Proyecto sobre dispensación excepcional en el Principado de Asturias / Project on exceptional dispensation in the Principality of Asturias

La farmacia comunitaria (FC) se enfrenta a diario con situaciones que impiden la dispensación adecuada del medicamento, poniendo en riesgo la continuidad de los tratamientos por parte de los pacientes, lo cual se traduce en problemas relacionados con los medicamentos (PRM). A través de este estudio piloto realizado en el Principado de Asturias, se ha querido cuantificar el número de incidencias de este tipo relacionadas con aquellos aspectos de la prescripción que podrían ser fácilmente subsanadas por el farmacéutico comunitario a través de intervenciones sencillas en el momento de la dispensación. Se llevó a cabo un estudio en diez farmacias de esta comunidad autónoma en el horario de apertura habitual a lo largo de quince días laborables. La muestra incluyó un total de 32.331 envases dispensados. En él se registraron 406 incidencias susceptibles de dispensación excepcional. La tasa de incidencia total alcanza el 1,26 % de las dispensaciones, lo que extrapolando al total de dispensaciones realizadas en Asturias durante el mes de octubre de 2020 daría una cifra de 27.030 dispensaciones totales susceptibles de dispensación excepcional.La tasa de incidencia total fue inferior en la farmacia urbana (1,03 %) frente a la semiurbana y rural (1,37 % y 1,39 %). La mayor parte de los casos (59,4 %) afectó a pacientes con aportación individual a la Seguridad Social correspondiente al 10 % (TSI2) y la edad media del paciente fue de 60,8 años. En cuanto al nivel asistencial, el 79 % de los casos corresponde a recetas de atención primaria (AP). El tipo más habitual de incidencia es “potencial interrupción por prescripción no activa en el momento de la dispensación (superado el margen de 10 días)” con una tasa de incidencia del 0,61 % de las dispensaciones, lo que supondría un total de 13.181 prescripciones susceptibles de dispensación excepcional por este tipo de incidencia...(AU)

Muscle activation, strength, and volume in people with patellofemoral osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE: This systematic review investigated whether people with patellofemoral osteoarthritis (PFOA) have muscle strength, volume, and activation around the hip and knee that is different from asymptomatic controls. METHODS: Searches were carried out in five electronic databases, with terms related to PFOA, including muscle strength, volume and activation. Only studies with at least one group with symptomatic PFOA and one asymptomatic group were included. The methodological quality of the studies was assessed using the Downs and Black checklist. Certainty of evidence was assessed using the GRADE methodology. Using the random effects model, a meta-analysis was performed when there were at least two studies reporting the same domain. RESULTS: Eight studies (250 participants) met the inclusion criteria. Subjects with PFOA had weaker hip abduction (SMD -0.96; 95%CI = -1.34 to -0.57), hip external rotation (-0.55;-1.07 to -0.03), hip extension (-0.72;-1.16 to -0.28), and knee extension (-0.97;-1.41 to -0.53) when compared to asymptomatic controls. People with PFOA also presented with smaller volumes of the gluteus medius, gluteus minimus, tensor fascia lata, vastus medialis (VM), vastus lateralis (VL) and rectus femoris when compared to asymptomatic controls. Also, people with PFOA presented with changes in muscle activation for the VL, VM and gluteus maximus (GMax) when compared to asymptomatic controls. CONCLUSION: People with PFOA present with lower strength and volume of the hip and quadriceps muscles and altered muscle activation of the VM, VL and GMax during ascending and descending stairs when compared to asymptomatic controls. However, the certainty of these findings are very low. TRIAL REGISTRATION NUMBER: PROSPERO systematic review protocol (ID = CRD42020197776).

Clinical and ultrasound response to intralesional sodium thiosulfate for the treatment of calcinosis cutis in the setting of systemic sclerosis. A case-based review.

