[Seronegative autoimmune hepatitis]. / Hepatitis autoinmune seronegativa.

Autoimmune hepatitis (AIH) is a rare, chronic, inflammatory, and necrotic liver disease characterized by the presence of autoantibodies. Its etiology is unknown. It affects 1 in 200 000 people annually in the US and occurs predominantly in women. Its presentation varies from asymptomatic forms to cirrhosis and acute liver failure and its diagnosis is based on the measurement of autoantibodies, such as antinuclear autoantibodies (ANA), anti-smooth muscle antibodies (ASMA) and anti-liver and kidney microsomal antibodies (anti-LKM). 1). 10% of HAIs do not present antibodies, being called seronegative HAI, requiring a liver biopsy for diagnosis. To date the evidence remains limited and different societies have issued suggestions and recommendations. For this reason, we believe it is relevant to carry out a bibliographic review on the subject, capturing in this document the important information for the understanding and management of this pathology.

La hepatitis autoinmune (HAI) es una enfermedad inflamatoria y necrótica del hígado, crónica e infrecuente caracterizada por la presencia de autoanticuerpos. Su etiología es desconocida. Afecta a 1 de cada 200 000 personas anualmente en los EE. UU. y se presenta predominantemente en mujeres. Su presentación varía desde formas asintomáticas hasta la cirrosis y falla hepática aguda y su diagnóstico se basa en la medición de autoanticuerpos, como los autoanticuerpos antinucleares (ANA), anticuerpos antimúsculo liso (ASMA) y anticuerpos antimicrosomales de hígado y riñón (anti-LKM-1). El 10% de las HAI no presentan anticuerpos, denominándose HAI seronegativa, necesitando biopsia hepática para el diagnóstico. Hasta la fecha la evidencia sigue siendo limitada y diferentes sociedades han emitido sugerencias y recomendaciones. Por tal motivo creemos relevante realizar una revisión bibliográfica sobre el tema plasmando en este documento la información importante para la compresión y el manejo de esta patología.

Molecular detection of Toxoplasma gondii in domestic and wild guinea pigs (Cavia spp.) from the Marangani district in Cuzco, Peru.

Toxoplasmosis is a foodborne disease caused by the protozoan Toxoplasma gondii, and transmitted to humans by eating raw or undercooked meat, mainly. Poultry, beef, and pork are the main meats consumed in Peru; despite this, guinea pig meat is also widely consumed. For this reason, the objective of this study was to molecularly detect T. gondii in domestic and wild guinea pigs from the Marangani district in Cuzco, Peru, and identify some risk factors associated with this pathogen. DNA was extracted from the brain tissue samples of guinea pigs (30 domestic and 30 wild), and PCR protocols were used to amplify the internal transcribed spacer (ITS-1) region and a 529 bp fragment from the T. gondii genome. T. gondii DNA was detected in 14 (23.3%) guinea pigs. T. gondii frequency was 33.3% in domestic guinea pigs and 13.3% in wild guinea pigs. Our results demonstrated that guinea pigs represent an important source for T. gondii infection in human populations in this locality.

Confronting the Unseen: A Journey Through Primary Intra-orbital Squamous Cell Carcinoma.

Cases of squamous cell carcinoma (SCC) that are primary in origin occur even more infrequently due to the lack of squamous epithelium that is typically present in the orbital region. When SCC occurs in the orbit, it is more commonly due to invasion or metastasis from a local site. We report an uncommon case of intra-orbital SCC in a 74-year-old male, which is likely of primary origin. Brain, face, orbital, and neck magnetic resonance imaging proceeded to gather more information on the extent of the patient's orbital malignancy, which showed significant orbital burden and intracranial extension. The biopsy was performed with final pathology results showing moderately differentiated SCC. The patient was discharged with a follow-up with oncology for chemotherapy and a follow-up with oculoplastics for surgical intervention in nine months, after completing a course of chemotherapy with irradiation. We provide this case to shed insight into the difficulties associated with the extremely uncommon occurrence of primary SCC of the orbit.

GLS and GLS2 Glutaminase Isoenzymes in the Antioxidant System of Cancer Cells.

