Influence of the Type of Antiretroviral Treatment on the Time to Reach High Pharmacotherapy Complexity in People Living With HIV.

BACKGROUND: The introduction of antiretroviral therapy (ARV) has significantly improved the survival of people living with HIV (PLWH), increasing the proportion of individuals over 50 years old. This aging trend poses challenges, such as the development of age-related comorbidities and a higher prevalence of polypharmacy. The pharmacotherapeutic complexity, assessed using the Medication Regimen Complexity Index (MRCI), is crucial for identifying and optimizing treatment, especially in elderly and polymedicated patients. OBJECTIVE: The main objective was to assess the association between different ARV regimens and the time required to reach a high level of pharmacotherapeutic complexity in PLWH. METHODS: A single-center observational analytical research study was conducted, including adult PLWH on active ARV from January 2010 to December 2021 with follow-up until December 2023. An analysis of the time to reach MRCI ≥11.25 was performed, followed by a Cox regression model to determine the influence of ARV on high MRCI. RESULTS: A total of 789 PLWH were included, median age of 52 years (interquartile range: 45-58). Overall, 195 patients had an MRCI value ≥11.25 with a mean time to reach it of 181.86 months (95% confidence interval [CI]: 176.24 to 187.49). Significant differences were observed in sex, advanced age, AIDS stage, presence of comorbidities, polypharmacy, and ARV-related variables. A multivariate Cox proportional hazards model showed an association between integrase inhibitor (INSTI)-containing regimens (hazard ratio [HR]: 1.83; 95% CI: 1.08 to 3.10) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (HR: 0.72; 95% CI: 0.52 to 0.98) with the time to reach high MRCI. CONCLUSIONS AND RELEVANCE: In summary, NNRTI-based regimens were associated with a lower likelihood of developing high MRCI compared to INSTI-based regimens, which was associated with a higher likelihood. These conclusions are based on a profile of PLWH that included advanced age and a high prevalence of comorbidities and polypharmacy. Identifying high MRCI may help us implement pharmacotherapeutic optimization strategies to improve health outcomes.

Tratamiento de paciente clase III esqueletal por hipoplasia maxilar con canino superior retenido / Treatment of skeletal class III patient due to maxillary hypoplasia with retained upper canine

La maloclusión clase III esqueletal por hipoplasia maxilar puede provocar la retención de algunas piezas dentales, ocupando los caninos superiores el tercer lugar de los dientes más afectados; por lo que es necesario el trabajo interdisciplinario con otras especialidades odontológicas para su correcto abordaje quirúrgico. Mientras que, para la corrección de la hipoplasia maxilar, el expansor Hyrax es el tratamiento ortopédico más utilizado en pacientes con crecimiento remanente. Se presenta caso clínico de paciente femenina de 14 años, clase III esqueletal por hipoplasia maxilar, biotipo mesofacial, perfil cóncavo, mordida cruzada anterior y posterior unilateral izquierda con canino superior derecho retenido. Los principales objetivos fueron: corregir la mordida cruzada y traccionar el canino retenido a su correcta posición. Al finalizar el tratamiento se eliminó la mordida cruzada y se logró la expansión palatina, incorporando así, el canino retenido en el arco dentario. En conclusión, el correcto diagnóstico, el adecuado plan de tratamiento y la atención temprana de la paciente fueron factores indispensables ya que proporcionaron un pronóstico favorable y un tratamiento conservador, evitando futuras complicaciones y tratamientos invasivos.

