J Patient Rep Outcomes. 2023 Nov 9;7(1):112. doi: 10.1186/s41687-023-00650-3.

ABSTRACT

BACKGROUND: Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220).

METHODS: All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test-retest reliability; and validity by convergent and known-groups analyses.

RESULTS: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0-10 numeric scale, which were subsequently recoded to a 0-4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test-retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30-0.73 and 0.50-0.82, respectively).

CONCLUSIONS: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www.

CLINICALTRIALS: gov/ct2/show/NCT03548220 .

PMID:37943362 | DOI:10.1186/s41687-023-00650-3

Blood Coagul Fibrinolysis. 2023 Dec 1;34(8):545-548. doi: 10.1097/MBC.0000000000001249. Epub 2023 Oct 20.

ABSTRACT

Glanzmann's Thrombasthenia (GT) is a rare hemorrhagic condition caused by a platelet surface receptor disorder of the glycoprotein (GP) IIb/IIIa. Symptoms of GT are various forms of hemorrhages, such as purpura, epistaxis and menorrhagia. Gastrointestinal bleeding (GIB) is a rare expression of the condition and may occur due to traumas in the GI tract or as a consequence of gastrointestinal angiodysplasia (GIADs). In this case report, we present a middle-aged woman with recurrent GIB consequent to GIADs with persistent melena and iron deficiency anemia. After several unsuccessful therapeutic interventions, the patient was studied by the hereditary hemorrhagic telangiectasia's (HHT - Osler-Weber-Rendu disease) unit, where she received bevacizumab, showing a complete improvement in symptoms as well as a reduction in her GIADs. This case shows that bevacizumab could be a possible line of treatment for patients with coagulation disorders with GIADs.

PMID:37942747 | DOI:10.1097/MBC.0000000000001249

BMC Oral Health. 2023 Nov 8;23(1):843. doi: 10.1186/s12903-023-03586-8.

ABSTRACT

BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity.

CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated.

CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

PMID:37940896 | PMC:PMC10633900 | DOI:10.1186/s12903-023-03586-8

Mol Psychiatry. 2023 Nov 8. doi: 10.1038/s41380-023-02313-7. Online ahead of print.

ABSTRACT

Neurodevelopmental changes and impaired stress resistance have been implicated in the pathogenesis of bipolar disorder (BD), but the underlying regulatory mechanisms are unresolved. Here we describe a human cerebral organoid model of BD that exhibits altered neural development, elevated neural network activity, and a major shift in the transcriptome. These phenotypic changes were reproduced in cerebral organoids generated from iPS cell lines derived in different laboratories. The BD cerebral organoid transcriptome showed highly significant enrichment for gene targets of the transcriptional repressor REST. This was associated with reduced nuclear REST and REST binding to target gene recognition sites. Reducing the oxygen concentration in organoid cultures to a physiological range ameliorated the developmental phenotype and restored REST expression. These effects were mimicked by treatment with lithium. Reduced nuclear REST and derepression of REST targets genes were also observed in the prefrontal cortex of BD patients. Thus, an impaired cellular stress response in BD cerebral organoids leads to altered neural development and transcriptional dysregulation associated with downregulation of REST. These findings provide a new model and conceptual framework for exploring the molecular basis of BD.

PMID:37938767 | DOI:10.1038/s41380-023-02313-7

J Med Genet. 2023 Nov 7:jmg-2023-109473. doi: 10.1136/jmg-2023-109473. Online ahead of print.

ABSTRACT

BACKGROUND: Titinopathies are caused by mutations in the titin gene (TTN). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very complex neuromuscular pathologies due to the variable age of onset of symptoms, the great diversity of pathological and muscular impairment patterns (cardiac, skeletal muscle or mixed) and both autosomal dominant and recessive modes of transmission. Until now, only few CNVs in TTN have been reported without clear genotype-phenotype associations.