A pathway frequently altered in cancer is glutaminolysis, whereby glutaminase (GA) catalyzes the main step as follows: the deamidation of glutamine to form glutamate and ammonium. There are two types of GA isozymes, named GLS and GLS2, which differ considerably in their expression patterns and can even perform opposing roles in cancer. GLS correlates with tumor growth and proliferation, while GLS2 can function as a context-dependent tumor suppressor. However, both isoenzymes have been described as essential molecules handling oxidant stress because of their involvement in glutathione production. We reviewed the literature to highlight the critical roles of GLS and GLS2 in restraining ROS and regulating both cellular signaling and metabolic stress due to their function as indirect antioxidant enzymes, as well as by modulating both reductive carboxylation and ferroptosis. Blocking GA activity appears to be a potential strategy in the dual activation of ferroptosis and inhibition of cancer cell growth in a ROS-mediated mechanism.

Discovery of GLPG3667, a Selective ATP Competitive Tyrosine Kinase 2 Inhibitor for the Treatment of Autoimmune Diseases.

Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound 9 (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced in vivo mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).

A Prospective Observational Study of Frailty in Geriatric Revitalization Aimed at Community-Dwelling Elderly.

(1) Background: The increasing life expectancy brings an increase in geriatric syndromes, specifically frailty. The literature shows that exercise is a key to preventing, or even reversing, frailty in community-dwelling populations. The main objective is to demonstrate how an intervention based on multicomponent exercise produces an improvement in frailty and pre-frailty in a community-dwelling population. (2) Methods: a prospective observational study of a multicomponent exercise program for geriatric revitalization with people aged over 65 holding Barthel Index scores equal to, or beyond, 90. The program was developed over 30 weeks, three times a week, in sessions lasting 45-50 min each. Frailty levels were registered by the Short Physical Performance Battery, FRAIL Questionnaire Screening Tool, and Timed "Up & Go" at the beginning of the program, 30 weeks later (at the end of the program), and following 13 weeks without training; (3) Results: 360 participants completed the program; a greater risk of frailty was found before the program started among older women living in urban areas, with a more elevated fat percentage, more baseline pathologies, and wider baseline medication use. Furthermore, heterogeneous results were observed both in training periods and in periods without physical activity. However, they are consistent over time and show improvement after training. They show a good correlation between TUG and SPPB; (4) Conclusions: A thirty-week multicomponent exercise program improves frailty and pre-frailty status in a community-dwelling population with no functional decline. Nevertheless, a lack of homogeneity is evident among the various tools used for measuring frailty over training periods and inactivity periods.

Study of late toxicity biomarkers of locally advanced head and neck cancer patients treated with radiotherapy plus cisplatin or cetuximab points to the relevance of skin macrophages (TOX-TTCC-2015-01).

PURPOSE: Radiotherapy (RT) with concomitant cisplatin (CRT) or cetuximab (ERT) are accepted treatment options for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Long-term adverse events (AEs) have a vast impact on patients' quality of life. This study explored tissue biomarkers which could help predict late toxicity. METHODS/PATIENTS: Single-institution prospective study including patients aged ≥ 18 with histologically confirmed newly diagnosed LA-SCCHN treated with RT and either concomitant cisplatin q3w or weekly cetuximab, according to institutional protocols. All patients underwent pre- and post-treatment skin biopsies of neck regions included in the clinical target volume. Angiogenesis, macrophages, and extracellular matrix (ECM) markers were evaluated by immunohistochemistry (IHC). RESULTS: From April 15, 2016, to December 11, 2017; 31 patients were evaluated [CRT = 12 (38.7%) and ERT = 19 (61.3%)]. 27 patients (87%) had received induction chemotherapy. All patients finished RT as planned. IHC expression of vasculature (CD34) and collagen (Masson's Trichrome) did not differ significantly between and within CRT and ERT arms. Conversely, an increased CD68 and CD163 macrophage infiltration expression was observed after treatment, without significant impact of treatment modality. Patients with higher late toxicity showed lower expression of macrophage markers in pre-treatment samples compared with those with lower late toxicity, with statistically significant differences for CD68. CONCLUSIONS: Angiogenesis and ECM biomarkers did not differ significantly between CRT and ERT. Macrophage markers increased after both treatments and deserve further investigation as predictors of late toxicity in LA-SCCHN patients. [Protocol code: TOX-TTCC-2015-01/Spanish registry of clinical studies (REec): 2015-003012-21/Date of registration: 27/01/2016].

Effects of PEEP on intracranial pressure in patients with acute brain injury: An observational, prospective and multicenter study.