Skeletal class III malocclusion due to maxillary hypoplasia can cause the retention of some teeth, with the upper canines occupying the third place of the most affected teeth; therefore, interdisciplinary work with other dental specialties is necessary for its correct surgical approach. Likewise, for the correction of maxillary hypoplasia, the Hyrax expander is the most commonly used orthopedic treatment in patients with remnant growth. We present a clinical case of a 14-year-old female patient, skeletal class III due to maxillary hypoplasia, mesofacial biotype, concave profile, left unilateral anterior and posterior crossbite with retained right upper canine. The main objectives were: to correct the crossbite and pull the retained canine to its correct position. At the end of the treatment, the crossbite was eliminated and palatal expansion was achieved, thus incorporating the canine retained in the dental arch. In conclusion, the correct diagnosis, the adequate treatment plan and the early care of the patient were indispensable factors since they pro-vided a favorable prognosis and conservative treatment, avoiding future complications and invasive treatments.

Learning, internalisation and integration of the COVID-19 pandemic in healthcare workers: A qualitative document analysis.

The COVID-19 pandemic triggered an unprecedented health crisis that impacted healthcare systems worldwide. This study explores how Spanish healthcare workers learned, internalised and integrated values and work behaviours during the COVID-19 pandemic and their impact on the personal sphere. This documentary research, using images, narratives and audiovisual content, was framed within the interpretative hermeneutic paradigm. Categories and subcategories emerged after a final theoretical sampling that focused on the analysis. Data triangulation between researchers favoured theoretical saturation. A total of 117 images and 27 texts were selected. The analysis identified three stages: bewilderment, seeking functionality in the chaos and integrating chaos into care. The data reflects how the need for security and knowledge, and the exhaustion and frustration caused by the initial working conditions, prompted adaptive responses. These responses involved focusing on problem-solving and strengthening group sentiments and solidarity. Subsequently, the data indicates the acceptance of new structural, organisational and communication aspects. The findings of the analysis will contribute towards finding a framework that can help understand community health crisis events.

Correlates of Theta and Gamma Activity during Visuospatial Incidental/Intentional Encoding and Retrieval Indicate Differences in Processing in Young and Elderly Healthy Participants.

Incidental visuospatial learning acquired under incidental conditions is more vulnerable to aging than in the intentional case. The theta and gamma correlates of the coding and retrieval of episodic memory change during aging. Based on the vulnerability of incidental coding to aging, different theta and gamma correlates could occur under the incidental versus intentional coding and retrieval of visuospatial information. Theta and gamma EEG was recorded from the frontotemporal regions, and incidental/intentional visuospatial learning was evaluated in young (25-60 years old) and elderly (60-85 years old) participants. The EEG recorded during encoding and retrieval was compared between incidental low-demand, incidental high-demand, and intentional conditions through an ANCOVA considering the patient's gender, IQ, and years of schooling as covariates. Older adults exhibited worse performances, especially in place-object associations. After the intentional study, older participants showed a further increase in false-positive errors. Higher power at the theta and gamma bands was observed for frontotemporal derivations in older participants for both encoding and retrieval. Under retrieval, only young participants had lower power in terms of errors compared with correct responses. In conclusion, the different patterns of power and coherence support incidental and intentional visuospatial encoding and retrieval in young and elderly individuals. The correlates of power with behavior are sensitive to age and performance.

Profile of female survivors of sexual violence in the first 6 months of the COVID-19 quarantine in the city of Campinas, Brazil: A cross-sectional retrospective study.

OBJECTIVES: Describe the characteristics and changes in the profile of women who sought care after experiencing sexual violence (SV) during the first six months of the COVID-19 pandemic in a Brazilian city. METHODS: This is a cross-sectional retrospective study. Data from emergency care and legal abortion requests of women assisted at the Women's Health Care Center Hospital (School of Medical Sciences, University of Campinas, Brazil) due to SV experienced between March 23 and August 23, 2020 (Quarantine Group, QG), were collected and compared with data from the same period of the previous biennium (Comparison Group, CG). χ2 and Fisher's exact tests were used to compare groups; the significance level was 5%. RESULTS: Data for 236 women were analyzed; 70 women were included in the QG and 166 in the CG. In the QG, there was a restriction in the area of origin of women, with a higher proportion of women who lived in Campinas (P = 0.0007) and a higher frequency of chronic SV (P = 0,035). There were no rapes associated with the use of social media or apps in the QG, but 9.8% of women in the CG experienced rape associated with the use of social media or apps. There were higher rates of domestic violence (P = 0.022) and intimidation through physical force (P = 0.011) in the first two months. CONCLUSION: The COVID-19 quarantine affected the profile of women who sought care after experiencing SV. The quarantine resulted in changes in the area of origin of patients, hindering access to health services and leading to higher rates of chronic and domestic SV, particularly in the first 2 months of the pandemic.

