Systematic review of thyroid function in NKX2-1-related disorders: Screening and diagnosis.

BACKGROUND: NKX2-1-related disorders (NKX2-1-RD) are rare conditions affecting lung, thyroid, and brain development, primarily caused by pathogenic variants or deletions in the NKX2-1 gene. Congenital hypothyroidism (CH) is a common endocrine manifestation, leading to irreversible intellectual disability if left untreated. OBJECTIVES: The aim was to evaluate the current evidence for the use of screening and diagnostic techniques for endocrine alterations in patients with NKX2-1-RD. METHODS: This systematic review was reported following the PRISMA guidelines. Two separate research questions in PICO format were addressed to cover initial screening and diagnosis procedures for endocrine diseases in patients with NKX2-1-RD. Eligibility criteria focused on patients with genetic confirmation of the disease and hypothyroidism. Various databases were searched, and data were extracted and assessed independently by two reviewers. RESULTS: Out of 1012 potentially relevant studies, 46 were included, for a total of 113 patients. CH was the most frequent endocrine alteration (45% of patients). Neonatal screening was reported in only 21% of patients based on blood TSH measurements. TSH thresholds varied widely across studies, making hypothyroidism detection ranges difficult to establish. Diagnostic tests using serum TSH were used to diagnose hypothyroidism or confirm its presence. 35% of patients were diagnosed at neonatal age, and 42% at adult age. Other hormonal dysfunctions identified due to clinical signs, such as anterior pituitary deficiencies, were detected later in life. Thyroid scintigraphy and ultrasonography allowed for the description of the thyroid gland in 30% of cases of hypothyroidism. Phenotypic variability was observed in individuals with the same variants, making genotype-phenotype correlations challenging. CONCLUSION: This review highlights the need for standardized protocols in endocrine screening for NKX2-1-RD, emphasizing the importance of consistent methodology and hormone threshold levels. Variability in NKX2-1 gene variants further complicates diagnostic efforts. Future research should concentrate on optimizing early screening protocols and diagnostic strategies.

Evaluation of the safety, efficacy, effectiveness and cost-effectiveness of implantable Holter for prolonged monitoring in patients with previous stroke: a systematic review.

Background: Atrial fibrillation (AF), which is associated with cryptogenic stroke, is the most common sustained arrhythmia in the general population. Because AF is asymptomatic and intermittent, its detection rate increases with the duration of monitoring. The objective of this study is to review the available evidence on the safety, efficacy, effectiveness and cost-effectiveness of AF diagnosis by prolonged monitoring with an implantable Holter monitor in adult patients with idiopathic or cryptogenic stroke of suspected cardioembolic origin, compared to conventional monitoring. Methods: Two independent reviewers performed a systematic review of the literature, identifying relevant studies through a structured search of Medline (Ovid), EMBASE, Web of Science and Cochrane Library and the databases of national and international health technology assessment agencies. The quality of the included studies was assessed with AGREE-II, AMSTAR-2 and CHEC. GRADE criteria were used to summarise the evidence. Results: Four of the 211 papers identified were included: 1 clinical practice guideline, 2 systematic reviews, and 1 economic evaluation. The quality of the evidence reviewed was low. An implantable Holter monitor might be more effective in detecting AF than conventional monitoring. Serious adverse events were similar in both groups. The economic evaluation suggests that the technology is cost-effective. Conclusions: The available evidence suggests the diagnostic superiority of the implantable Holter monitor over the traditional Holter monitor. Due to the low quality of the evidence, further and higher quality studies on these technologies are needed before solid conclusions can be drawn.

Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

Efficacy and safety of baroreflex activation therapy for heart failure with reduced ejection fraction: systematic review.

Baroreflex activation therapy (BAT) is a possible adjuvant treatment for patients with heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy and may be an alternative therapy in patients with contraindications or drug intolerance. Our aim was to evaluate the efficacy and safety of BAT in patients with HFrEF. The protocol for this study was registered with PROSPERO (CRD42022349175). Searches were conducted using MEDLINE, preMedLine (via PubMed), EMBASE, Cochrane Library, Web of Science, Trip Medical Database, WHO International Clinical Trials Registry, and ClinicalTrials.gov. We included randomized controlled trials that compared the effects of BAT with pharmacological treatment. We assessed the risk of bias of each study using the Cochrane RoB2 tool and the certainty of the results using the GRADE approach. We performed a meta-analysis of treatment effects using a fixed-effects or random-effects model, depending on the heterogeneity observed. Two studies were included in the meta-analysis (HOPE4HF and BeAT-HF). The results showed that BAT led to statistically significant improvements in New York Heart Association functional class (relative risk 2.13; 95% confidence interval [CI, 1.65 to 2.76]), quality of life (difference in means -16.97; 95% CI [-21.87 to -12.07]), 6 min walk test (difference in means 56.54; 95% CI [55.67 to 57.41]) and N-terminal probrain natriuretic peptide (difference in means -120.02; 95% CI [-193.58 to -46.45]). The system- and procedure-related complication event-free rate varied from 85.9% to 97%. The results show that BAT is safe and improves functional class, quality of life and congestion in selected patients with HFrEF. Further studies and long-term follow-up are needed to assess efficacy in reducing cardiovascular events and mortality.