OBJECTIVE: To analyze the impact of positive end-expiratory pressure (PEEP) changes on intracranial pressure (ICP) dynamics in patients with acute brain injury (ABI). DESIGN: Observational, prospective and multicenter study (PEEP-PIC study). SETTING: Seventeen intensive care units in Spain. PATIENTS: Neurocritically ill patients who underwent invasive neuromonitorization from November 2017 to June 2018. INTERVENTIONS: Baseline ventilatory, hemodynamic and neuromonitoring variables were collected immediately before PEEP changes and during the following 30 min. MAIN VARIABLES OF INTEREST: PEEP and ICP changes. RESULTS: One-hundred and nine patients were included. Mean age was 52.68 (15.34) years, male 71 (65.13%). Traumatic brain injury was the cause of ABI in 54 (49.54%) patients. Length of mechanical ventilation was 16.52 (9.23) days. In-hospital mortality was 21.1%. PEEP increases (mean 6.24-9.10 cmH2O) resulted in ICP increase from 10.4 to 11.39 mmHg, P < .001, without changes in cerebral perfusion pressure (CPP) (P = .548). PEEP decreases (mean 8.96 to 6.53 cmH2O) resulted in ICP decrease from 10.5 to 9.62 mmHg (P = .052), without changes in CPP (P = .762). Significant correlations were established between the increase of ICP and the delta PEEP (R = 0.28, P < .001), delta driving pressure (R = 0.15, P = .038) and delta compliance (R = -0.14, P = .052). ICP increment was higher in patients with lower baseline ICP. CONCLUSIONS: PEEP changes were not associated with clinically relevant modifications in ICP values in ABI patients. The magnitude of the change in ICP after PEEP increase was correlated with the delta of PEEP, the delta driving pressure and the delta compliance.

Association of Frailty with Postoperative Survival and Outcomes Following Hemodialysis Vascular Access Creation.

BACKGROUND: The literature suggests that for patients to experience the purported advantages of an arteriovenous fistula (AVF) over arteriovenous graft (AVG), a minimum survival of 18 months is required. With the vascular access guideline shift away from "Fistula First" toward shared decision making, patient survival after vascular access creation is a major factor to consider in optimal access selection. The objective of this study is to examine outcomes of vascular access in patients with short survival and factors associated with short survival, including frailty. METHODS: We performed a retrospective review of 200 access procedures performed between August 2018 and November 2020 at a single institution. Maturation was defined as the date when the surgeon deemed the access ready to be used for dialysis. A modified Risk Analysis Index (RAI) score was used to calculate frailty. RESULTS: Within 3 years after access creation, 55 (27.5%) patients were recorded as dead (mortality within 3 years of access creation [3YMORT]). In the 3YMORT group, 5 did not follow-up with the surgeon prior to death and 22/34 (65%) of AVF versus 15/16 (94%) of AVGs were deemed mature prior to death (P = 0.03). Of the accesses that matured, the median days to maturation for AVF was 69 (interquartile range [IQR] 53, 87) versus 28 (IQR 18, 32) for AVG (P < 0.001). Patients in the 3YMORT group were older (70.6 vs. 63.4, P = 0.004) and had a lower body mass index (24.8 vs. 27.4, P = 0.03). Patients in the 3YMORT group had higher prevalence of dysrhythmia (35% vs. 15%, P = 0.002), chronic obstructive pulmonary disorder (20% vs. 10%, P = 0.048) and dialysis dependence at the time of access creation (91% vs. 75%, P = 0.01). There was no significant difference in sex, white race, Hispanic ethnicity, coronary artery disease, congestive heart failure, previous coronary artery bypass graft or percutaneous coronary intervention, diabetes, hypertension, and peripheral arterial disease between the 2 groups. The 3YMORT group had a significantly higher prevalence of frailty (78% vs. 49%, P = 0.0002). Patients categorized as frail by the RAI had a significantly higher risk of 3YMORT (odds ratio [OR] 3.74, 95% confidence interval [CI] 1.82-7.66) compared to nonfrail patients. Patients categorized as very frail by the RAI had an even higher risk of 3YMORT (OR 4.20, 95% CI 1.95-9.05), compared to nonfrail patients. CONCLUSIONS: Patients with short life expectancy after vascular access creation may have high rates of AVF nonmaturation and longer time to maturation. Factors associated with high risk of mortality within 3 years of vascular access creation correlate well with factors included in the RAI frailty score. Patients who are frail or very frail may be appropriate candidates for AVG creation over AVF considering their high risk for short life expectancy.