Conductive extracellular matrix derived/chitosan methacrylate/ graphene oxide-pegylated hybrid hydrogel for cell expansion.

Electrical stimulation has emerged as a cornerstone technique in the rapidly evolving field of biomedical engineering, particularly within the realms of tissue engineering and regenerative medicine. It facilitates cell growth, proliferation, and differentiation, thereby advancing the development of accurate tissue models and enhancing drug-testing methodologies. Conductive hydrogels, which enable the conduction of microcurrents in 3D in vitro cultures, are central to this advancement. The integration of high-electroconductive nanomaterials, such as graphene oxide (GO), into hydrogels has revolutionized their mechanical and conductivity properties. Here, we introduce a novel electrostimulation assay utilizing a hybrid hydrogel composed of methacryloyl-modified small intestine submucosa (SIS) dECM (SISMA), chitosan methacrylate (ChiMA), and GO-polyethylene glycol (GO-PEG) in a 3D in vitro culture within a hypoxic environment of umbilical cord blood cells (UCBCs). Results not only demonstrate significant cell proliferation within 3D constructs exposed to microcurrents and early growth factors but also highlight the hybrid hydrogel's physiochemical prowess through comprehensive rheological, morphological, and conductivity analyses. Further experiments will focus on identifying the regulatory pathways of cells subjected to electrical stimulation.

Job satisfaction in midwives working in labour ward: A systematic review with meta-analysis.

PROBLEM: There is little documented evidence of job satisfaction in midwives who work in birthing rooms. BACKGROUND: Job satisfaction in midwives who work in birthing rooms may have changed in recent decades due to the medicalization of maternal health. AIM: To analyse job satisfaction levels among midwives working in birthing rooms. METHODS: We searched Web of Science, SCOPUS, MEDLINE, CUIDEN and CINAHL for observational and mixed method studies. The literature search was carried out from September to October 2022. FINDINGS: A total of 13 studies were included in the systematic review. A meta-analysis of the variable "midwives' job satisfaction" was performed on 12 of the studies. Midwives rated their job satisfaction positively: DME, CI (95%) = 1.24 [0.78, 1.69]. Subgroup 1: DME, CI (95%) = 2.41 [2.05, 2.76]); Subgroup 2: DME, CI (95%) = 0.76 [0.65, 0.86]; subgroup 3: DME, CI (95%) = 1.11 [0.95, 1.27]; subgroup 4: DME, CI (95%) = 0.10 [-0.11, 0.31]. DISCUSSION: Although midwives show high levels of satisfaction, the heterogeneity of instruments, lack of specificity and limited number of studies found restrict the outcomes. CONCLUSION: There are no specific measurement instruments for assessing job satisfaction among midwives working in labour wards, so it is possible that these data do not correspond to reality as they do not take into account specific professional aspects within this field of practice.

Concordance between two models of stratification for patients living with HIV infection to providing pharmaceutical care. / [Artículo traducido] Concordancia entre 2 modelos de estratificación de pacientes que viven con el VIH para la prestación de atención farmacéutica.