Calcinosis cutis (CC) is defined as the deposition of calcium salts on the skin and subcutaneous tissue. It is associated with different conditions, including some autoimmune diseases, and it can generate significant inflammation, pain, and functional impairment. Different therapies have been tried with limited results. Intralesional sodium thiosulfate seems a promising therapeutic option. We report a patient with diffuse systemic sclerosis who presented with two symmetrical plaques on both axillae, which caused pain and skin retraction. The clinical diagnosis was consistent with CC, which was confirmed by skin biopsy and ultrasound. The patient was treated with a 250 mg/ml solution of sodium thiosulfate injected into the plaques. Complete resolution was achieved after three monthly sessions. The only reported adverse effect was a transient burning sensation during the injections. Given its effectiveness and safety, we believe that intralesional sodium thiosulfate could become a valid first-line option for the treatment of CC.

Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis.

L-selectin, a lectin-like receptor on all leukocyte classes, functions in adhesive and signaling roles in the recruitment of myeloid cells from the blood to sites of inflammation. Here, we consider L-selectin as a determinant of neurological recovery in a murine model of spinal cord injury (SCI). Spinal cord-injured, L-selectin knock-out (KO) mice (male) showed improved long-term recovery with greater white matter sparing relative to wild-type (WT) mice and reduced oxidative stress in the injured cord at 72 h post-SCI. There was a partial and transient reduction in accumulation of neutrophils in the injured spinal cords of KOs at 24 h post-injury. To complement these findings with KO mice, we sought a pharmacologic means for lowering L-selectin levels. We found that diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), induced the shedding of L-selectin from the cell surface of myeloid subsets, specifically neutrophils and non-classical monocytes, in the blood and the injured spinal cord. Diclofenac administration to injured WT mice enhanced neurological recovery to a level comparable to that of KOs but did not improve recovery in KOs. While diclofenac treatment had no effect on myeloid cell accumulation, there was a reduction in oxidative stress at 72 h post-SCI. These findings implicate L-selectin in secondary pathogenesis beyond a role in leukocyte recruitment and raise the possibility of repurposing diclofenac for the treatment of SCI.

Non-Small Cell Lung Cancer Invading the Descending Thoracic Aorta: Surgical Resection Without Using Cardiopulmonary Bypass and Without Cross-Clamping the Aorta: Long-Term Follow-Up of 2 Cases.

Lung cancer can sometimes invade vital adjacent mediastinal structures, such as the descending thoracic aorta. We describe 2 cases where pulmonary resection was performed en bloc including a patch of the descending thoracic aorta. These procedures were easily performed using an aortic endoprosthesis in the same anesthetic procedure. We also comment some aspects about an intraoperative endoleak, postoperative evolution, and long-term follow-up.

Is the prognosis of occult N2 disease similar to that of positive positron emission tomography-computed tomography (PET/CT) scan single-station N2 disease in patients with non-small cell lung cancer treated by surgical resection?

OBJECTIVE: A retrospective study, using a prospective database, was conducted on patients treated with surgery in order to analyze the prognosis between two groups: NSCLC (non-small cell lung cancer) patients with occult N2 disease and patients with single station N2 disease observed on pre-operative integrated PET/CT scan. METHODS: A total of 772 patients underwent surgical treatment for lung cancer from January 2007 to December 2014. All of them had an integrated PET/CT scan in the pre-operative work-up and a pulmonary resection plus mediastinal lymphadenectomy were performed in all cases. In the selected cases, no one received induction treatment. All patients from both groups had N2 disease after examination of the histopathology specimen. Clinical and pathological characteristics, disease free survival, and overall survival, were analyzed in both groups. RESULTS: A total of 34 cases presented occult N2 disease, whereas 11 cases showed single station N2 disease on pre-operative PET/CT scan. Mean disease free survival and mean overall survival for occult N2 disease compared to single-station N2 disease on PET/CT scan was 36.0 months (95% CI: 24.9-47.1) and 38.9 months (95% CI: 20.6-57.1), p=.586; and 52.3 months (95% CI: 38.9-65.7) and 38.2 months (95% CI: 21.9-54.5), p=.349, respectively. CONCLUSION: The prognosis of patients with single-station N2 disease on PET/CT scan treated by surgical resection and mediastinal lymphadenectomy as first line treatment was similar to those with occult N2 disease. More studies are needed to support our findings.