Clinical impact of remote heart failure management using the multiparameter ICD HeartLogic alert.

INTRODUCTION AND OBJECTIVES: The multiparametric implantable cardioverter-defibrillator HeartLogic index has proven to be a sensitive and timely predictor of impending heart failure (HF) decompensation. We evaluated the impact of a standardized follow-up protocol implemented by nursing staff and based on remote management of alerts. METHODS: The algorithm was activated in HF patients at 19 Spanish centers. Transmitted data were analyzed remotely, and patients were contacted by telephone if alerts were issued. Clinical actions were implemented remotely or through outpatient visits. The primary endpoint consisted of HF hospitalizations or death. Secondary endpoints were HF outpatient visits. We compared the 12-month periods before and after the adoption of the protocol. RESULTS: We analyzed 392 patients (aged 69±10 years, 76% male, 50% ischemic cardiomyopathy) with implantable cardioverter-defibrillators (20%) or cardiac resynchronization therapy defibrillators (80%). The primary endpoint occurred 151 times in 86 (22%) patients during the 12 months before the adoption of the protocol, and 69 times in 45 (11%) patients (P<.001) during the 12 months after its adoption. The mean number of hospitalizations per patient was 0.39±0.89 pre- and 0.18±0.57 postadoption (P<.001). There were 185 outpatient visits for HF in 96 (24%) patients before adoption and 64 in 48 (12%) patients after adoption (P<.001). The mean number of visits per patient was 0.47±1.11 pre- and 0.16±0.51 postadoption (P<.001). CONCLUSIONS: A standardized follow-up protocol based on remote management of HeartLogic alerts enabled effective remote management of HF patients. After its adoption, we observed a significant reduction in HF hospitalizations and outpatient visits.

Comparative effectiveness of non-compounded polidocanol 1% endovenous microfoam (Varithena) ablation versus endovenous thermal ablation utilizing a systematic review and network meta-analysis.

OBJECTIVE: We compared the effectiveness and safety of polidocanol 1% endovenous microfoam ablation vs endovenous thermal ablation with radiofrequency or laser energy for treatment of venous insufficiency caused by lower extremity truncal vein incompetence via network meta-analysis of published comparative evidence. METHODS: We conducted a systematic literature review following best practices, including a prospective protocol. We screened studies published in English from 2000 to 2023 for randomized and nonrandomized studies reporting direct or indirect comparisons between polidocanol 1% endovenous microfoam and endovenous thermal ablation. Thirteen studies met our eligibility criteria for the network meta-analysis. The co-primary effectiveness outcomes were the closure rate ≥3 months after procedure and the average change in the Venous Clinical Severity Score. For the subgroup of venous ulcer patients, the ulcer healing rate was the primary effectiveness outcome. The secondary outcomes included safety and patient-reported outcomes. Network meta-analyses were conducted on outcomes having sufficient data. Categorical outcomes were summarized using odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity tests and estimates of network inconsistency were used to investigate the robustness of our meta-analysis. RESULTS: We found that polidocanol 1% endovenous microfoam was not significantly different statistically from endovenous thermal ablation for venous closure (OR, 0.65; 95% CI, 0.36-1.18; P = .16). Although not the primary aim of the study, the network meta-analysis also provided evidence to confirm our supposition that polidocanol 1% endovenous microfoam was significantly differentiated statistically from physician-compounded foam, with higher odds for vein closure (OR, 2.91; 95% CI, 1.58-5.37; P < .01). A sensitivity analysis using the longest available time point for closure in each study, with a minimum of 12 months of follow-up (median, 48 months; range, 12-72 months), showed results similar to those of the main analysis. No association was found between the risk of deep vein thrombosis and the treatment received. The available data were insufficient for a network meta-analysis of Venous Clinical Severity Score improvement and ulcer healing rates. CONCLUSIONS: Polidocanol 1% endovenous microfoam was not significantly different statistically from endovenous thermal ablation for venous closure and deep vein thrombosis risk for chronic venous insufficiency treatment, based on a network meta-analysis of published evidence. Polidocanol 1% endovenous microfoam was significantly differentiated statistically from physician-compounded foam, with higher odds of vein closure. A sensitivity analysis found venous closure findings were robust at follow-up intervals of 12 months or greater and for up to 6 years. New evidence meeting the inclusion criteria for this review will be incorporated at regular intervals into a living network meta-analysis.