OBJECTIVE: To determine the degree of agreement of two differents stratification models for pharmaceutical care to people living with HIV. METHODS: This was a single-centre observational prospective cohort study of patients with regular follow-up in pharmaceutical care consultations according to the Capacity-Motivation-Opportunity methodology, conducted between January 1st and March 31th, 2023. Patients received the pharmacotherapeutic interventions applied routinely to ambulatory care patients according to this model. As part of the usual clinical practice, the presence or absence of the variables that apply to both stratification models were collected. The scores obtained and the corresponding stratification level were collected for each patient according to both stratification models published (ST-2017 and ST-2022). To analyze the reliability between the measurements of two numerical score models of the stratification level with both tools, their degree of concordance was calculated using the intraclass correlation coefficient. Likewise, reliability was also evaluated from a qualitative perspective by means of Cohen's Kappa coefficient. Additionally, the existence of correlation between the scores of the two models was assessed by calculating Pearson's correlation coefficient. RESULTS: Of the total of 758 patients being followed in the cohort, finally, 233 patients were enrolled. The distribution of patients for each stratification model was: ST-2017: 59.7% level-3, 25.3% level-2 and 15.0% level-1, while for ST-2022: 60.9% level-3, 26.6% level-2 and 12.4% level-1. It was observed that the reclassification was symmetrical (p=0.317). The qualitative analysis of the agreement between the models showed a good Cohen's kappa value, (K=0.66). A value of 0.563 was found as the intraclass correlation coefficient. Finally, the correlation analysis between the quantitative scores of the two models yielded a Pearson correlation coefficient of 0.86. CONCLUSIONS: The concordance between the two models was good, which confirms that the multidimensional adaptation and simplification of the model were correct and that its use can be extended in routine clinical practice.

Analysis to retreatment with monoclonal antibodies in chronic/episodic migraine: Real world data. / [Artículo traducido] Análisis del retratamiento con anticuerpos monoclonales en la migraña crónica/episódica: datos en vida real.

OBJECTIVE: To analyze the response to retreatment in patients with chronic/episodic migraine who discontinued therapy with erenumab/fremanezumab after one year of treatment. METHODS: Observational, retrospective, single-center, multidisciplinary study in patients with chronic/episodic migraine who received therapy with erenumab/fremanezumab for at least one year and discontinued it after achieving an adequate response (optimization). The evaluation of the response after retreatment included the following variables: migraine days per month, MIDAS and HIT-6 scales at the beginning of retreatment and 3 months later. The response was evaluated in different subgroups (episodic/chronic, erenumab/fremanezumab and time until retreatment). RESULTS: 48 patients were included. 70.8% (n=34) required retreatment with mAb, with a median of 3.9 (2.9-6.4) months until reintroduction. Clinical response after retreatment was achieved in 67.6% (n=23) of patients. No statistically significant differences were found in the analyzed subgroups. CONCLUSION: Interruption of treatment with erenumab/fremanezumab for chronic/episodic migraine produces a clinical worsening of the disease requiring retreatment in most cases, approximately after 4 months. Two out of three patients respond positively after restarting monoclonal therapy. This response does not appear to be related to the type of migraine, the specific monoclonal antibody prescribed, or the time to retreatment.

Telematic Interview in Telepharmacy: a comprehensive guide for pharmacotherapeutic follow-up and and informed drug delivery. / [Artículo traducido] Entrevista telemática en telefarmacia: documento de consenso para el seguimiento farmacoterapéutico y la entrega informada de medicamentos.

Telepharmacy is defined as the practice of remote pharmaceutical care, using information and communication technologies. Given its growing importance in outpatient pharmaceutical care, the Spanish Society of Hospital Pharmacy developed a consensus document, Guía de entrevista telemática en atención farmacéutica, as part of its strategy for the development and expansion of telepharmacy, with key recommendations for effective pharmacotherapeutic monitoring and informed dispensing and delivery of medications through telematic interviews. The document was developed by a working group of hospital pharmacists with experience in the field. It highlights the benefits of telematic interviewing for patients, hospital pharmacy professionals, and the healthcare system as a whole, reviews the various tools for conducting telematic interviews, and provides recommendations for each phase of the interview. These recommendations cover aspects such as tool/platform selection, patient selection, obtaining authorization and consent, assessing technological skills, defining objectives and structure, scheduling appointments, reviewing medical records, and ensuring humane treatment. Telematic interview is a valuable complement to face-to-face consultations but its novelty requires a strategic and formal framework that this consensus document aims to cover. The use of appropriate communication tools and compliance with recommended procedures ensure patient safety and satisfaction. By implementing telematic interviews, healthcare institutions can improve patient care, optimize the use of resources and promote continuity of care.