METHODS: Our study includes eight families with dominant titinopathies. We performed next-generation sequencing or comparative genomic hybridisation array analyses and found CNVs in the TTN gene. We characterised these CNVs by RNA sequencing (RNAseq) analyses in six patients' muscles and performed genotype-phenotype inheritance association study by combining the clinical and biological data of these eight families.

RESULTS: Seven deletion-type CNVs in the TTN gene were identified among these families. Genotype and RNAseq results showed that five deletions do not alter the reading frame and one is out-of-reading frame. The main phenotype identified was distal myopathy associated with contractures. The analysis of morphological, clinical and genetic data and imaging let us draw new genotype-phenotype associations of titinopathies.

CONCLUSION: Identifying TTN CNVs will further increase diagnostic sensitivity in these complex neuromuscular pathologies. Our cohort of patients enabled us to identify new deletion-type CNVs in the TTN gene, with unexpected autosomal dominant transmission. This is valuable in establishing new genotype-phenotype associations of titinopathies, mainly distal myopathy in most of the patients.

PMID:37935568 | DOI:10.1136/jmg-2023-109473

Soins. 2023 Nov;68(880):30-32. doi: 10.1016/j.soin.2023.09.008. Epub 2023 Oct 20.

ABSTRACT

The transition from pediatrics to adult wards concerns all chronic diseases with a pediatric onset, but there are a number of specific features in the case of severe forms of hereditary epidermolysis bullosa: worsening wound surface and chronicity with age, appearance or increase in certain complications (carcinological, renal, nutritional, dental), sometimes difficult therapeutic choices, sometimes life-threatening prognosis. But one of the major problems limiting the patient's autonomy is the difficulty of finding a paramedic to take over skin care, often provided from birth by a parent who has become a caregiver through necessity.

PMID:37931994 | DOI:10.1016/j.soin.2023.09.008

BMJ Case Rep. 2023 Nov 6;16(11):e257108. doi: 10.1136/bcr-2023-257108.

ABSTRACT

A male patient in his early childhood presented to rheumatology with a hoarse voice and recurrent oral and cutaneous ulceration. Serological investigation revealed persistently elevated inflammatory markers. Despite compliance to treatment, flare-ups persisted, prompting the use of further treatment. An airway endoscopy revealed cystic changes to the left vocal cord. Referral to ophthalmology revealed multiple, waxy, skin-coloured, beaded papules on thickened, irregular eyelid margins with distichiasis, in keeping with moniliform blepharosis. Enrolment into the 100 000-genome project helped clinch the diagnosis of lipoid proteinosis. Although this case highlights the diagnostic power of genetics, it also sheds light on the importance of targeted clinical referral. When one considers the typical symptoms and signs of lipoid proteinosis, referral to a centre of rare diseases would have proven effective in not only avoiding polypharmacy but also reducing the psychological burden of several years of uncertainty must have had on our patient.

PMID:37931963 | DOI:10.1136/bcr-2023-257108

Orphanet J Rare Dis. 2023 Nov 1;18(1):342. doi: 10.1186/s13023-023-02956-3.

ABSTRACT

BACKGROUND: The Orphan Regulation ((EC) No 141/2000) has successfully redirected private and public investment towards previously neglected areas through incentives, regulatory obligations and rewards. However, the growth in the number of licensed orphan medicinal products (OMPs) has led to concerns about increased costs. The aims were to investigate the trend in the costs of OMPs to the National Health Service in Wales, to attribute costs of medicines within and outside periods of marketing exclusivity, and estimate the contribution of individual medicines to the overall costs of OMPs.

METHODS: Expenditure on OMPs in Wales was analysed between the 2014/15 and 2019/20 financial years using data on prescriptions dispensed in primary care, secondary care, and specialised commissioned services. OMP spend was calculated as a proportion of total medicines expenditure, whether it was incurred during, or outside the marketing exclusivity period (MEP), and by therapeutic area and medicine.