The new record of drought and warmth in the Amazon in 2023 related to regional and global climatic features.

In 2023 Amazonia experienced both historical drought and warm conditions. On October 26th 2023 the water levels at the port of Manaus reached its lowest record since 1902 (12.70 m). In this region, October monthly maximum and minimum temperature anomalies also surpassed previous record values registered in 2015 (+ 3 °C above the normal considering the 1981-2020 average). Here we show that this historical dry and warm situation in Amazonia is associated with two main atmospheric mechanisms: (i) the November 2022-February 2023 southern anomaly of vertical integrated moisture flux (VIMF), related to VIMF divergence and extreme rainfall deficit over southwestern Amazonia, and (ii) the June-August 2023 downward motion over northern Amazonia related to extreme rainfall deficit and warm conditions over this region. Anomalies of both atmospheric mechanisms reached record values during this event. The first mechanism is significantly correlated to negative sea surface temperature (SST) anomalies in the equatorial Pacific (November-February La Niña events). The second mechanism is significantly correlated to positive SST anomalies in the equatorial Pacific, related to the impacts of June-September El Niño on the Walker Circulation. While previous extreme droughts were linked to El Niño (warmer North Tropical Atlantic SST) during the austral summer (winter and spring), the transition from La Niña 2022-23 to El Niño 2023 appears to be a key climatic driver in this record-breaking dry and warm situation, combined to a widespread anomalous warming over the worldwide ocean.

Nintedanib in chronic fibrosing interstitial lung diseases. A case series.

Progressive pulmonary fibrosis (PPF) can be fatal in non-idiopathic interstitial lung diseases. We report a descriptive series of 13 patients with PPF who received treatment with nintedanib, a multitargeted tyrosine kinase inhibitor with antifibrotic effect. Although the reduced number of patients and the observational nature of a case series prevent us from providing strong evidence, our results suggest that nintedanib could be effective in PPF of various etiologies. Nintedanib could also be useful in specific populations such as patients awaiting lung transplant and elderly patients.

Multidisciplinary Management of Patients With Chronic Obstructive Pulmonary Disease and Cardiovascular Disease

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) frequently coexist, increasing the prevalence of both entities and impacting on symptoms and prognosis. CVD should be suspected in patients with COPD who have high/very high risk scores on validated scales, frequent exacerbations, precordial pain, disproportionate dyspnea, or palpitations. They should be referred to cardiology if they have palpitations of unknown cause or angina pain. COPD should be suspected in patients with CVD if they have recurrent bronchitis, cough and expectoration, or disproportionate dyspnea. They should be referred to a pulmonologist if they have rhonchi or wheezing, air trapping, emphysema, or signs of chronic bronchitis. Treatment of COPD in cardiovascular patients should include long-acting muscarinic receptor antagonists (LAMA) or long-acting beta-agonists (LABA) in low-risk or high-risk non-exacerbators, and LAMA/LABA/inhaled corticosteroids in exacerbators who are not controlled with bronchodilators. Cardioselective beta-blockers should be favored in patients with CVD, the long-term need for amiodarone should be assessed, and antiplatelet drugs should be maintained if indicated. (AU)

Radiological usual interstitial pneumonia pattern is associated with two-year mortality in patients with idiopathic pulmonary fibrosis.

