Recommendations for implementing the INTERACT3 care bundle for intracerebral hemorrhage in Latin America: results of a Delphi method.

INTRODUCTION: The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3) showed that the implementation of a care bundle improves outcomes after acute intracerebral hemorrhage (ICH). We aimed to establish consensus-based recommendations for the broader integration of the care bundle across Latin American countries (LAC). METHODS: A 3-phase Delphi study allowed a panel of 32 healthcare workers from 14 LAC to sequentially rank statements relevant to 7 domains (training, resources/infrastructure, patient education, blood pressure, temperature, glycemic control, and anticoagulation reversal). Pre-defined consensus threshold was 75%. RESULTS: A total of 43 statements reached consensus by the third round, with 12 new statements emerging through rounds. The highest-ranked statements in each domain emphasized critical aspects but successful implementation requires appropriate resourcing. Key priorities were continuous training of all healthcare workers in ICH management, establishing protocols aligned with available resources, and collaborative interdisciplinary care supported by institutional networks. Statements related to anticoagulation reversal had the highest priority. CONCLUSIONS: Consensus statements are provided to facilitate integration of the INTERACT3 care bundle to reduce disparities in ICH outcomes in LAC.

Implementation of low-intensity thrombolysis monitoring care in routine practice: process evaluation of the Optimal Post rtPA-IV Monitoring in Acute Ischemic Stroke (OPTIMISTmain) study in the United States.

INTRODUCTION: The ongoing OPTIMISTmain study, an international, multicenter, stepped-wedge cluster randomized trial, aims to determine effectiveness and safety of low-intensity versus standard monitoring in thrombolysis-treated patients with mild-to-moderate acute ischemic stroke (AIS). An embedded process evaluation explored integration and impact of the intervention on care processes at participating US sites. METHODS: A mixed-methods approach with quantitative and qualitative data were collected between September 2021 and November 2022. Implementer surveys were undertaken at pre- and post-intervention phases to understand the perceptions of low-intensity monitoring strategy. A sample of stroke care nurses were invited to participate in semi-structured interviews at an early stage of post-intervention. Qualitative data were analyzed deductively using the normalization process theory; quantitative data were tabulated. RESULTS: Interviews with 21 nurses at 8 hospitals have shown low-intensity monitoring was well accepted, as there were less time constraints and reduced workload for each patient. There were initial safety concerns over missing deteriorating patients and difficulties in changing established routines. Proper training, education, and communication, and changing the habits and culture of care, were key elements to successfully adopting the new monitoring care into routine practice. Similar results were found in the post-intervention survey (42 nurses from 13 hospitals). Nurses reported time being freed up to provide patient education (56%), daily living care (50%), early mobilization (26%), mood/cognition assessment (44%), and other aspects (i.e. communication, family support). CONCLUSIONS: Low-intensity monitoring for patients with mild-to-moderate acute ischemic stroke, facilitated by appropriate education and organizational support, appears feasible and acceptable at US hospitals.

Evolution of clinical and radiological presentations of spondyloepimetaphyseal dysplasia, RPL13-related: Description of 11 further cases.

Spondyloepimetaphyseal dysplasia (SEMD), RPL13-related is caused by heterozygous variants in RPL13, which encodes the ribosomal protein eL13, a component of the 60S human ribosomal subunit. Here, we describe the clinical and radiological evolution of 11 individuals, 7 children and 4 adults, from 6 families. Some of the skeletal features improved during the course of this condition, whilst others worsened. We describe for the first time "corner fractures" as a feature of this dysplasia which as with other dysplasias disappear with age. In addition, we review the heights and skeletal anomalies of these reported here and previously in a total of 25 individuals from 15 families. In this study, six different RPL13 variants were identified, five of which were novel. All were located in the apparently hotspot region, located in intron 5 and exon 6. Splicing assays were performed for two of the three previously undescribed splicing variants. Until now, all splice variants have occurred in the intron 5 splice donor site, incorporating an additional 18 amino acids to the mutant protein. Here, we report the first variant in intron 5 splice acceptor site which generates two aberrant transcripts, deleting the first three and four amino acids encoded by exon 6. Thus, this study doubles the number of SEMD-RPL13-related cases and variants reported to date and describes unreported age-related clinical and radiological features.

The main Optimal Post rTpa-Iv Monitoring in Ischemic Stroke Trial (OPTIMISTmain): protocol for a pragmatic, stepped wedge, cluster randomized controlled trial.