RESULTS: Overall spend on OMPs and all medicines increased from £32 m to £82 m, and from £1,030 m to £1,198 m, respectively, with the proportion of spend on OMPs more than doubling from 3.1% to 6.9% per annum. Average year-on-year growth in the costs of OMPs was 21%, compared to 2% for other medicines. Costs following MEP expiry contributed significantly to overall OMP costs, increasing from £8 m to £30 m, corresponding to an increase from 24% to 37%. Treatments for 'malignant disease and immunosuppression', 'nutrition and blood' and the 'respiratory system' accounted for 90% of all OMP spend. Half of total OMP annual expenditure was on just 4 medicines in 2014/15, increasing to 8 in 2019/20.

CONCLUSIONS: Both the number of OMPs and the amount spent on OMPs in Wales has increased over time, possibly as a consequence of favourable licensing conditions, permissive health technology assessment policies and dedicated funding.

PMID:37915031 | PMC:PMC10621215 | DOI:10.1186/s13023-023-02956-3

ACR Open Rheumatol. 2023 Nov 2. doi: 10.1002/acr2.11627. Online ahead of print.

ABSTRACT

OBJECTIVE: Systemic sclerosis (SSc) is an orphan disease that can lead to severe involvement of the gastrointestinal tract with a significant impact on patients' quality of life (QoL). The Mediterranean diet (MD) was consistently demonstrated to have beneficial effects on chronic diseases based on biological bases. We aimed to evaluate the adherence to the MD of Italian patients with SSc to preliminarily assess its association with gastrointestinal symptoms and other disease features, mood, and QoL.

METHODS: In this cross-sectional study, adherence to the MD was measured in 387 patients from four SSc Italian referral centers through the 14-item Mediterranean Diet Adherence Screener (14-MEDAS) questionnaire. We also registered patients' reported outcomes related to the QoL and mood.

RESULTS: Overall, an optimal adherence to MD was observed in 14.7% of patients with SSc, a moderate adherence in 71.3%, and a low adherence in 14.0%. In univariate analysis, poor adherence to the MD was associated with a more prominent depressive mood, time missed at work, and perception of more severe Raynaud's phenomenon and digital ulcers, whereas the 14-MEDAS score inversely correlated with depression score and reflux.

CONCLUSION: In our cohort of patients with SSc, overall adherence to MD was moderate. Patients with lower adherence to MD also reported worse outcomes related to QoL and mood. Administration of the 14-MEDAS could be a reasonable choice to assess adherence to the MD in patients with SSc. Future initiatives to study the role of MD in the management of patients with SSc are warranted.

PMID:37916477 | DOI:10.1002/acr2.11627

BMC Health Serv Res. 2023 Oct 31;23(1):1187. doi: 10.1186/s12913-023-10049-x.

ABSTRACT

BACKGROUND: Rare disease registries (RDRs) facilitate monitoring of rare diseases by pooling small datasets to increase clinical and epidemiological knowledge of rare diseases and promote patient centred best practice. The aim of this study was to understand the current state of RDRs in Australia, data captured, impact on patient outcomes, funding models, and barriers and enablers regarding their establishment and maintenance.

METHODS: An exploratory sequential mixed methods study design was adopted. First, a list of Australian RDRs, primary contacts and data custodians was generated through online and consumer group (Rare Voices Australia (RVA)) contacts. A cross-sectional, anonymous online survey was distributed to registry custodians, managers, or principal investigators of 74 identified Australian RDRs, 88 RVA Partners, 17 pharmaceutical organizations and 12 RVA Scientific and Medical Advisory Committee members. Next, managers and coordinators of RDRs and databases who participated in the survey were invited to participate in semi-structured interviews. Quantitative and qualitative data were analysed using basic descriptive statistics and content analysis, respectively.