Ratio between maximum standardized uptake value of N1 lymph nodes and tumor predicts N2 disease in patients with non-small cell lung cancer in 18F-FDG PET-CT scan.

OBJECTIVE: F-18 fluorodeoxyglucose integrated PET-CT scan is commonly used in the work-up of lung cancer to improve preoperative disease stage. The aim of the study was to analyze the ratio between SUVmax of N1 lymph nodes and primary lung cancer to establish prediction of mediastinal disease (N2) in patients operated on non-small cell lung cancer. MATERIAL AND METHOD: This is a retrospective study of a prospective database. Patients operated on non-small cell lung cancer (NSCLC) with N1 disease by PET-CT scan were included. None of them had previous induction treatment, but they underwent standard surgical resection plus systematic lymphadenectomy. RESULTS: There were 51 patients with FDG-PET-CT scan N1 disease. 44 (86.3%) patients were male with a mean age of 64.1±10.8 years. Type of resection: pneumonectomy=4 (7.9%), lobectomy/bilobectomy=44 (86.2%), segmentectomy=3 (5.9%). HISTOLOGY: adenocarcinoma=26 (51.0%), squamous=23 (45.1%), adenosquamous=2 (3.9%). Lymph nodes after surgical resection: N0=21 (41.2%), N1=12 (23.5%), N2=18 (35.3%). Mean ratio of the SUVmax of N1 lymph node to the SUVmax of the primary lung tumor (SUVmax N1/T ratio) was 0.60 (range 0.08-2.80). ROC curve analysis to obtain the optimal cut-off value of SUVmax N1/T ratio to predict N2 disease was performed. At multivariate analysis, we found that a ratio of 0.46 or greater was an independent predictor factor of N2 mediastinal lymph node metastases with a sensitivity and specificity of 77.8% and 69.7%, respectively. CONCLUSIONS: SUVmax N1/T ratio in NSCLC patients correlates with mediastinal lymph node metastasis (N2 disease) after surgical resection. When SUVmax N1/T ratio on integrated PET-CT scan is equal or superior to 0.46, special attention should be paid on higher probability of N2 disease.

Linkage and association analysis of ADHD endophenotypes in extended and multigenerational pedigrees from a genetic isolate.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.

Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease.

The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer's disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p.Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P=1.29 × 10⁻¹²; NPHP1, rs10173717, P=1.74 × 10⁻¹²; CADPS2, rs3757536, P=1.54 × 10⁻¹°; GREM2, rs12129547, P=1.69 × 10⁻¹³, among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions.

Bioengineering RNA silencing across the life kingdoms.

RNA silencing negatively regulates gene expression at transcriptional and posttranscriptional levels, guided by small RNA molecules. It modulates core regulatory pathways across the eukaryotes, such as developmental processes or stress responses. The widespread existence of this phenomenon and the key pathways regulated have led to the development of a new technology based on the modification of gene expression, which has been applied successfully in different areas such as medicine or agriculture. Here we review the most important patents related to RNA silencing across the life kingdoms, including biotechnological applications into medicine, crop science and bioengineering.

Sperm cryopreservation in brown bear (Ursus arctos): preliminary aspects.

The development of sperm cryopreservation procedures in brown bear is the basis for establishing a specific genetic resource bank aimed at the preservation of a Cantabric brown bear population, which is seriously threatened. Several issues complicate the development of these cryopreservation procedures: lack of previous specific studies, a high incidence of urospermia and spermagglutination observed in bear ejaculates. Moreover, the availability of individuals for research from these threatened populations is problematic. In the case of the Cantabric brown bear, we have used males from other populations, but of the same species, as surrogates, to carry out a direct extrapolation of the results. Urospermia-- Moreover, 70% of the ejaculates are urine contaminated and spermagglutination have a detrimental effect on post-thawing cell quality recovery in this species. Considering the high value of these samples (autochthonous population with few individuals), a pre-selection of the ejaculates is not a viable alternative. Preventive methods reducing the mentioned detrimental effects need to be developed. On the basis of previous data, we can suppose that bear spermatozoa resist freezing injuries well. Nevertheless, because of the scarcity of this information, it is necessary to conduct further research on bear semen freezing under field conditions. Epidydimal spermatozoa can be important for genetic resource banking of threatened populations and thus specific cryobiological protocols need to be assayed. To date, 168 brown bear ejaculates have been frozen by the ITRA-ULE group at the University of León (Spain) in the development of methodologies for the preservation of brown bear sperm.