Introduction Careful monitoring of patients who receive intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is resource-intensive, and potentially less relevant in those with mild degrees of neurological impairment who are at low-risk of symptomatic intracerebral hemorrhage (sICH) and other complications. \ Methods OPTIMISTmain is an international, multicenter, prospective, stepped wedge, cluster randomized, blinded outcome assessed trial aims to determine whether a less-intensity monitoring protocol is at least as effective, safe and efficient as standard post-IVT monitoring in patients with mild deficits post-AIS. Clinically-stable adult patients with mild AIS (defined by a NIHSS <10) who do not require intensive care within 2 hours post-IVT are recruited at hospitals in Australia, Chile, China, Malaysia, Mexico, UK, US and Vietnam. An average of 15 patients recruited per period (overall 60 patient participants) at 120 sites for a total of 7200 IVT-treated AIS patients will provide 90% power (one-sided α 0.025). The initiation of eligible hospitals is based on a rolling process whenever ready, stratified by country. Hospitals are randomly allocated using permuted blocks into 3 sequences of implementation, stratified by country and the projected number of patients to be recruited over 12 months. These sequences have four periods that dictate the order in which they are to switch from control (usual care) to intervention (implementation of low intensity monitoring protocol) to different clusters of patients in a stepped manner. Compared to standard monitoring, the low-intensity monitoring protocol includes assessments of neurological and vital signs every 15 minutes for 2 hours, 2 hourly (versus every 30 minutes) for 8 hours, and 4 hourly (versus every 1 hour) until 24 hours, post-IVT. The primary outcome measure is functional recovery, defined by the modified Rankin scale (mRS) at 90 days, a seven-point ordinal scale (0 [no residual symptom] to 6 [death]). Secondary outcomes include death or dependency, length of hospital stay, and health-related quality of life, sICH and serious adverse events. Conclusion OPTIMISTmain will provide Level I evidence for the safety and effectiveness of a low-intensity post-IVT monitoring protocol in patients with mild severity of AIS.

Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.

BACKGROUND: C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models. METHODS: Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants. RESULTS: Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9. CONCLUSION: In conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).

Stroke care and collaborative academic research in Latin America.

OBJECTIVE: A narrative overview of regional academic research collaborations to address the increasing burden and gaps in care for patients at risk of, and who suffer from, stroke in Latin America (LA). MATERIALS AND METHODS: A summary of experiences and knowledge of the local situation is presented. No systematic literature review was performed. RESULTS: The rapidly increasing burden of stroke poses immense challenges in LA, where prevention and manage-ment strategies are highly uneven and inadequate. Clinical research is increasing through various academic consortia and networks formed to overcome structural, funding and skill barriers. However, strengthening the ability to generate, analyze and interpret randomized evidence is central to further develop effective therapies and healthcare systems in LA. CONCLUSIONS: Regional networks foster the conduct of multicenter studies -particularly randomized controlled trials-, even in resource-poor regions. They also contribute to the external validity of international studies and strengthen systems of care, clinical skills, critical thinking, and international knowledge exchange.

Identification of the third FGF9 variant in a girl with multiple synostosis-comparison of the genotype:phenotype of FGF9 variants in humans and mice.

Multiple synostosis syndrome (SYNS) is a heterogeneous group of genetic disorders mainly characterized by multiple joint synostosis due to variants in either NOG, GDF5, FGF9 or GDF6. To date, only two FGF9 variants have been associated with SYNS, characterized with hand and feet joint synostosis and fusion of the elbow and vertebral lumbar joints. Craniosynostosis was also observed in one family. Here, we report the clinical and radiological description of a young girl with a third heterozygous FGF9 variant, NM_002010.2:c.427A>T;p.(Asn143Tyr), which interestingly, is located at the same amino acid as the well characterized spontaneous Eks mouse variant. We also compare the genotype: phenotypes observed between humans and mice with SYNS.

The Regeneración Urbana, Calidad de Vida y Salud - RUCAS project: a Chilean multi-methods study to evaluate the impact of urban regeneration on resident health and wellbeing.