The VR leadless pacemaker: Results of an expert panel using the RAND/UCLA method.

BACKGROUND: Leadless pacemakers were developed to reduce complications associated with transvenous pacemaker implantation and long-term follow-up. Existing international guidelines lack detailed instructions on patients suitable for leadless pacemaker implantation. Our aim was to develop a consensus document that provides medical guidance for all health professionals involved in the indication and implantation of Transcatheter Pacing System single-chamber device (VR leadless) pacemakers for patients with atrial fibrillation or in sinus rhythm. METHODS: A panel of experts, including interventional and non-interventional cardiologists, used the Research ANd Development/University of California at Los Angeles (RAND/UCLA) method to rate the appropriateness of leadless pacemaker implantation for 64 scenarios in patients with atrial fibrillation and 192 scenarios in sinus rhythm. The scenarios were rated individually and again during a moderated group session. Median ratings and level of agreement were calculated to classify each scenario as appropriate, inappropriate, or questionable. RESULTS: This consensus statement, based on available literature and the experts' opinions, summarizes recommendations for standardizing and optimizing leadless pacemaker implantation. The limitation for vascular access via the superior vena cava was the most influential variable when indicating leadless pacemaker implantation in both patients with atrial fibrillation and patients in sinus rhythm. CONCLUSIONS: Life expectancy, risk of infection, prosthetic valve, left ventricular ejection fraction (LVEF), limitation for vascular access via the superior vena cava, and mobility and exercise capacity determine who is advised to undergo VR leadless pacemaker implantation. More prospective studies are needed to optimize existing recommendations.

Exploring the values, preferences, and information needs of patients with NKX2-1-related disorders: A qualitative study protocol.

BACKGROUND: NKX2-1-related disorders have a prevalence of 1:500,000 and are therefore considered a rare condition according to the European Commission's definition. The European Reference Network of Rare Neurological Disorders is developing the first clinical practice guideline on the management of this condition, with the support of the Andalusian Health Technology Assessment Area, Endo-ERN, ERN-Lung and Imegen, within the framework of the ERNs Guidelines programme (DG SANTE/2018/B3/030). Within the scope of this programme, it becomes necessary to explore the patient perspective in order to include it in the ongoing clinical practice guideline and accompanying patient information booklet. METHODS AND ANALYSIS: This study will use qualitative methods to explore the values, preferences and information needs of patient with NKX2-1-related disorders and their caregivers. Participants will come from a variety of countries throughout Europe. One focus group and four semi-structured interviews will be conducted. Pairs will analyse the data using Grounded Theory. The Andalusian Regional Ministry of Health's Ethics Coordinating Committee for Biomedical Research (Sevilla, Andalucía, Spain) has approved this study protocol (29/03/2022). DISCUSSION: This is the first study to explore the values, preferences, and information needs of patients with NKX2-1-related disorders. The proposed study's findings will contribute to the generation of useful knowledge that will provide guidance to improve the care given to patients with the studied condition. While this study will provide valuable insights into the perspectives of patients with NKX2-1-related disorders, the findings are unlikely to be generalizable to patients with other conditions.

An innovative framework to determine the implementation level of personalized medicine: A systematic review.

