Liquid biopsy for molecular characterization of diffuse large B-cell lymphoma and early assessment of minimal residual disease.

Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next-generation sequencing (NGS) approach (EuroClonality-NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high-risk International Prognostic Index and a trend to shorter 2-year progression-free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5-log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2-year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2-year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2-year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality-NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.

Baseline NT-proBNP levels as a predictor of short-and long-term prognosis in COVID-19 patients: a prospective observational study.

BACKGROUND: Up to 20% of COVID-19 patients can suffer COVID-19-related myocardial injury. Elevated cardiac biomarkers, such as hs-cTnT and NT-proBNP, have been related to worse short-term prognosis. However, data on NT-proBNP and long-term prognosis are scarce. We have evaluated the potential association of baseline age-adjusted NT-proBNP levels and outcomes at one-year follow-up in COVID-19 patients. METHODS: This was a single-center prospective study of 499 COVID-19 patients in whom NT-proBNP was assessed at hospital admission. NT-proBNP levels were age-adjusted and patients were classified as high or low NT-proBNP. Clinical and demographic characteristics, comorbidities, laboratory results, and in-hospital complications and mortality were compared between the two groups. Survivors of the acute phase of COVID-19 were followed up for one year from admission to detect readmissions and mortality. RESULTS: The 68 patients with high NT-proBNP levels at hospital admission were older, with more cardiovascular risk factors, cardiovascular disease, comorbidities, myocardial injury, and higher levels of inflammatory markers than patients with low NT-proBNP levels. They also had more in-hospital complications and a higher acute-phase mortality rate (60.3% vs. 10.2%, p < 0.001). High NT-proBNP levels were an independent marker of death during hospitalization (HR 1.95; CI 1.07-3.52). At one-year follow-up, high NT-proBNP levels were independently associated with mortality (HR 2.69; CI 1.47-4.89). Among survivors of the acute phase of COVID-19, there were no differences in hospital readmissions between those with high vs. low NT-proBNP levels, but survivors with high baseline NT-proBNP levels showed a higher 1-year mortality rate (7.4% vs. 1.3%, p = 0.018). CONCLUSIONS: High age-adjusted NT-proBNP levels at the time of hospital admission for COVID-19 are associated with poor short and long-term prognosis. High NT-proBNP seems also to be related to worse prognosis in survivors of the acute phase of COVID-19. A closer follow-up on these patients may be crucial.

A quantitative comparative surgical analysis of the endoscopic transorbital approach and frontotemporal-orbitozygomatic approach for extradural exposure of the cavernous sinus.

OBJECTIVE: Recently, the endoscopic superior eyelid transorbital approach (SETA) has emerged as a potential alternative to access the cavernous sinus (CS). Several previous studies have attempted to quantitatively compare the traditional open anterolateral skull base approaches with transorbital exposure; however, these comparisons have been limited to the area of exposure provided by the bone opening and trajectory, and fail to account for the main avenues of exposure provided by subsequent requisite surgical maneuvers. The authors quantitatively compare the surgical access provided by the frontotemporal-orbitozygomatic (FTOZ) approach and the SETA following applicable periclinoid surgical maneuvers, evaluate the surgical exposure of key structures in each, and discuss optimal approach selection. METHODS: SETA and FTOZ approaches were performed with subsequent applicable surgical maneuvers on 8 cadaveric heads. The lengths of exposure of cranial nerves (CNs) II-VI and the cavernous internal carotid artery; the areas of the space accessed within the supratrochlear, infratrochlear, and supramaxillary (anteromedial) triangles; the total area of exposure; and the angles of attack were measured and compared. RESULTS: Exposure of the extradural CS was comparable between approaches, whereas access was significantly greater in the FTOZ approach compared with the SETA. The lengths of extradural exposure of CN III, V1, V2, and V3 were comparable between approaches. The FTOZ approach provided marginally increased exposure of CNs IV (20.9 ± 2.36 mm vs 13.4 ± 3.97 mm, p = 0.023) and VI (14.1 ± 2.44 mm vs 9.22 ± 3.45 mm, p = 0.066). The FTOZ also provided significantly larger vertical (44.5° ± 6.15° vs 18.4° ± 1.65°, p = 0.002) and horizontal (41.5° ± 5.40° vs 15.3° ± 5.06°, p < 0.001) angles of attack, and thus significantly greater surgical freedom, and provided significantly greater access to the supratrochlear (p = 0.021) and infratrochlear (p = 0.007) triangles, and significantly greater exposure of the cavernous internal carotid artery (17.2 ± 1.70 mm vs 8.05 ± 2.37 mm, p = 0.001). Total area of exposure was also significantly larger in the FTOZ, which provided wide access to the lateral wall of the CS as well as the possibility for intradural access. CONCLUSIONS: This is the first study to quantitatively identify the relative advantages of the FTOZ and transorbital approaches at the target region following requisite surgical maneuvers. Understanding these data will aid in selecting an optimal approach and maneuver set based on target lesion size and location.