BACKGROUND: The available evidence of the health effects of urban regeneration is scarce In Latin America, and there are no studies focused on formal housing that longitudinally evaluate the impact of housing and neighborhood interventions on health. The "Regeneración Urbana, Calidad de Vida y Salud" (Urban Regeneration, Quality of Life, and Health) or RUCAS project is a longitudinal, multi-method study that will evaluate the impact of an intervention focused on dwellings, built environment and community on the health and wellbeing of the population in two social housing neighborhoods in Chile. METHODS: RUCAS consists of a longitudinal study where inhabitants exposed and unexposed to the intervention will be compared over time within the study neighborhoods (cohorts), capitalizing on interventions as a natural experiment. Researchers have developed a specific conceptual framework and identified potential causal mechanisms. Proximal and more distal intervention effects will be measured with five instruments, implemented pre- and post-interventions between 2018 and 2021: a household survey, an observation tool to evaluate dwelling conditions, hygrochrons for measuring temperature and humidity inside dwellings, systematic observation of recreational areas, and qualitative interviews. Survey baseline data (956 households, 3130 individuals) is presented to describe sociodemographics, housing and health characteristics of both cohorts, noting that neighborhoods studied show worse conditions than the Chilean population. DISCUSSION: RUCAS' design allows for a comprehensive evaluation of the effects that the intervention could have on various dimensions of health and health determinants. RUCAS will face some challenges, like changes in the intervention process due to adjustments of the master plan, exogenous factors -including COVID-19 pandemic and associated lockdowns- and lost to follow-up. Given the stepped wedge design, that the study capitalizes on within household changes over time, the possibility of adjusting data collection process and complementarity of methods, RUCAS has the flexibility to adapt to these circumstances. Also, RUCAS' outreach and retention strategy has led to high retention rates. RUCAS will provide evidence to inform regeneration processes, highlighting the need to consider potential health effects of regeneration in designing such interventions and, more broadly, health as a key priority in urban and housing policies.

First case of compound heterozygous BHLHA9 variants in mesoaxial synostotic syndactyly with phalangeal reduction.

Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) is an extremely rare autosomal recessive limb abnormality characterized by the fusion of third and fourth fingers. To date, only homozygous missense and frameshift mutations have been reported in BHLHA9 associated to MSSD. In this study, we report a patient who presented with clinical and radiological features of MSSD. A customized skeletal dysplasia NGS panel revealed the presence of two novel compounds heterozygous variants in BHLHA9: NM_001164405.1: c.[226A>T][269G>C]; p.[(Lys76*)][(Arg90Pro)]. Thus, this is the first case of MSSD in a nonconsanguineous family.

Spondyloepiphyseal dysplasia type Stanescu: Expanding the clinical and molecular spectrum of a very rare type II collagenopathy.

Spondyloepiphyseal dysplasia type Stanescu (SED-S) is a very rare type II collagenopathy. We describe an 8-year-old boy who presented with short trunk, C2-C3 vertebral fusion, hand, foot, leg and thigh pain, stiffness and limited joint mobility, and waddling gait. Radiographs showed platyspondyly with anterior wedging and endplate irregularities, broad femoral necks, and large epiphyses and epiphyseal equivalents. Differential diagnosis included progressive pseudorheumatoid dysplasia and SED-S. A skeletal dysplasia custom-designed NGS panel was performed and the heterozygous pathogenic variant c.620G>A; p.(Gly207Glu) in COL2A1 was detected, establishing the diagnosis of SED-S. Vertebral fusions, observed in our patient, have not been previously described in this dysplasia. This variant has not been previously associated with SED-S, but was reported in two other families with spondyloepiphyseal dysplasia. Thus, this case expands the clinical and mutational spectrum of SED-S and demonstrates that SED-S significantly overlaps with other skeletal dysplasias.

[Acute myocardial infarction caused by thrombosis of left main coronary artery. Report of two cases]. / Importancia del electrocardiograma en el diagnóstico del infarto agudo al miocardio por obstrucción del tronco común de arteria coronaria izquierda.

Acute myocardial infarction caused by thrombosis of left main coronary artery generate acute cardiac failure, cardiogenic shock and death. Along with the clinical history, the electrocardiogram (EKG) is the most useful tool for its recognition and timely management. Classically the EKG shows ST elevation > 1 mm in aVR or V1 with ST depression in the other leads. Urgent coronary angiography with percutaneous coronary angioplasty using drug eluting stents is recommended when the diagnosis is made. We report two cases to exemplify the clinical presentation, EKG and angiographic findings and therapeutic approach.

Utilizing Physiological Principles of Motor Unit Recruitment to Reduce Fatigability of Electrically-Evoked Contractions: A Narrative Review.