Background: Personalized medicine (PM) is now the new frontier in patient care. The application of this new paradigm extends to various pathologies and different patient care phases, such as diagnosis and treatment. Translating biotechnological advances to clinical routine means adapting health services at all levels is necessary. Purpose: This article aims to identify the elements for devising a framework that will allow the level of PM implementation in the country under study to be quantitatively and qualitatively assessed and that can be used as a guideline for future implementation plans. Methods: A systematic review was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The research question was: What are the domains for determining the level of implementation of PM at the national level? The domains for assessing the degree of PM implementation, which would form the framework, were established. Results: 19 full-text studies that met the inclusion criteria were peer-selected in the systematic review. From all the studies that were included, 37 elements-encompassed in 11 domains-were extracted for determining the degree of PM implementation. These domains and their constituent elements comprise the qualitative and quantitative assessment framework presented herein. Each of the elements can be assessed individually. On the other hand, the domains were standardized to all have the same weight in an overall assessment. Conclusions: A framework has been developed that takes a multi-factorial approach to determine the degree of implementation of PM at the national level. This framework could also be used to rank countries and their implementation strategies according to the score they receive in the application of the latter. It could also be used as a guide for developing future national PM implementation strategies. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022338611, Identifier: CRD42022338611.

Barriers for the evaluation of advanced therapy medicines and their translation to clinical practice: Umbrella review.

Advanced therapy medicinal products (ATMPs) are a fast-growing field of medicine with wide potential application. Nevertheless, so far, only 19 have obtained European Union (EU) marketing authorisation and only 13 of these have translated successfully into clinical practice. This study conducts an umbrella review to identify the main barriers for the evaluation of ATMPs and their translation into clinical practice across the development lifecycle. 71 systematic reviews were included, of which 50 dealt primarily with effectiveness and safety, 13 with translation from pre-clinical to human subjects. Others dealt with economic issues and translation from health technology assessment to market access. The literature highlights the importance of synergistic research groups or networks that collaborate across the in-vitro science, preclinical and clinical investigation phases, and the role of private investor capital and public-private collaborations. Most ATMPs reviewed seem to have a favourable safety profile although considerable uncertainties remain. Randomised controlled trials are not always feasible in these patient groups. Greater sharing of data is recommended, both at preclinical and post-marketing real world evidence. There are considerable variations between EU countries in how they regulate hospital exemption for ATMPs, and this can lead to inequitable access for patients.

Diagnostic accuracy of optical coherence tomography angiography in the detection of neovasculature in age-related macular degeneration: a meta-analysis.

This work is a systematic review and meta-analysis to evaluate the diagnostic accuracy of optical coherence tomography angiography (OCTA) in the identification of choroidal neovascularization due to age-related macular degeneration (AMD) in comparison with fluorescein angiography (FA). A systematic search of the literature was carried out on Medline, EMBASE, Web of Science, Cochrane Library and Center for Reviews and Dissemination. Studies comparing OCTA with FA for the diagnosis of choroidal neovascularization due to AMD that included data on the diagnostic validity of the test or the data necessary for its calculation were selected. The QUADAS-2 tool was used to assess the risk of bias in selected studies. The quantitative analysis of the results was performed by meta-analysis. Seven primary studies were included. The quality of the evidence was good. The total population included in the meta-analysis comprised 553 eyes, with a cumulative sensitivity and specificity of 85.9% (95% CI 81.9-89.3%) and 89% (95% CI 83.5-93.2%), respectively, cumulative positive and negative likelihood ratios of 8.36 and 0.15, respectively (95% CI of 3.05-22.890 and 0.09-0.24, respectively), and a cumulative diagnostic odds ratio of 67.21 (95% CI 22.58-200.05). The evidence obtained does not demonstrate the superiority of OCTA over FA. Its use as a support technique could improve patient flow and reduce the number of FA.

ImmunoCAP ISAC in food allergy diagnosis: a systematic review of diagnostic test accuracy.

OBJECTIVE: To assess the diagnostic test accuracy of the component-resolved diagnosis device ImmunoCAP ISAC, compared with oral food challenge. DESIGN: Systematic review reported according to the PRISMA-DTA recommendations. DATA SOURCES: Medline, Embase and Cochrane Library databases were searched from inception to May 2019 and updated in March 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included diagnostic test accuracy studies comparing ISAC component results as the index test with oral food challenge as the reference test, in people of any age suspected of IgE mediated food allergy to milk, egg, peanut, shrimp, hake, apple, peach, kiwi, melon, walnut, hazelnut, wheat or pineapple. Risk of bias was evaluated using the QUADAS-2 tool. RESULTS: We screened 799 titles and included 11 studies - seven prospective and two retrospective cohort studies, two case-control studies. Included studies evaluated IgE to Gald1 (three studies, 300 participants, 140 with egg allergy), Bosd5 (three studies, 242 participants, 146 with milk allergy) and Arah1 or 2 (seven studies, 546 participants, 346 with peanut allergy). No studies were identified for other ISAC components. Risk of bias was high or unclear mainly due to inadequate blinding. Applicability was of high or unclear concern due to unclear thresholds, inappropriate exclusions and variable populations. Gald1 sensitivity ranged from 58 to 84%, specificity 87%-97%. Bosd5 sensitivity 24%-40%, specificity 94%-95%. Arah1 sensitivity 45%-91%, specificity 41%-93%. Arah2 sensitivity 70%-94%, specificity 75%-95%. CONCLUSIONS: Diagnostic test accuracy information for ISAC components was only available for milk, egg and peanut. Specificity is generally higher than sensitivity, which contrasts with the performance of skin prick and standard specific IgE tests for diagnosing food allergy. Higher quality information is needed to determine the clinical utility of ISAC for food allergy diagnosis. SYSTEMATIC REVIEW REGISTRATION: Not registered.