Effectiveness of motor imagery in complex regional pain syndrome: A systematic review with meta-analysis.

OBJECTIVE: The purpose of this study was to determine the effects of motor imagery (MI) on pain intensity and disability in individuals with complex regional pain syndrome (CRPS). METHODS: A systematic search was conducted in various electronic databases to identify all relevant studies: PubMed, CINAHL, WOS, PEDro, CENTRAL, and Scopus. Randomized controlled trials assessing the effects of MI in individuals with CRPS were included. The risk of bias was assessed with the Cochrane Risk of Bias tool, the methodological quality was evaluated using PEDro scale, and the level of evidence was reported according to the GRADE. Between-groups standardized mean differences (SMD) were calculated. RESULTS: Six studies were included. The meta-analysis found moderate-quality evidence that MI improves pain intensity and related disability as immediate (pain: SMD -1.07, 95% CI: -1.53 to -0.60; disability: SMD 1.05, 95% CI: 0.59 to 1.51), short-term (pain: SMD -1.28, 95% CI: -2.14 to -0.42; disability: SMD 1.37; 95% CI: 0.16 to 2.58), and long-term effects (pain: SMD -1.18; 95% CI: -1.89 to -0.46; disability: SMD 1.18; 95% CI: 0.46 to 1.89), as compared with a comparison group. The risk of bias of the trials was relatively low, but the imprecision of the results downgraded the level of evidence. CONCLUSIONS: Moderate-quality evidence suggests a positive effect of MI for improving pain intensity and disability immediately after and at short-term in individuals with CRPS.

Gender and addiction and other mental disorders comorbidity: sociodemographic, clinical, and treatment differences.

The co-occurrence of substance use disorders (SUD) and other mental disorders (OMD) is assumed to be high, but the details are uncertain in Spain. The objective of the present study was to know the prevalence of this comorbidity, as well as the pharmacological treatment, both in specific addiction treatment networks and in mental health networks, with a gender perspective. Observational, multicenter study, with a randomized sample, of patients under treatment for SUD or OMD in Spain (N = 1783). A specific questionnaire, collecting sociodemographic and clinical variables, diagnosed SUD and OMD, and prescribed psychotropic drugs, was completed by treating clinicians. Differences between females and males were searched. A high prevalence of OMD was found in those patients treated for their SUD (71%), and also of diagnoses of SUD (59%) in people treated for OMD. Significant relationships between addiction to certain substances and specific mental disorders were found (with no main differences between women and men). The treatments for OMD were very common in the addiction treatment networks, but that of SUDs in those patients treated in the mental health networks was less than expected. A high prescription of benzodiazepines was found. Women were less frequently diagnosed with cannabis, opioid, and especially cocaine use disorders, and they had fewer psychotic disorders and more affective, anxiety, sleep, and eating disorders, with the rest being the same, including personality disorders. Women had fewer treatments with agonists and more with antagonists, and more prescriptions of anxiolytics and antidepressants. This study provides preliminary information on the coexistence in routine clinical practice of addictive disorders and other mental disorders in Spain, and on the treatment provided, and shows differences in prevalence and clinical characteristics, and especially in treatment approaches between women and men. Thus, should be useful to adapt the treatment response with greater precision, and with a gender perspective.

A new platform for autoimmune diseases. Inducing tolerance with liposomes encapsulating autoantigens.