RESULTS: Forty RDRs responded to the survey; nine were national, five were based in Australia and New Zealand, and the remaining were global. Of the 40 survey respondents, eight were interviewed. Most of the RDRs captured similar information regarding patient characteristics, comorbidities and clinical features, diagnosis, family history, genetic testing, procedures or treatment types, response to treatments and complications of treatments. Better treatment outcomes, changes in process of care and changes in quality of care were the most frequently reported benefits of the RDRs. The main challenges proved to be cost/funding of data collection, data completeness, and patient consent. When asked, the participants identified opportunities and challenges regarding potential options to streamline RDRs in Australia in the future.

CONCLUSION: Findings from this study highlighted significant dataset heterogeneity based on the individual disease, and current lack of interoperability and coordination between different existing RDRs in Australia. Nevertheless, a nationally coordinated approach to RDRs should be investigated given the particular benefits RDRs offer, such as access to research and the monitoring of new disease-modifying treatments.

PMID:37907945 | PMC:PMC10619239 | DOI:10.1186/s12913-023-10049-x

bioRxiv. 2023 Oct 20:2023.10.18.562924. doi: 10.1101/2023.10.18.562924. Preprint.

ABSTRACT

Inherited retinal diseases (IRDs) encompass a genetically diverse group of conditions in which mutations in genes critical to retinal function lead to progressive loss of photoreceptor cells and subsequent visual impairment. A handful of ribosome-associated genes have been implicated in retinal disorders alongside neurological phenotypes. This study focuses on the HBS1L gene, encoding HBS1 Like Translational GTPase which has been recognized as a critical ribosomal rescue factor. Previously, we have reported a female child carrying biallelic HBS1L mutations, manifesting growth restriction, developmental delay, and hypotonia. In this study, we describe her ophthalmologic findings, compare them with the Hbs1ltm1a/tm1a hypomorph mouse model, and evaluate the underlying microscopic and molecular perturbations. The patient was noted to have impaired visual function observed by electroretinogram (ERG), with dampened amplitudes of a- and b-waves in both rod- and cone-mediated responses. Hbs1ltm1a/tm1a mice exhibited profound retinal thinning of the entire retina, specifically of the outer retinal photoreceptor layer, detected using in vivo imaging of optical coherence tomography (OCT) and retinal cross sections. TUNEL assay revealed retinal degeneration due to extensive photoreceptor cell apoptosis. Loss of HBS1L resulted in comprehensive proteomic alterations in mass spectrometry analysis, with169 proteins increased and 480 proteins decreased including many critical IRD-related proteins. GO biological process and GSEA analyses reveal that these downregulated proteins are primarily involved in photoreceptor cell development, cilium assembly, phototransduction, and aerobic respiration. Furthermore, apart from the diminished level of PELO, a known partner protein, HBS1L depletion was accompanied by reduction in translation machinery associated 7 homolog (Tma7), and Endothelial differentiation-related factor 1(Edf1) proteins, the latter of which coordinates cellular responses to ribosome collisions. This novel connection between HBS1L and ribosome collision sensor (EDF1) further highlights the intricate mechanisms underpinning ribosomal rescue and quality control that are essential to maintain homeostasis of key proteins of retinal health, such as rhodopsin.

PMID:37905068 | PMC:PMC10614867 | DOI:10.1101/2023.10.18.562924

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Nov 10;40(11):1382-1386. doi: 10.3760/cma.j.cn511374-20220120-00048.

ABSTRACT

OBJECTIVE: To summarize the clinical features and biological characteristics of Helsmoortel Van der Aa syndrome (HVDAS) due to hotspot mutations of the ADNP gene in order to facilitate early diagnosis.

METHODS: Clinical data and result of genetic testing for a girl with HVDAS due to hotspot mutation of the ADNP gene was summarized. Related literature was also reviewed.

RESULTS: The patient, a 2-year-old girl, had presented with growth retardation, facial dysmorphism, psychomotor and language delay and recurrent respiratory infections. Whole exome sequencing revealed that she has harbored a heterozygous c.2496_2499delTAAA (p.Asn832Lysfs*81) variant of the ADNP gene, which was not found in either of her parents.

