcomes. The complex nature of current treatment schemes necessitates a multidisciplinary approach including surgeons, medical oncologists, radiation oncologists, interventionalists and pain specialists. This review recapitulates the current state-of-the-art, evidence-based data on the treatment of spinal metastases and integrates these data into a decision framework, NOMS, which is based on four sentinel pillars of decision making in metastatic spine tumors: Neurological status, Oncologic tumor behavior, Mechanical stability, and Systemic disease burden and medical co-morbidities.

Prevention of breast cancer in the context of a national breast screening programme.

Breast cancer is not only increasing in the west but also particularly rapidly in eastern countries where traditionally the incidence has been low. The rise in incidence is mainly related to changes in reproductive patterns and lifestyle. These trends could potentially be reversed by defining women at greatest risk and offering appropriate preventive measures. A model for this approach was the establishment of Family History Clinics (FHCs), which have resulted in improved survival in younger women at high risk. New predictive models of risk that include reproductive and lifestyle factors, mammographic density and measurement of risk-associated single nucleotide polymorphisms (SNPs) may give more precise information concerning risk and enable better targeting for mammographic screening programmes and of preventive measures. Endocrine prevention using anti-oestrogens and aromatase inhibitors is effective, and observational studies suggest lifestyle modification may also be effective. However, referral to FHCs is opportunistic and predominantly includes younger women. A better approach for identifying older women at risk may be to use national breast screening programmes. Here were described pilot studies to assess whether the routine assessment of breast cancer risk is feasible within a population-based screening programme, whether the feedback and advice on risk-reducing interventions would be welcomed and taken up, and to consider whether the screening interval should be modified according to breast cancer risk.

Review of biomarkers in colorectal cancer.

AIM: Advances in molecular technology have resulted in the discovery of many putative biomarkers relevant to colorectal cancer (CRC). METHOD: Literature searches were performed on PubMed and EMBASE using the words 'colorectal cancer', AND 'biomarkers OR markers'. Biomarkers that are either currently in clinical use or have potential clinical use were identified. RESULTS: Most potential markers are in the discovery phase waiting to undergo clinical validation. Hypermethylation of the plasma septin-9 gene shows promise as a nonstool-based screening tool. Hypermethylation of the DYPD gene (encodes the enzyme dihydropyrimidine dehydrogenase) and variation of the uridine diphosphate-glucuronosyltransferase 1A (UGT1A1) gene have predictive value for side effects and the efficacy of 5-fluoruracil and irinotecan, respectively. Mismatch repair protein immunohistochemistry is able to predict response to 5-fluorouracil, and the KRAS (Kirsten rat sarcoma viral oncogene) and B-RAF (v-RAF murine sarcoma viral oncogene homolog B1) somatic gene mutation status can predict the response to anti-epidermal growth factor receptor therapy. CONCLUSION: Recent advances indicate that the widespread use of biomarkers may herald the next major advance in the diagnosis and management of CRC.

SMARCB1 mutations are not a common cause of multiple meningiomas.

BACKGROUND: Schwannomas and meningiomas are both part of the tumour spectrum of neurofibromatosis type 2 (NF2) and are associated with somatic loss of chromosome 22. They are also found commonly within the general population, unrelated to NF2. Germline SMARCB1 mutations have recently been identified as a pathogenic cause of a subset of familial schwannomatosis cases, and SMARCB1 is a candidate gene for causation of both schwannomas and meningiomas. Recently, Bacci et al reported a germline SMARCB1 mutation associated with familial schwannomatosis and multiple meningiomas. They concluded that SMARCB1 mutations can predispose to multiple meningiomas. METHODS: We screened the SMARCB1 gene in a panel of 47 patients with multiple meningioma unrelated to NF2. RESULTS: We found no germline mutations. CONCLUSION: We conclude that while meningiomas may be associated with the schwannomatosis phenotype, SMARCB1 is not a major contributor to multiple meningioma disease.