Autoimmune diseases (AIDs) are caused by the loss of self-tolerance and destruction of tissues by the host's immune system. Several antigen-specific immunotherapies, focused on arresting the autoimmune attack, have been tested in clinical trials with discouraging results. Therefore, there is a need for innovative strategies to restore self-tolerance safely and definitively in AIDs. We previously demonstrated the therapeutic efficacy of phosphatidylserine (PS)-liposomes encapsulating autoantigens in experimental type 1 diabetes and multiple sclerosis. Here, we show that PS-liposomes can be adapted to other autoimmune diseases by simply replacing the encapsulated autoantigen. After administration, they are distributed to target organs, captured by phagocytes and interact with several immune cells, thus exerting a tolerogenic and immunoregulatory effect. Specific PS-liposomes demonstrate great preventive and therapeutic efficacy in rheumatoid arthritis and myasthenia gravis. Thus, this work highlights the therapeutic potential of a platform for several autoimmunity settings, which is specific, safe, and with long-term effects.

Natural killer cell subsets in endometrial fluid: a pilot study of their association with the endometrial cycle and reproductive parameters.

PURPOSE: To investigate if there are natural killer (NK) cells in endometrial fluid (EF) and their relationship with the endometrial cycle and reproductive parameters. METHODS: The population under study consisted of 43 women aged 18-40 undergoing infertility workup at our University Hospital in 2021-2022. The EF samples were obtained at the first visit to our unit, on occasion of the mock embryo transfer. The day of the cycle was considered only in cycles of 27-29 days. An immunophenotype study of NK in EF was performed by flow cytometry analysis. In a subgroup of women, on the same day, NK was studied in EF and peripheral blood. RESULTS: Our study is the first to evidence NK cells in EF. None of the NK cells observed corresponded to a mature peripheral blood NK cell population (stages 4-5), and neither endometrial nor decidual uNK cells were detected. Nevertheless, we found 2 patient groups with an NK cell subset with a higher expression of CD16+, which could belong to an intermediate or transient stage between the uNK and pbNK NK cell population in the EF. We found that CD16 was significantly increased in the mid-late luteal phase and its correlation with the day of the cycle. The NK immunophenotype was different in EF and peripheral blood. CONCLUSION: We described a new component of the EF, the NK cells, whose CD16 activity is closely correlated with the day of the cycle. These cells could play a role in implantation/implantation failure.

Polycystic ovarian syndrome and miscarriage in IVF: systematic revision of the literature and meta-analysis.

PURPOSE: To evaluate the risk of miscarriage in IVF cycles in women with PCOS. METHODS: Systematic review and meta-analysis. Systematic search of MEDLINE, EMBASE and Google Scholar. The language search was restricted to English, Spanish and French, from 2000 to 2019, with crosschecking of references from relevant articles. Inclusion criteria were: (1) IVF cycles (2) a group of patients with PCOS was considered separately, (3) the miscarriage rate was reported, (4) there was a control group, (5) definition of PCOS according the Rotterdam criteria. Exclusion criteria were been excluded from the meta-analysis: (1) publication prior to the year 2000, (2) animal studies, (3) reviews, (4) abstracts or conference papers, (5) letters, (6) case reports, (7) studies comparing different IVF techniques, (8) studies comparing groups with and without metformin or other treatments, (9) studies on induced abortions. Risk of bias was assessed by the Newcastle-Ottawa score (NOS). All the included studies had a low risk of bias (NOS scores ranging 7-8). The review protocol was registered in PROSPERO (CRD42020186713). Seventeen studies were included in the meta-analysis. There was a total of 10,472 pregnancies (2650 in PCOS and 7822 in controls) of which 1885 were miscarriages (682 in PCOS and 1203 in controls). We considered the miscarriage rate (MR), preclinical MR, early MR, and late MR. RESULTS: In IVF pregnancies the risk of miscarriage was significantly increased when considering miscarriages in total (RR = 1.59; CI = 1.45-1.75), preclinical miscarriages (RR = 1.59; CI = 1.35-1.88), and early miscarriages (RR = 1.44; CI = 1.16-1.79). The increased miscarriage rate persisted in Chinese and Western populations when considered separately. The risk of miscarriage was increased in the subgroup of fresh transfers (RR = 1.21; CI = 1.06-1.39) as well as in the subgroup including either fresh or frozen transfers (RR = 1.95; CI = 1.72-2.22). CONCLUSION: PCOS is linked to an increased MR in IVF pregnancies both of miscarriages in total, and to an increase in preclinical and early miscarriages. PROSPERO NUMBER: CRD42020186713.