CONCLUSION: Although the typical features of the HVDAS have included intellectual disability and autism spectrum disorders, growth retardation and premature primary tooth eruption may also be present. In addition, the phenotypic difference among individuals carrying hot spot variants of the ADNP gene was not prominent.

PMID:37906146 | DOI:10.3760/cma.j.cn511374-20220120-00048

JMIR Public Health Surveill. 2023 Oct 31;9:e50147. doi: 10.2196/50147.

ABSTRACT

BACKGROUND: Rare diseases (RDs) affect millions of people worldwide, and these diseases can severely impact the health-related quality of life (HRQoL) of those affected. Despite this, there is a lack of research measuring HRQoL using the EQ-5D-5L, which is one of the most widely used generic preference-based instruments to measure HRQoL in populations living with RDs.

OBJECTIVE: This study aimed to measure HRQoL using the EQ-5D-5L in a large number of patients with various types of RDs in China, and to examine the relationship between respondents' socioeconomic characteristics and preference-based health utility scores.

METHODS: The data used in this study were obtained from a web-based survey conducted in China. The survey aimed to explore and understand the health and socioeconomic status of patients with RDs in China. We recruited registered and eligible members, including patients or their primary caregivers, from 33 RD patient associations to complete the questionnaires via their internal social networks. HRQoL was measured using the EQ-5D-5L utility score, which was calculated based on an established Chinese value set. Utility scores have been presented based on demographics and disease-related information. Univariate linear regression analysis was used to assess the differences in the EQ-5D-5L utility scores between subgroups.

RESULTS: A total of 12,502 respondents completed the questionnaire and provided valid responses, including 6919 self-completed respondents and 5583 proxy-completed respondents. Data from 10,102 participants over the age of 12 years were elicited for analysis. Among patients with RDs, 65.3% (6599/10,102), 47.5% (4799/10,102), 47.0% (4746/10,102), 24.8% (2506/10,102), and 18.4% (1855/10,102) reported no problems for "self-care," "usual activities," "mobility," "pain/discomfort," and "anxiety/depression," respectively. A full health state was reported by 6.0% (413/6902) and 9.2% (295/3200) of self- and proxy-completed patients, respectively. Among self-completed patients, 69.9% (4826/6902) and 50.4% (3478/6902) reported no problems for "self-care" and "usual activities," respectively, whereas only 17.7% (1223/6902) reported problems for "anxiety/depression." Proxy-completed respondents showed a higher proportion of reporting extreme problems than self-completed respondents in all 5 dimensions. The mean utility scores reported by self- and proxy-completed respondents were 0.691 and 0.590, respectively. Different types of caregivers reported different utility scores, and among them, proxy-completed (mother) respondents reported the highest mean utility score.

CONCLUSIONS: The establishment of a normative profile for RD patients can facilitate patients' adaptation and assess the effectiveness of interventions to improve the HRQoL and well-being of this population. Differences between self- and proxy-completed HRQoL assessed by the EQ-5D-5L have been identified in this study. This finding highlights the importance of incorporating perspectives from both patients and their proxies in clinical practice. Further development of the patient cohort is necessary to assess long-term changes in HRQoL in the RD population.

PMID:37906229 | DOI:10.2196/50147

Medicina (Kaunas). 2023 Oct 4;59(10):1770. doi: 10.3390/medicina59101770.

ABSTRACT

Gastritis cystica profunda (GCP) has been defined as a rare submucosal benign gastric lesion with cystic gland growth. Due to its unclear etiopathogenesis, this lesion is often misdiagnosed and mistaken for other gastric masses. Currently, a standardized treatment for GCP lesions is still missing. Here, we illustrate a case of a patient admitted to our general surgery department for melena and general discomfort. No history of peptic ulcer or gastric surgery was present. Upper GI endoscopy was performed, showing a distal gastric lesion with a small ulceration on the top. CT-scan and endoscopic ultrasound confirmed the presence of the lesion, compatible with a gastric stromal tumor, without showing any eventual metastasis. Surgical gastric resection was performed. Histological findings were diagnostic for GCP, with cistically ectasic submucosal glands, chronic inflammation, eosinophilic infiltration and foveal hyperplasia. GCP is a very exceptional cause of upper-GI bleeding with specific histological features. Its diagnosis as well as its therapy are challenging, resulting in several pitfalls. Even though it is a rare entity, GCP should always be considered in the differential diagnosis of gastric submucosal lesions.