Streptococcus iniae in aquaculture: a review of pathogenesis, virulence, and antibiotic resistance.

One of the main challenges in aquaculture is pathogenic bacterial control. Streptococcus iniae stands out for its ability to cause high mortality rates in populations of commercially important fish populations and its recent recognition as an emerging zoonotic pathogen. The rise in identifying over 80 strains some displaying antibiotic resistance coupled with the emerging occurrence of infections in marine mammal species and wild fish underscores the urgent need of understanding pathogenesis, virulence and drug resistance mechanisms of this bacterium. This understanding is crucial to ensure effective control strategies. In this context, the present review conducts a bibliometric analysis to examine research trends related to S. iniae, extending into the mechanisms of infection, virulence, drug resistance and control strategies, whose relevance is highlighted on vaccines and probiotics to strengthen the host immune system. Despite the advances in this field, the need for developing more efficient identification methods is evident, since they constitute the basis for accurate diagnosis and treatment.

Comparative analysis of the prevalence 3-HIT concept in people living with HIV and seronegative patients with chronic conditions. Cross-3HIT Project.

OBJECTIVES: This study aimed to assess and compare the occurrence of 3-HIT in people living with HIV (PLWH) and seronegative patients. Additionally, the study investigated whether HIV infection could serve as a predictor of the presence of 3-HIT. METHODS: A cross-sectional study was conducted between December 2022 and January 2023 to compare PLWH with a group of seronegative patients with chronic diseases attending an outpatient hospital pharmacy service. The 3-HIT concept encompasses the simultaneous presence of non-adherence to concomitant treatment (NAC), drug-drug interactions (DDIs), and high pharmacotherapeutic complexity in polymedicated patients. The assessment of 3-HIT compliance included NAC, evaluated using both the Morisky-Green questionnaire and electronic pharmacy dispensing records. DDIs were analysed using the Liverpool University and Micromedex databases. Pharmacotherapeutic complexity was measured using the Medication Regimen Complexity Index (MRCI) tool. Logistic regression analysis was performed to identify independent factors related to 3-HIT. Additionally, an explanatory logistic model was created to investigate whether HIV infection, along with other adjustment variables, could predict compliance with the 3-HIT concept. RESULTS: The study included 145 patients: 75 PLWH and 70 seronegative patients. The median age was 40 versus 39 years, respectively (p=0.22). Seronegative patients exhibited a higher prevalence of NAC (p<0.01). HIV infection was identified as a protective factor in the context of DDIs (p<0.01). Male sex (p<0.01) and age (p=0.01) were identified as being associated with an MRCI ≥11.25 points. A higher prevalence of 3-HIT was observed in seronegative patients (18.7% vs 48.6%, p<0.01). However, the developed regression model identified HIV infection as a risk factor associated with an increased likelihood of 3-HIT (OR 4.00, 95% CI 1.88 to 8.52, p<0.01). CONCLUSIONS: The 3-HIT concept exhibited a high prevalence among seronegative patients with chronic diseases, with HIV infection identified as a predicted risk factor for NAC and the development of 3-HIT.

EEG before chimeric antigen receptor T-cell therapy and early after onset of immune effector cell-associated neurotoxicity syndrome.