'Learning by doing', a model for improving the promotion of healthy lifestyles by student nurses.

BACKGROUND: 'Learning by doing' is a learning model based on performing actions and gaining experience. The 'nursing process' is a systematic, rational method for providing nursing care. During their university education, nursing students need to acquire the ability to promote healthy lifestyles. OBJECTIVE: To determine the effectiveness of a learning strategy based on learning by doing and grounded in the use of the nursing process, on the lifestyle of nursing students. METHODS: This quasi-experimental intervention (before-after), performed over 2011-2022, involved 2300 nursing students at a university nursing school in Spain. The risk factors for chronic diseases-being a smoker, being overweight, or having high blood pressure-to which each student was exposed were recorded. Those positive for at least one risk factor selected companion students as 'support nursing students' who became responsible for designing an individualised care plan to reduce the risk(s) faced. To ensure the correct use of the nursing process, teachers approved and monitored the implementation of the care plans. Whether risk-reduction objectives were met was determined three months later. RESULTS: The students with risk factors largely improved their lifestyles (targets for reducing smoking/body weight were met) with the help of their supporting peers. CONCLUSIONS: The learning by doing method demonstrated its effectiveness, improving the lifestyle of at-risk students via the use of the nursing process.

Colorectal cancer survival: prevalence of psychosocial distress and unmet supportive care needs.

PURPOSE: The aim of this study was to determine the prevalence of distress and unmet supportive care needs in post-treatment colorectal cancer (CRC) survivors. Also, to explore the association between both variables and to identify potential associated sociodemographic and cancer-related risk factors. METHODS: A cross-sectional study of 200 CRC survivors who at least 1 month before had completed the primary treatment for CRC was conducted. The Brief Symptom Inventory-18 (BSI-18) and the Spanish version of Cancer Survivors' Unmet Needs (S-CaSUN) were used. RESULTS: One in five CRC survivors showed clinical distress and 86% expressed at least one unmet need. Distress was positively associated with the prevalence of needs in all domains. All comprehensive care and information needs were expressed by at least 20% of survivors and some by more than 50%. Other needs also mentioned by 20% of survivors were financial support, ongoing case manager, and concerns about cancer recurrence. The risk factors associated were lower socioeconomic status, younger age, and a primary treatment that includes more than surgery. CONCLUSIONS: The findings highlight the relevance of extending psychosocial care beyond the CRC primary medical treatment. A person-centered approach that addresses informational, emotional, social, and physical needs can increase satisfaction with care and also prevent psychological morbidity in CRC survivors.

Multimodal Chronic Pain Therapy for Adults via Smartphone: Randomized Controlled Clinical Trial.

BACKGROUND: Combination therapies delivered remotely via the internet or mobile devices are increasingly being used to improve and promote the self-management of chronic conditions. However, little is known regarding the long-term effects of these interventions. OBJECTIVE: The aim of this study is to evaluate the effectiveness of a multimodal intervention program that measures associated variables such as catastrophizing, pain acceptance, and quality of life using a mobile device in people with chronic pain in an outpatient setting. METHODS: A randomized controlled clinical trial was performed using parallel treatment groups. A total of 209 patients with chronic musculoskeletal pain were randomly assigned to one of the two study arms. The intervention group received a standard web-based psychosocial therapy-type program of activities through a smartphone for 6 weeks. The control group only had access to the Find out more section of the app, which contained audiovisual material for pain management based on a self-help approach. The primary outcome was catastrophizing measured using the Pain Catastrophizing Scale (PCS). Secondary outcomes were pain acceptance measured using the Chronic Pain Acceptance Questionnaire and health-related quality of life measured using the EuroQol Visual Analogue Scale. Assessments were conducted at baseline (T1), after treatment (T2), and at the 3-month follow-up (T3). The variations between the different phases were assessed using the percentage change rescaled with log base 2. The Cohen d was calculated based on the results of the linear mixed model. The investigators of the study who evaluated the results were not involved in patient recruitment and were blinded to the group assignment. RESULTS: Positive effects were found in the intervention group (T2-T1) in catastrophizing between the baseline and posttreatment phases (P<.001) and in helplessness (-0.72 vs 0.1; P=.002), rumination (-1.59 vs -0.53; P<.001), acceptance (0.38 vs 0.05; P=.001), and quality of life (0.43 vs -0.01; P=.002), although no significant changes were found for magnification (0.2 vs 0.77; P=.14) and satisfaction with health (0.25 vs -0.27; P=.13). Three months after treatment, significant differences were observed in the intervention group for the outcome variable of catastrophizing (PCS; -0.59 vs 0.2; P=.006) and the PCS subscales of helplessness (-0.65 vs 0.01; P=.07), rumination (1.23 vs -0.59; P=.04), and magnification (0.1 vs 0.86; P=.02). CONCLUSIONS: The results of our study suggest that app-based mobile multidimensional treatments for adults with chronic pain improve catastrophizing, quality of life, and psychological flexibility immediately after treatment and that the effects are maintained for the primary outcome of catastrophizing for at least 3 months following treatment. Moreover, they promote self-management and can be used to complement face-to-face pain treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT04509154; https://clinicaltrials.gov/ct2/show/NCT04509154.