Metodología cualitativa para la validación de un cuestionario de recursos y servicios en cuidados paliativos / Qualitative methodology for a palliative care resources and services questionnaire validation

Objetivo: Establecer la validez de composición, contenido y criterios de un cuestionario de recursos para la provisión de servicios en Cuidados Paliativos (CP) a través de una metodología cualitativa, mediante grupos focales con profesionales de CP; en el marco de un proyecto de validación y evaluación de los resultados de un cuestionario de recursos para la provisión de servicios en (CP) en la Comunidad de Madrid (CM). Método: Se lleva a cabo un abordaje cualitativo para la validación del cuestionario de recursos. Se selecciona el grupo de discusión como técnica de elección para obtener un discurso en base a la experiencia personal de los profesionales implicados en el ámbito de los CP. Los grupos se componen de médicos, enfermeras, psicólogos, trabajadores sociales y agente de pastoral. Resultado: Los temas de discusión en los grupos fueron: dispersión geográfica de los recursos humanos, motivación laboral y personal, "ayuda psico-emocional" para profesionales, valoración integral y holística del paciente, equidad de los equipos, presupuesto social, apoyo al cuidador, ayuda entre equipos, sobrecarga laboral y humana, relación con la gerencia, futuro de los equipos: "estar quemados", trabajo en equipo, formación en CP, labor de enfermería en CP, protocolo de acogida en CP y aclaraciones terminológicas o conceptuales. Conclusiones: Este trabajo pretende ser el punto de partida para la elaboración y validación de un cuestionario en la provisión de servicios en CP, y así evaluar los recursos humanosy técnicos de nuestra red asistencial sanitaria paliativa

Objective: To establish the composition, content and criteria validity of a questionnaire of resources for services provision in Palliative Care (PC) through a qualitative methodology using focus groups with PC professionals. This is a part of a validation and evaluation research project for the provision of services (CP) in the Community of Madrid (CM). Methods: We performed a qualitative approach to the resource questionnaire validation. It was selected the focus group technique based on the personal experience of the professionals involved in PC. The groups were made up of physicians, nurses, psychologists, social workers and pastoral agent. Results: Discussion items in the groups were: human resources, geographical dispersion, work and personal motivation, "psycho-emotional" help for professionals, comprehensive and holistic patient approach, equipment equity, social budget, caregiver support , support between teams, overburden and human relationship with CEOs, future of teams: "be burned", team-working, teaching in PC, PC nursing work, PC welcome protocol and terminological and conceptual clarifications. Conclusions: This study tries to be the starting point for the development and validation of the PC provision of services questionnaire. It will be useful to assess the human and technical resources of our palliative health care network (AU)

Post-introduction observation of healthcare technologies after coverage: the Spanish proposal.

OBJECTIVES: When a new health technology has been approved by a health system, it is difficult to guarantee that it is going to be efficiently adopted, adequately used, and that effectiveness, safety, and consumption of resources and costs are in line with what was expected in preliminary investigations. Many governmental institutions promote the idea that efficient mechanisms should be established aimed at developing and incorporating continuous evidence into health technologies management. The purpose of this article is to stimulate the discussion on systematic post-introduction observation of health technologies. METHODS: Literature review and input of HTA experts. RESULTS: The study addresses the key issues related to post-introduction observation and presents a summary of the guide commissioned by the Spanish Ministry of Health, Social Policy and Equality to the Galician HTA agency for the prioritization and implementation of systematic post-introduction observation in Spain. The manuscript describes the prioritization tool developed as part of this project and discusses the main aspects of protocol development, observation implementation, and assessment of results. CONCLUSIONS: The observation of prioritized health technologies after they are introduced in standard clinical practice can provide useful information for health organizations. However, implementing the observation of health technologies can require specific policy frameworks, commitment from different stakeholders, and dedicated funding.