BACKGROUND: Immune effector cell-associated neurotoxicity syndrome (ICANS) is common after chimeric antigen receptor T-cell (CAR-T) therapy. OBJECTIVE: This study aimed to assess the impact of preinfusion electroencephalography (EEG) abnormalities and EEG findings at ICANS onset for predicting ICANS risk and severity in 56 adult patients with refractory lymphoma undergoing CAR-T therapy. STUDY DESIGN: EEGs were conducted at the time of lymphodepleting chemotherapy and shortly after onset of ICANS. RESULTS: Twenty-eight (50%) patients developed ICANS at a median time of 6 days after CAR-T infusion. Abnormal preinfusion EEG was identified as a risk factor for severe ICANS (50% vs. 17%, P = 0.036). Following ICANS onset, EEG abnormalities were detected in 89% of patients [encephalopathy (n = 19, 70%) and/or interictal epileptiform discharges (IEDs) (n = 14, 52%)]. Importantly, IEDs seemed to be associated with rapid progression to higher grades of ICANS within 24 h. CONCLUSIONS: If confirmed in a large cohort of patients, these findings could establish the basis for modifying current management guidelines, enabling the identification of patients at risk of neurotoxicity, and providing support for preemptive corticosteroid use in patients with both initial grade 1 ICANS and IEDs at neurotoxicity onset, who are at risk of neurological impairment.

Telematic interview in telepharmacy: consensus document for farmacotherapeutic monitoring and informed drug delivery.

Telepharmacy is defined as the practice of remote pharmaceutical care, using information and communication technologies. Given its growing importance in outpatient pharmaceutical care, the Spanish Society of Hospital Pharmacy developed a consensus document, "Guía de entrevista telemática en atención farmacéutica," as part of its strategy for the development and expansion of telepharmacy, with key recommendations for effective pharmacotherapeutic monitoring and informed dispensing and delivery of medications through telematic interviews. The document was developed by a working group of hospital pharmacists with experience in the field. It highlights the benefits of telematic interviewing for patients, hospital pharmacy professionals, and the healthcare system as a whole, reviews the various tools for conducting telematic interviews, and provides recommendations for each phase of the interview. These recommendations cover aspects such as tool/platform selection, patient selection, obtaining authorization and consent, assessing technological skills, defining objectives and structure, scheduling appointments, reviewing medical records, and ensuring humane treatment. Telematic interview is a valuable complement to face-to-face consultations but its novelty requires a strategic and formal framework that this consensus document aims to cover. The use of appropriate communication tools and compliance with recommended procedures ensure patient safety and satisfaction. By implementing telematic interviews, healthcare institutions can improve patient care, optimize the use of resources and promote continuity of care.

Analysis of retreatment with monoclonal antibodies in chronic/episodic migraine: Real world data.

OBJECTIVE: To analyze the response to retreatment in patients with chronic/episodic migraine who discontinued therapy with erenumab/fremanezumab after 1 year of treatment. METHODS: Observational, retrospective, single-center, multidisciplinary study in patients with chronic/episodic migraine who received therapy with erenumab/fremanezumab for at least 1 year and discontinued it after achieving an adequate response (optimization). The evaluation of the response after retreatment included the following variables: DMM, MIDAS, and HIT-6 scales at the beginning of retreatment and 3 months later. The response was evaluated in different subgroups (episodic/chronic, erenumab/fremanezumab, and time until retreatment). RESULTS: 48 patients were included. 70.8% (n=34) required retreatment with mAb, with a median of 3.9 (2.9-6.4) months until reintroduction. Clinical response after retreatment was achieved in 67.6% (n=23) of patients. No statistically significant differences were found in the analyzed subgroups. CONCLUSION: Interruption of treatment with erenumab/fremanezumab for chronic/episodic migraine produces a clinical worsening of the disease requiring retreatment in most cases, approximately after 4 months. Two out of three patients respond positively after restarting monoclonal therapy. This response does not appear to be related to the type of migraine, the specific monoclonal antibody prescribed, or the time to retreatment.

Chronodisruption and Gut Microbiota: Triggering Glycemic Imbalance in People with Type 2 Diabetes.