Detection of Wolbachia and Leishmania DNA in sand flies (Diptera: Psychodidae, Phlebotominae) from a focus of cutaneous leishmaniasis in Tabasco, Mexico.

Phlebotomine sand flies are the main vectors of Leishmania genus species worldwide; therefore, the detection of some reproductive parasites, such as Wolbachia, has been considered a possible strategy for biological control. In Mexico, leishmaniasis cases have been recorded in 25 states, yet only two sand fly species have been related to Wolbachia spp. Although the state of Tabasco has a high number of leishmaniasis cases, only few studies have been done on sand fly species. The aim of this study was to analyze the diversity of sand fly species and to detect Wolbachia spp. and/or Leishmania spp. in the captured specimens. Sand flies were collected at the locality of Huimango, Tabasco, Mexico, during October 2019, using nine light traps (CDC) and two Shannon traps per night. The specimens were identified and females were analyzed by PCR for the DNA detection for pathogens. A total of 193 sand fly specimens belonging to five species were morphologically identified. Pintomyia ovallesi was the most abundant species (76.84%), followed by Micropygomyia cayennensis (6.40%). Furthermore, first records of four sand fly species were established for the state of Tabasco, thereby increasing the species richness in the state from four to eight. We observed a natural infection rate of 9.7% (10/103) for Leishmania and 0.91% (1/103) for Wolbachia. The importance of conducting entomological surveys in endemic areas of leishmaniasis in Mexico is highlighted, to determine whether other sand fly species may be potential vectors of Leishmania spp., and if some Wolbachia strains could be relevant for the control of leishmaniasis.

Calcium, Ca2+-ATPase, Calmodulin, and Calbindin D-28KD Localization in Testis of Leptodactylus chaquensis (Anura: Leptodactylidae).

The intracellular localization of Ca2+, Ca2+-ATPase, Calmodulin, and Calbindin D-28KD have been studied in testes of the toad Leptodactylus chaquensis, using ultracytochemical and immunohistochemical techniques. The Ca2+ presences in the nucleus and into the mitochondria of the germ cells, together with the activity of Ca2+-ATPase detected in the nuclear envelope and mitochondrial crests, suggest the participation of this transporter in the storage of Ca2+. In Sertoli cells, Ca2+ deposits were also found in vesicles and lamellar bodies. Calmodulin and Calbindin D-28KD were revealed in the cytoplasm of both cell types. At the spermatozoon level, the cation deposits were located in the subacrosomal space and in the acrosomal vesicle. Ca2+-ATPase activity was observed in the acrosomal and plasma membranes of the gamete that suggests the existence of a transport system responsible for maintaining low cytoplasmic Ca2+ levels. The activity of Ca2+-ATPase and the location of Ca2+ deposits in gamete tail would be related to flagellar movement. The colocalization of Ca2+ deposits and their binding proteins in efferent duct cells would probably be associated with secretory activity. Considering that intracellular Ca2+ is present in different gonadal cells, this work would provide a better understanding of the cation importance in the testicular functions of this species.

A century later, still fighting back: antigen-specific immunotherapies for type 1 diabetes.