Introduction: The new diagnostic guidelines for idiopathic pulmonary fibrosis (IPF) did not rule out the possibility of combining the radiological patterns of usual interstitial pneumonia (UIP) and probable UIP, given the similar management and diagnostic capacity. However, the prognostic implications of these patterns have not been fully elucidated, with different studies showing heterogeneous results. We applied the new criteria to a retrospective series of patients with IPF, assessing survival based on radiological patterns, findings, and their extension. Methods: Two thoracic radiologists reviewed high-resolution computed tomography images taken at diagnosis in 146 patients with IPF, describing the radiological findings and patterns. The association of each radiological finding and radiological patterns with two-year mortality was analysed. Results: The two-year mortality rate was 40.2% in IPF patients with an UIP radiological pattern versus 7.1% in those with probable UIP. Compared to the UIP pattern, probable UIP was protective against mortality, even after adjusting for age, sex, pulmonary function, and extent of fibrosis (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.06-0.99). Receiving antifibrotic treatment was also a protective factor (HR 0.51, 95%CI 0.27-0.98). Honeycombing (HR 3.62, 95%CI 1.27-10.32), an acute exacerbation pattern (HR 4.07, 95%CI 1.84-8.96), and the overall extent of fibrosis (HR 1.04, 95%CI 1.02-1.06) were predictors of mortality. Conclusions: In our series, two-year mortality was higher in patients with IPF who presented a radiological pattern of UIP versus probable UIP on the initial scan. Honeycombing, an acute exacerbation pattern, and a greater overall extent of fibrosis were also predictors of increased mortality. The prognostic differences between the radiological pattern of UIP and probable UIP in our series would support maintaining them as two differentiated patterns.

Telehealth in Informal Caregivers of Stroke Survivors: A Systematic Review.

Background: There has been an increase in people with disabilities who require continuous care, which often falls to informal carers (ICs). Stroke is one of the conditions where ICs are most needed. Therefore, it is necessary for ICs to improve their caregiving skills and self-care capacity. Telehealth (TH) can facilitate them. The aim of this systematic review is to summarize the evidence of the effects of interventions on ICs of stroke patients. Methods: The search was conducted in Pubmed, Scopus, Web of Science, CINALH, Psychology and Behavioral Sciences Collection, and APA PsycInfo. Key search terms included "stroke", "informal caregiver" and "telemedicine". Only randomised clinical trials were included. Results: A total of 2031 articles were found in the databases, 476 were screened and 19 clinical trials met the eligibility criteria. Different TH programmes have evaluated many outcomes related to physical and emotional health. The TH tools included phone, videophone, web-based interventions, and social media. The most investigated outcome was depression; although contradictory results were found, the TH may have helped to prevent an increase in depressive symptoms. There were inconsistent results on the caregiving burden and the preparedness of the IC. However, TH has positive effects on the health of the ICs, reducing the number of unhealthy days, anxiety, task difficulty perception, and improving psychological health. Conclusions: TH may be a useful tool to improve the abilities and health of ICs of SS. No adverse effects have been reported. More quality studies evaluating the effects of telemedicine on the ICs of stroke survivors, as well as the most appropriate doses, are needed.

Composition, Optical Resonances, and Doping of InP/InGaP Nanowires for Tandem Solar Cells: a Micro-Raman Analysis.

We present a micro-Raman study of InP/InGaP tandem junction photovoltaic nanowires. These nanowires render possible InGaP compositions that cannot be made in thin films due to strain. The micro-Raman spectra acquired along the nanowires reveal the existence of compositional changes in the InGaP alloy associated with the doping sequence. The heavily Zn-doped InxGa1-xP (x is the In molar fraction) side of the tunnel diode is Ga rich, x = 0.25, with respect to the n-type and intrinsic segments of the top cell, which are close to the nominal composition of the NWs (x = 0.35). The p-type end segment is still Ga-rich. Electromagnetic resonances are observed in the tunnel diode. The Raman signal arising from the InGaP side of the tunnel diode is significantly enhanced. This enhancement permits the observation of a Raman mode that can be associated with an LO phonon plasmon coupled mode (LOPCM). This mode has not been previously reported in the literature of InGaP, and it permits the Raman characterization of the tunnel diode. The analysis of this mode and its relation to the LO phonon modes of the alloy, InP-like and GaP-like, allows to establish an apparent one-mode behavior for the phonon plasmon coupling. It indicates that hole plasma couples to the GaP-like LO mode. The LOPCMs are modeled using the Lindhard Mermin formalism for the dielectric function.

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.

The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (32), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC50 of 282.8 nM on SIK1, 7.8 nM on SIK2 and 3.8 nM on SIK3). We outline efforts made to increase selectivity against SIK1 and improve CYP time-dependent inhibition properties through the structure-activity relationship. The dual activity of 32 in modulating the pro-inflammatory cytokine TNFα and the immunoregulatory cytokine IL-10 is demonstrated in vitro in human primary myeloid cells and human whole blood, and in vivo in mice stimulated with lipopolysaccharide. Compound 32 shows dose-dependent activity in disease-relevant mouse pharmacological models.