Assessment of a rapid referral pathway for suspected colorectal cancer in Madrid.

OBJECTIVE: To assess the results achieved with a rapid referral pathway for suspected colorectal cancer (CRC), comparing with the standard referral pathway. METHODS: Three-year audit of patients suspected of having CRC routed via a rapid referral pathway, and patients with CRC routed via the standard referral pathway of a health care district serving a population of 498,000 in Madrid (Spain). Outcomes included referral criteria met, waiting times, cancer diagnosed and stage of disease. RESULTS: Two hundred and seventy-two patients (mean age 68.8 years, SD 14.0; 51% male) were routed via the rapid referral pathway for colonoscopy. Seventy-nine per cent of referrals fulfilled the criteria for high risk of CRC. Fifty-two cancers were diagnosed: 26% Stage A (Astler-Coller), 36% Stage B, 24% Stage C and 14% Stage D. Average waiting time to colonoscopy for the rapid referral patients was 18.5 days (SD 19.1) and average waiting time to surgery was 28.6 days (SD 23.9). Colonoscopy was performed within 15 days in 65% of CRC rapid referral patients compared to 43% of standard pathway patients (P = 0.004). Overall waiting time for patients with CRC in the rapid referral pathway was 52.7 days (SD 32.9); while for those in the standard pathway, it was 71.5 days (SD 57.4) (P = 0.002). Twenty-six per cent Stage A CRC was diagnosed in the rapid referral pathway compared to 12% in the standard pathway (P < 0.001). CONCLUSION: The rapid referral pathway reduced waiting time to colonoscopy and overall waiting time to final treatment and appears to be an effective strategy for diagnosing CRC in its early stages.

The safety and efficacy of robotic image-guided radiosurgery system treatment for intra- and extracranial lesions: a systematic review of the literature.

BACKGROUND: The CyberKnife is a new, frameless stereotactic radiosurgery system. This work reviews its safety and efficacy in the treatment of intra- and extracranial lesions. METHODS: A literature search was made of the Medline, Embase, Pascal Biomed, CINAHL and Cancerlit databases. Health technology assessment reports on stereotactic radiosurgery systems were also consulted. All searches were made in June 2007. Data on efficacy and safety were extracted and then synthesized into the present review. RESULTS: Thirty five clinical studies were identified, the majority of which included no patient comparison group. These studies assessed the use of the CyberKnife mainly in the treatment of primary and metastatic intracranial and spinal tumours. CONCLUSIONS: The CyberKnife system allows to carry out standard radiosurgical and fractionated stereotactic radiotherapy procedures. The use of this system offers an alternative for the treatment of inoperable tumours, and of lesions located close to critical structures that cannot be treated using other types of stereotactic radiosurgery system. Unfortunately, the quality of the reviewed papers still does not allow definite conclusions to be drawn regarding the safety and efficacy of these treatments.

[Design and analysis of a study on etiologic factors in urological clinical research]. / Diseño y análisis de un estudio de factores etiológicos en investigación clínica urológica.

The objective of etiologic research is to look for the causes of disease, their relationships with it, and their relative magnitude on the appearance of the disease. The observational studies (in which there is no manipulation of the study factor), that are performed when the knowledge about the disease to be studied allows to specify beforehand one or more hypothesis that can be tested are called etiologic or analytic studies. The objective of etiologic studies is to identify risk factors for a given disease, to estimate their effects on the appearance of disease, and also to suggest a possible strategy of interventions to diminish the appearance of disease. Case-control and cohort studies are the etiologic studies more often used, characteristics of which will be exposed in this article.

Diseño y análisis de un estudio de factores etiológicos en investigación clínicaurológica / Design and analysis of a study of the etiologic factors in clinical research in urology

La investigación etiológica tiene por objetivo buscar las causas de la enfermedad, sus relaciones con ella, y su magnitud relativa en la aparición de la enfermedad. Los estudios observacionales (en los que no existe manipulación del factor de estudio) que se realizan cuando los conocimientos de la enfermedad a estudio permiten especificar a priori una o más hipótesis que pueden ser testadas, son los denominados estudios etiológicos o analíticos. El objetivo de los estudios etiológicos es identificar factores de riesgo de una enfermedad, estimar sus efectos en la aparición de la enfermedad y asimismo, sugerir una posible estrategia de intervención para disminuir la aparición de la enfermedad.Los estudios etiológicos utilizados con más frecuencia son los estudios caso-control y los estudios de cohortes, de los que se expondrán sus características más importantes en este artículo. (AU)