Type 1 diabetes (T1D) is a chronic metabolic disease caused by the autoimmune destruction of insulin-producing ß-cells. Ever since the 1920s, the fate of patients suffering from T1D was dramatically improved owing to the isolation and production of insulin, and the scientific field has largely progressed as a result of the evidence gathered about its underpinnings and mechanisms. The last years have seen this knowledge transformed into actual antigen-specific immunotherapies with potential to restore selectively the breach of tolerance to ß-cell autoantigens and halt the autoimmune aggression. However, so far, the results of both prevention and reversion trials in T1D have been rather discouraging, so there is still an urgent need to optimize those immunotherapies and their associated factors, for example, posology and administration patterns, route and timing. In this review, we look back on what has been achieved in the last century and identify the main autoantigens driving the autoimmune attack in T1D. Then, we take a deep dive into the numerous antigen-specific immunotherapies trialed and the ones still at a preclinical phase, ranging from peptides, proteins and agent combinations to gene transfer, nanoparticles, cell-based strategies and novel approaches exploiting naturally occurring tolerogenic processes. Finally, we provide insight into the several features to be considered in a T1D clinical trial, the ideal time point for intervention and the biomarkers needed for monitoring the successful regulatory effect of the antigen-specific immunotherapy. Although further research and optimization remain imperative, the development of a therapeutic armamentarium against T1D autoimmunity is certainly advancing with a confident step.

Circulating LEAP-2 is associated with puberty in girls.

BACKGROUND/OBJECTIVES: Liver-expressed antimicrobial peptide 2 (LEAP-2) was recently identified as an endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status in humans. Despite the relevant role of ghrelin in childhood, puberty, and childhood obesity, the potential implication of LEAP-2 in these aspects remains totally unknown. We aimed to investigate the regulation of circulating plasma LEAP-2 in childhood and adolescent either lean or obese. METHODS AND RESULTS: Plasma levels of LEAP-2 were analyzed in a cross-sectional study with lean and obese children and adolescents (n = 150). Circulating LEAP-2 levels were significantly higher in girls than in boys independently of whether they were obese or lean. In addition, LEAP-2 was significantly increased (p < 0.001) in pubertal than in prepubertal girls, while no changes were found in boys between both developmental stages. Moreover, in girls LEAP-2 was positively correlated with insulin, IGF-1, HOMA-IR and triglycerides and negatively with ghrelin. In boys, LEAP-2 was positively correlated with leptin and negatively with vitamin D levels. CONCLUSION: This study reveals a sexual dimorphism in LEAP-2 levels in children and adolescents. These changes and the higher levels during puberty imply that LEAP-2 may contribute to some of the biological adaptations occurring during pubertal development in terms of food intake, energy balance, growth rate, and puberty onset. Future studies assessing LEAP-2 levels in longitudinal studies and its implications in growth rate, puberty onset, and reproductive hormones will help to understand the relevance of this hormone in this stage of life.

Current development of alternative treatments for endothelial decompensation: Cell-based therapy.

Current treatment for corneal endothelial dysfunction consists in the replacement of corneal endothelium by keratoplasty. Owing to the scarcity of donor corneas and the increasing number of transplants, alternative treatments such as cell-based therapies are necessary. In this article, we highlight the biological aspects of the cornea and the corneal endothelium, as well as the context that surrounds the need for new alternatives to conventional keratoplasty. We then review some of those experimental treatments in more detail, focusing on the development of the in vitro and preclinical phases of two cell-based therapies: tissue-engineered endothelial keratoplasty (TE-EK) and cell injection. In the case of TE-EK graft construction, we analyse the current progress, considering all the requirements it must meet in order to be functional. Moreover, we discuss the inherent drawbacks of endothelial keratoplasties, which TE-EK grafts should overcome in order to make surgical intervention easier and to improve the outcomes of current endothelial keratoplasties. Finally, we analyse the development of preclinical trials and their limitations in terms of performing an optimal functional evaluation of cell-based therapy, and we conclude by discussing early clinical trials in humans.

Oral Versus Long-Acting Injectable Antipsychotic Treatment for People With Severe Schizophrenia: A 5-Year Follow-up of Effectiveness.