Neuromuscular electrical stimulation (NMES) is used to produce contractions to restore movement and reduce secondary complications for individuals experiencing motor impairment. NMES is conventionally delivered through a single pair of electrodes over a muscle belly or nerve trunk using short pulse durations and frequencies between 20 and 40Hz (conventional NMES). Unfortunately, the benefits and widespread use of conventional NMES are limited by contraction fatigability, which is in large part because of the nonphysiological way that contractions are generated. This review provides a summary of approaches designed to reduce fatigability during NMES, by using physiological principles that help minimize fatigability of voluntary contractions. First, relevant principles of the recruitment and discharge of motor units (MUs) inherent to voluntary contractions and conventional NMES are introduced, and the main mechanisms of fatigability for each contraction type are briefly discussed. A variety of NMES approaches are then described that were designed to reduce fatigability by generating contractions that more closely mimic voluntary contractions. These approaches include altering stimulation parameters, to recruit MUs in their physiological order, and stimulating through multiple electrodes, to reduce MU discharge rates. Although each approach has unique advantages and disadvantages, approaches that minimize MU discharge rates hold the most promise for imminent translation into rehabilitation practice. The way that NMES is currently delivered limits its utility as a rehabilitative tool. Reducing fatigability by delivering NMES in ways that better mimic voluntary contractions holds promise for optimizing the benefits and widespread use of NMES-based programs.

Reliability of Hand-Held Transcranial Doppler with M-mode Ultrasound in Middle Cerebral Artery Measurement.

PURPOSE: To determine the intra- and interrater agreement of mean flow velocity (MFV) and pulsatility index (PI) measurement in middle cerebral arteries, assessed by transcranial Doppler (TCD) with M-mode. METHODS: Masked experienced neurosonologists performed TCD with M-mode using handheld probe in healthy adult volunteers. The Bland-Altman method for concordance and intraclass correlation coefficient were used. RESULTS: Seventy-seven healthy volunteers and seven raters participated (3 on regular TCD shift and 4 off-shift). The intrarater absolute mean difference between measurements was 5.5 cm/s [95% confidence interval (CI), 4.7-6.3] for MVF and 0.073 (95% CI, 0.063-0.083) for PI. The difference between MFV measurements was significantly higher in off-shift raters (p = 0.015). The interrater absolute mean difference between measurements was 6.5 cm/s (95% CI, 5.5-7.5) for MVF and 0.065 (95% CI, 0.059-0.071) for PI. No influence was found for the middle cerebral artery side, volunteer's sex, or age, and there was no significant difference between raters. The intraclass correlation coefficient was 82.2% (95% CI 77.8-85.6) and 72.9% (95% CI 67.4-77.6) for MFV and PI, respectively. CONCLUSIONS: There exists good intra- and interrater agreement in MFV and PI measurements using M-mode TCD. These results support the use of this noninvasive tool and are important for clinical and investigational purposes.

Head Position in the Early Phase of Acute Ischemic Stroke: An International Survey of Current Practice.

BACKGROUND: Evidence to recommend a specific head position for patients in the early phase of acute ischemic stroke (AIS) is scarce. The aim of this study was to assess current head position practice for AIS patients among physicians from hospitals in different countries. METHODS: A cross-sectional survey research design was used; physicians who are part of a stroke research network were invited to participate by e-mail. Descriptive statistics were used. RESULTS: An invitation to participate was delivered to 298 doctors from 16 countries and 42.9% completed all survey questions. Participant responses were evenly divided in sitting up and lying flat position as the most usual at their hospital: 52.8% (95% confidence interval [CI], 43.7-61.0) of respondents preferred sitting up, whereas 47.2% (95% CI, 38.2-55.5) preferred lying flat; 53.9% (95% CI, 45.3-62.5) of participants answered that no written protocol specifying the indicated head position for stroke patients was available at their hospital or department, and 71% (95% CI, 63.2-78.9) recognized being uncertain about the best position for AIS patients. CONCLUSIONS: Common practice differs between physicians, and there is a lack of consensus about the best strategy regarding head position for AIS patients in many countries. An opportunity exists for a randomized trial to resolve this uncertainty and develop evidence-based consensus protocols to improve patient management and outcomes.

[Human papillomavirus testing in cervical cancer screening at a public health service of Santiago, Chile]. / Examen de detección de virus papiloma humano en el tamizaje de cáncer cervicouterino en un Servicio de Salud de Santiago, Chile.