The desynchronization of physiological and behavioral mechanisms influences the gut microbiota and eating behavior in mammals, as shown in both rodents and humans, leading to the development of pathologies such as Type 2 diabetes (T2D), obesity, and metabolic syndrome. Recent studies propose resynchronization as a key input controlling metabolic cycles and contributing to reducing the risk of suffering some chronic diseases such as diabetes, obesity, or metabolic syndrome. In this analytical review, we present an overview of how desynchronization and its implications for the gut microbiome make people vulnerable to intestinal dysbiosis and consequent chronic diseases. In particular, we explore the eubiosis-dysbiosis phenomenon and, finally, propose some topics aimed at addressing chronotherapy as a key strategy in the prevention of chronic diseases.

Concordance between two models of stratification for patients living with HIV infection to providing pharmaceutical care.

OBJECTIVE: To determine the degree of agreement of 2 differents stratification models for pharmaceutical care to people living with HIV. METHODS: This was a single-center observational prospective cohort study of patients with regular follow-up in pharmaceutical care consultations according to the Capacity-Motivation-Opportunity methodology, conducted between January 1 and March 31, 2023. Patients received the pharmacotherapeutic interventions applied routinely to ambulatory care patients according to this model. As part of the usual clinical practice, the presence or absence of the variables that apply to both stratification models were collected. The scores obtained and the corresponding stratification level were collected for each patient according to both stratification models published (ST-2017 and ST-2022). To analyze the reliability between the measurements of 2 numerical score models of the stratification level with both tools, their degree of concordance was calculated using the intraclass correlation coefficient. Likewise, reliability was also evaluated from a qualitative perspective by means of Cohen's Kappa coefficient. Additionally, the existence of correlation between the scores of the 2 models was assessed by calculating Pearson's correlation coefficient. RESULTS: Of the total of 758 patients being followed in the cohort, finally, 233 patients were enrolled. The distribution of patients for each stratification model was: ST-2017: 59.7% level-3, 25.3% level-2, and 15.0% level-1, while for ST-2022: 60.9% level-3, 26.6% level-2, and 12.4% level-1. It was observed that the reclassification was symmetrical (P=.317). The qualitative analysis of the agreement between the models showed a good Cohen's kappa value, (K=0.66). A value of 0.563 was found as the intraclass correlation coefficient. Finally, the correlation analysis between the quantitative scores of the 2 models yielded a Pearson correlation coefficient of 0.86. CONCLUSIONS: The concordance between the 2 models was good, which confirms that the multidimensional adaptation and simplification of the model were correct and that its use can be extended in routine clinical practice.

Expanding the Clinical Spectrum of DRP2-Associated Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined. METHODS: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain. RESULTS: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections. DISCUSSION: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.

2,3,7,8-Tetrachlorodibenzo-p-dioxin and kynurenine induce Parkin expression in neuroblastoma cells through different signaling pathways mediated by the aryl hydrocarbon receptor.

Parkin regulates protein degradation and mitophagy in dopaminergic neurons. Deficiencies in Parkin expression or function lead to cellular stress, cell degeneration, and the death of dopaminergic neurons, which promotes Parkinson's disease. In contrast, Parkin overexpression promotes neuronal survival. Therefore, the mechanisms of Parkin upregulation are crucial to understand. We describe here the molecular mechanism of AHR-mediated Parkin regulation in human SH-SY5Y neuroblastoma cells. Specifically, we report that the human Parkin gene (PRKN) is transcriptionally upregulated by the aryl hydrocarbon receptor (AHR) through two different selective ligand-dependent pathways. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a stress-inducing AHR ligand, indirectly promotes PRKN transcription by inducing ATF4 expression via TCDD-mediated endoplasmic reticulum (ER) stress. In contrast, kynurenine, a nontoxic AHR agonist, induces PRKN transcription by promoting AHR binding to the PRKN promoter without activating ER stress. Our results demonstrate that AHR activation may be a potential pharmacological pathway to induce human Parkin, but such a strategy must carefully consider the choice of AHR ligand to avoid neurotoxic side effects.