ABSTRACT: The objective here is to compare the effectiveness of long-acting injectable antipsychotics (LAI-APs) and oral ones (OAPs) in patients with severe (Global Clinical Impression-Severity ≥ 5) schizophrenia (N = 688). A 5-year follow-up study has been conducted in patients undergoing standard treatment in mental health units (MHUs) or on a severe mental illness program (SMIP). A total of 8.7% of the patients on the SMIP discontinued treatment, whereas 43.6% did so in MHUs (p < 0.0001). In both cases, treatment retention was significantly higher in patients on LAI-APs (p < 0.001). Also, hospital admissions were in both cases fewer among those on LAI-APs (p < 0.001). There was a significant link between suicide attempts and OAP treatment (p < 0.01). Given the relationship between the use of LAI-APs versus oral treatments in achieving higher adherence and less relapses and suicide attempts, the use of second-generation antipsychotics LAIs should be considered more suitable for people with severe schizophrenia.

Generation of Mesenchymal Cell Lines Derived from Aged Donors.

Background: Mesenchymal stromal cells (MSCs) have the capacity for self-renewal and multi-differentiation, and for this reason they are considered a potential cellular source in regenerative medicine of cartilage and bone. However, research on this field is impaired by the predisposition of primary MSCs to senescence during culture expansion. Therefore, the aim of this study was to generate and characterize immortalized MSC (iMSC) lines from aged donors. Methods: Primary MSCs were immortalized by transduction of simian virus 40 large T antigen (SV40LT) and human telomerase reverse transcriptase (hTERT). Proliferation, senescence, phenotype and multi-differentiation potential of the resulting iMSC lines were analyzed. Results: MSCs proliferate faster than primary MSCs, overcome senescence and are phenotypically similar to primary MSCs. Nevertheless, their multi-differentiation potential is unbalanced towards the osteogenic lineage. There are no clear differences between osteoarthritis (OA) and non-OA iMSCs in terms of proliferation, senescence, phenotype or differentiation potential. Conclusions: Primary MSCs obtained from elderly patients can be immortalized by transduction of SV40LT and hTERT. The high osteogenic potential of iMSCs converts them into an excellent cellular source to take part in in vitro models to study bone tissue engineering.

Analysis of Cryopreservation Protocols and Their Harmful Effects on the Endothelial Integrity of Human Corneas.

Corneal cryopreservation can partially solve the worldwide concern regarding donor cornea shortage for keratoplasties. In this study, human corneas were cryopreserved using two standard cryopreservation protocols that are employed in the Tissue Bank of the Teresa Herrera Hospital (Spain) to store corneas for tectonic keratoplasties (TK protocol) and aortic valves (AV protocol), and two vitrification protocols, VS55 and DP6. Endothelial viability and general corneal state were evaluated to determine the protocol that provides the best results. The potential corneal cryopreservation protocol was studied in detail taking into consideration some cryopreservation-related variables and the endothelial integrity and stroma arrangement of the resulting cryopreserved corneas. TK corneas showed mostly viable endothelial cells, while the others showed few (AV) or none (DP6 and VS55). The corneal structure was well maintained in TK and AV corneas. TK corneas showed endothelial acellular areas surrounded by injured cells and a normal-like stromal fiber arrangement. Cryoprotectant solutions of the TK protocol presented an increasing osmolality and a physiological pH value. Cooling temperature rate of TK protocol was of 1 °C/min to -40 °C and 3 °C/min to -120 °C, and almost all of dimethyl sulfoxide left the tissue after washing. Future studies should be done changing cryopreservation-related variables of the TK protocol to store corneas of optical grade.

Scientific Uncertainty and Guarantee of Supply of Medicines and Healthcare Products during the Crisis Caused by the SARS-CoV-2 in Spain.

The pandemic caused by the new SARS-CoV-2 coronavirus has created a climate of uncertainty. The application of the precautionary principle is therefore justified for some of the measures taken by the competent authorities. In Spain, these measures have been aimed, on the one hand, at stopping its spread by means of a state of alarm for the restriction of daily activities. On the other hand, they aimed at recommending the most appropriate treatment according to scientific research developments, as well as containment measures based on the use of health care products. These latest measures have led to an extraordinary increase in the use of medicines and health care products, which compromises their supply. Thus, authorities were forced to regulate certain actions in the legal supply chain of medicines and healthcare products, such as procurement and dispensing.