PMID:37893488 | DOI:10.3390/medicina59101770

Biomolecules. 2023 Sep 25;13(10):1441. doi: 10.3390/biom13101441.

ABSTRACT

Recent technical breakthroughs in genotyping and bioinformatics techniques have greatly facilitated the translation of genomics into clinical care [...].

PMID:37892123 | PMC:PMC10604584 | DOI:10.3390/biom13101441

Healthc Pap. 2023 Jul;21(3):70-71. doi: 10.12927/hcpap.2023.27198.

ABSTRACT

Rawson and Adams (2023) are certainly entitled to express their views about the lead and response articles by Sirrs et al. (2023a; 2023b). Their entitlement comes with a responsibility to accurately and comprehensively state their conflicts of interest (COI) so that readers can assess whether their arguments may be influenced by other interests.

PMID:37887173 | DOI:10.12927/hcpap.2023.27198

S Afr Med J. 2023 Aug 3;113(8):8. doi: 10.7196/SAMJ.2023.v113i8.1142.

NO ABSTRACT

PMID:37882112 | DOI:10.7196/SAMJ.2023.v113i8.1142

BMC Health Serv Res. 2023 Oct 25;23(1):1153. doi: 10.1186/s12913-023-10155-w.

ABSTRACT

We developed an algorithm to explore unexpected growth in the usage and costs of health technologies. We exploit data from the expenditures on technologies funded by the Colombian government under the compulsory insurance system, where all prescriptions for technologies not included in an explicit list must be registered in a centralized information system, covering the period from 2017 to 2022. The algorithm consists of two steps: an outlier detection method based on the density of the expenditures for selecting a first set of technologies to consider (39 technologies out of 106,957), and two anomaly detection models for time series to determine which insurance companies, health providers, and regions have the most notorious increases. We have found that most medicines associated with atypical behavior and significant monetary growth could be linked to the use of recently introduced drugs in the market. These drugs have valid patents and very specific clinical indications, often involving high-cost pharmacological treatments. The most relevant case is the Burosumab, approved in 2018 to treat a rare genetic disorder affecting skeletal growth. Secondly, there is clear evidence of anomalous increasing trend evolutions in the identified enteral nutritional support supplements or Food for Special Medical Purposes. The health system did not purchase these products before July 2021, but in 2022 they represented more than 500,000 USD per month.

PMID:37880691 | PMC:PMC10601102 | DOI:10.1186/s12913-023-10155-w

medRxiv. 2023 Oct 5:2023.10.05.23296595. doi: 10.1101/2023.10.05.23296595. Preprint.

ABSTRACT

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium. Each family's CNV data was analyzed using the seqr platform and candidate CNVs classified using the 2020 ACMG/ClinGen CNV interpretation standards. We developed additional evidence criteria to address situations not covered by the current standards. The addition of CNV calling to exome analysis identified causal CNVs for 173 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb with estimates that 44% would not have been detected by standard chromosomal microarrays. The causal CNVs consisted of 141 deletions, 15 duplications, 4 suspected complex structural variants (SVs), 3 insertions and 10 complex SVs, the latter two groups being identified by orthogonal validation methods. We interpreted 153 CNVs as likely pathogenic/pathogenic and 20 CNVs as high interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

PMID:37873196 | PMC:PMC10593084 | DOI:10.1101/2023.10.05.23296595

Nat Rev Drug Discov. 2023 Dec;22(12):937-938. doi: 10.1038/d41573-023-00168-9.

NO ABSTRACT

PMID:37872324 | DOI:10.1038/d41573-023-00168-9