BACKGROUND: Molecular techniques for human papillomavirus (HPV) detection have a good performance as screening tests and could be included in cervical cancer early detection programs. We conducted a population-based trial comparing HPV detection and Papanicolaou as primary screening tests, in a public health service in Santiago, Chile. AIM: To describe the experience of implementing this new molecular test and present the main results of the study. MATERIAL AND METHODS: Women aged 25 to 64 enrolled in three public health centers were invited to participate. In all women, samples were collected for Papanicolaou and HPV DNA testing, and naked-eye visual inspection of the cervix with acetic acid was performed. Women with any positive screening test were referred to the local area hospital for diagnostic confirmation with colposcopy and biopsy of suspicious lesions. RESULTS: Screening results were obtained for 8265 women, of whom 931 (11.3%) were positive to any test. The prevalence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was 1.1%; nine women had invasive cervical cancer. Sensitivities for the detection of CIN2+ were 22.1% (95% confidence interval (CI) 16.4-29.2) for Papanicolaou and 92.7% (95% CI 84.4-96.8) for HPV testing; specificities were 98.9% (95% CI 98.7-99.0) and 92.0% (95% CI 91.4-92.6) respectively. CONCLUSION: This experience showed that the implementation of a molecular test for cervical cancer screening is not a major challenge in Chile: it was well accepted by both the health team and the participants, and it may improve the effectiveness of the screening program.

Elevated lung cancer in younger adults and low concentrations of arsenic in water.

Arsenic concentrations greater than 100 µg/L in drinking water are a known cause of cancer, but the risks associated with lower concentrations are less well understood. The unusual geology and good information on past exposure found in northern Chile are key advantages for investigating the potential long-term effects of arsenic. We performed a case-control study of lung cancer from 2007 to 2010 in areas of northern Chile that had a wide range of arsenic concentrations in drinking water. Previously, we reported evidence of elevated cancer risks at arsenic concentrations greater than 100 µg/L. In the present study, we restricted analyses to the 92 cases and 288 population-based controls who were exposed to concentrations less than 100 µg/L. After adjustment for age, sex, and smoking behavior, these exposures from 40 or more years ago resulted in odds ratios for lung cancer of 1.00, 1.43 (90% confidence interval: 0.82, 2.52), and 2.01 (90% confidence interval: 1.14, 3.52) for increasing tertiles of arsenic exposure, respectively (P for trend = 0.02). Mean arsenic water concentrations in these tertiles were 6.5, 23.0, and 58.6 µg/L. For subjects younger than 65 years of age, the corresponding odds ratios were 1.00, 1.62 (90% confidence interval: 0.67, 3.90), and 3.41 (90% confidence interval: 1.51, 7.70). Adjustments for occupation, fruit and vegetable intake, and socioeconomic status had little impact on the results. These findings provide new evidence that arsenic water concentrations less than 100 µg/L are associated with higher risks of lung cancer.

The effect of a cognitive training therapy based on stimulation of brain oscillations in patients with mild cognitive impairment in a Chilean sample: study protocol for a phase IIb, 2 × 3 mixed factorial, double-blind randomised controlled trial.

BACKGROUND: The ageing population has increased the prevalence of disabling and high-cost diseases, such as dementia and mild cognitive impairment (MCI). The latter can be considered a prodromal phase of some dementias and a critical stage for interventions to postpone the impairment of functionality. Working memory (WM) is a pivotal cognitive function, representing the fundamental element of executive functions. This project proposes an intervention protocol to enhance WM in these users, combining cognitive training with transcranial electrical stimulation of alternating current (tACS). This technique has been suggested to enhance the neuronal plasticity needed for cognitive processes involving oscillatory patterns. WM stands to benefit significantly from this approach, given its well-defined electrophysiological oscillations. Therefore, tACS could potentially boost WM in patients with neurodegenerative diseases. METHODS: This study is a phase IIb randomised, double-blind clinical trial with a 3-month follow-up period. The study participants will be 62 participants diagnosed with MCI, aged over 60, from Valparaíso, Chile. Participants will receive an intervention combining twelve cognitive training sessions with tACS. Participants will receive either tACS or placebo stimulation in eight out of twelve training sessions. Sessions will occur twice weekly over 6 weeks. The primary outcomes will be electroencephalographic measurements through the prefrontal theta oscillatory activity, while the secondary effects will be cognitive assessments of WM. The participants will be evaluated before, immediately after, and 3 months after the end of the intervention. DISCUSSION: The outcomes of this trial will add empirical evidence about the benefits and feasibility of an intervention that combines cognitive training with non-invasive brain stimulation. The objective is to contribute tools for optimal cognitive treatment in patients with MCI. To enhance WM capacity, postpone the impairment of functionality, and obtain a better quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05291208. Registered on 28 February 2022. ISRCTN87597719 retrospectively registered on 15 September 2023.