Sperm parameters on Iberian red deer: electroejaculation and post-mortem collection.

Artificial reproductive technologies (ART) for cervids have improved, but a need remains for the collection of basic data. We studied two models of sperm collection in Iberian red deer, post-mortem (PM) in a wild population (179 samples) and by electroejaculation (EE) in a farmed population (37 samples), recording: testicular and epididymal weight, testicular diameter, sperm quantity, pH and osmolality and spermatozoa quality (motility by CASA, abnormal forms, cytoplasmic droplets, viability and acrosomal status). We tested the relationship of these parameters with stag age and compared the two models (PM and EE; medians showed). Genitalia parameters were linearly related to stag age (testicular diameter: 31.5-50.5mm for 2-9 years). Total number of spermatozoa collected were PM: 2.5x10(9) and EE: 3.6x10(9) (P>0.05), increasing with age only for PM. We found a positive relationship between testicular size and spermatozoa collected for PM. Osmolality and pH were PM: 6.28 and 378mOsm/kg; EE: 7.63 and 309mOsm/kg (P<0.05). The pH increased with age only for EE. Percentage of motile spermatozoa was similar for PM and EE, but motility quality was lower for PM. Abnormal forms, proximal and distal droplets were lower for EE (22%, 1.3%, 1.5% vs. PM: 23%, 4.3%, 83%). Viability was similar (74%) and intact acrosomes were higher for EE (97% vs. 89%). Both PM and EE samples could be used for germplasm banking. This study contributes with new data on red deer spermatology and for the development of ART in cervids.

[Descending necrotizing mediastinitis: treatment by transcervical thoracic drainage]. / Mediastinitis necrosante descendente: tratamiento con drenaje torácico transcervical.

We report the case of a 29-year-old man with descending necrotizing mediastinitis and subcarinal spread secondary to oropharyngeal infection. The thoracic infection was treated by placement of a transcervical thoracic drain, which was removed 15 days after surgery. The outcome was satisfactory and no further invasive treatment was required. We believe that transcervical thoracic drainage is a useful initial treatment for descending necrotizing mediastinitis with subcarinal spread but no pleural cavity involvement.

IncFII plasmid incompatibility product and its target are both RNA transcripts.

The region of DNA coding for incompatibility (inc) and copy number control (cop) of the IncFII plasmid NR1 is transcribed in both the rightward and leftward directions. The rightward transcripts serve as mRNA for the repA1 protein, which is required for replication. A small, 91-base leftward transcript is synthesized from the opposite DNA strand and is complementary to a portion of the rightward mRNA near its 5' end. A 262-base-pair Sau3A restriction fragment that encodes the small leftward transcript, but does not include the rightward transcription promoters, was cloned into the vector pBR322 or pUC8. The same fragment was cloned from an Inc- mutant of NR1 that does not make the small leftward transcript. Transcription through the cloned fragments in these derivatives was under control of the tetracycline resistance gene in pBR322 or the lac promoter-operator in pUC8. In one orientation of the inserted DNA, a hybrid transcript containing rightward NR1 RNA sequences was synthesized. In the other orientation, a hybrid transcript containing leftward NR1 RNA sequences was synthesized. These plasmids were used to vary the intracellular levels of the rightward or leftward NR1 RNA transcripts and to test their effects in trans on various coresident derivatives of NR1. An excess of rightward NR1 RNA in trans stimulated expression of the essential repA1 gene and caused an increase in the copy number of a coresident NR1 plasmid. An excess of leftward NR1 RNA in trans inhibited the expression of the repA1 gene and lowered the coresident NR1 copy number, thereby causing incompatibility. A pBR322 derivative with no transcription through the cloned NR1 DNA had no effect in trans. These results suggest that the small leftward transcript is the incompatibility inhibitor of NR1 and that its target is the complementary portion of the rightward mRNA.