Treatment of Localized Vulvar Pain with Neural Therapy: A Case Series and Literature Review.

BACKGROUND: Localized vulvar pain (LVP) is a common condition among fertile women, with physical and psychosexual implications. Treatment is complex with limited benefits. Neural therapy is a regulatory therapy that uses injections of local anesthetics in low concentrations in specific points to treat different conditions. CASE PRESENTATION: We present the cases of 5 women, ages 33-44 years, with LVP treated with procaine 0.5% injections in painful points. Complete relief from pain occurred in 2 patients, and significant improvement in 3. Only 1 or 2 sessions were required. Initial VAS score was ≥70 and decreased to ≤30 after the intervention. The improvement was maintained over time, with a minimum follow-up period of 6 months. None of the patients were able to have sex or use tampons due to pain, but they were able to resume after the intervention. CONCLUSIONS: In this case series, local injections of procaine showed a favorable outcome. Future randomized clinical trials could help elucidate the role of this intervention in LVP.

Efectividad y seguridad en la práctica clínica de anticuerpos anti PD-1/PD-L1 en monoterapia en el cáncer de pulmón no microcítico / Clinical efficacy and safety of anti PD-1/PD-L1 antibodies as monotherapy in patients with non-small-cell lung cancer

OBJETIVO: Evaluación de la efectividad y seguridad de inmunoterapia anti-PD-1 y anti-PD-L1 en monoterapia para pacientes con cáncer de pulmón no microcítico. MÉTODO: Estudio observacional retrospectivo que incluyó a pacientes con cáncer de pulmón no microcítico tratados con nivolumab, pembrolizumab y atezolizumab, durante 4 años en un hospital de tercer nivel. Se recogieron variables demográficas, clínicas (clasificación en la escala del Eastern Cooperative Oncology Group, estadio de la enfermedad, determinación y valor de PD-1), de tratamiento (fármaco, fecha de inicio, línea de tratamiento y número de ciclos), de efectividad (fecha y estado a fin de seguimiento) y de toxicidad. Los datos se extrajeron de la historia clínica informatizada. Se calcularon las tasas de supervivencia global y de supervivencia libre de progresión para diferentes tiempos de seguimiento. RESULTADOS: Se incluyeron 80 pacientes, 35 con nivolumab, 32 con pembrolizumab y 13 con atezolizumab. No se alcanzaron medianas de supervivencia global. En los pacientes tratados con nivolumab, la supervivencia a los 6, 12, 18 y 49 meses fue del 79,7%, 74,0%, 65,8% y 65,8%, respectivamente. La mediana de supervivencia libre de progresión fue de 15 meses. El 85,7% presentó toxicidad, siendo astenia (45,7%), hipotiroidismo (25,7%) y tos (20,0%) las más frecuentes. Para pembrolizumab, la tasa de supervivencia global al final del seguimiento fue del 100% en primera línea y del 70,9% en segunda línea de tratamiento. La mediana de supervivencia libre de progresión fue de 17 meses en primera línea y 24 meses en segunda línea de tratamiento. El 84,4% presentó toxicidad, siendo disnea (31,3%), artralgias (28,1%) y astenia (25,0%) las más frecuentes. Para atezolizumab la tasa de supervivencia global se mantuvo en 75,8% desde los 3 hasta los 7 meses. No se alcanzó la mediana de supervivencia libre de progresión; a los 3 y 6 meses, el 49,5% había progresado. El 69,2% presentó toxicidad, siendo astenia (30,8%) y tos, disnea y toxicidad cutánea (15,4%, para cada una) las más frecuentes. CONCLUSIONES: Se observa una tendencia de la muestra a la estabilización y cronificación de la enfermedad, hallándose una positiva y considerable tasa de supervivencia, en comparación con estudios previos. Se precisa ampliar el tamaño muestral y el tiempo de seguimiento para confirmar dicha tendencia

OBJECTIVE: To evaluate the efficacy and safety of anti-PD-1 and anti-PD-L1 immunotherapy agents as monotherapy in patients with non-small cell lung cancer. METHOD: This was a four-year retrospective observational study that included all patients with non-small cell lung cancer treated with nivolumab, pembrolizumab, and atezolizumab in a third level hospital. Demographic, clinical (ECOG status, stage, PD-L1 expression level), therapeutic (drug, start date, line of treatment and number of cycles), efficacy (date and status at the end of follow-up) and toxicity variables were collected. Data was extracted from the patient's electronic medical record. Overall survival and progression-free survival rates for different monitoring times were calculated. RESULTS: The study included 80 patients, 35 on nivolumab, 32 on pembrolizumab and 13 on atezolizumab. The median overall survival was not achieved. Overall survival at 6, 12, 18 and 49 months in patients treated with nivolumab was 79.7%, 74.0%, 65.8% and 65.8%, respectively. Median progression-free survival was 15 months. Adverse events were observed in 85.7% of cases, the most common being asthenia (45.7%), hypothyroidism (25.7%) and cough (20.0%). For pembrolizumab, the overall survival rate at the end of follow-up for first- and second-line treatment was 100% and 70.9%, respectively. Median progression-free survival was 17 months in the first-line and 24 months in the second-line setting. Adverse events were observed in 84.4% of subjects, the most common ones being dyspnea (31.3%), arthralgia (28.1%) and asthenia (25.0%). The overall survival rate from 3 to 7 months remained at 75.8% for atezolizumab. Median progression-free survival could not be determined. At 3 and 6 months, 49.5% of subjects had made some progress. The most frequent adverse events included toxicity (69.2%), asthenia (30.8%), and cough, dyspnea, and skin toxicity (15.4% each). CONCLUSIONS: Subjects showed a trend toward stabilization and chronification of the disease. A positive and considerable survival rate was observed, as compared with previous studies. Further studies are required with larger sample sizes and longer follow-up times to confirm these findings

La "nueva normalidad": ¿qué opinan nuestros pacientes? / The "new normality": what do our patients think?

OBJETIVO: Valorar la satisfacción percibida con el programa de Telefarmacia y envío a domicilio implantado, así como las preferencias de los pacientes y /o cuidadores por el modelo asistencial de atención farmacéutica y dispensación cuando se alcance la "nueva normalidad". MÉTODO: Se diseñó una encuesta electrónica anónima mediante la aplicación Microsoft Forms. La población diana fueron los pacientes, o cuidadores, atendidos en la Unidad de Atención Farmacéutica a Pacientes Externos mediante el modelo de Telefarmacia y envío de medicación a su domicilio entre el 30 de abril al 18 de mayo de 2020. RESULTADOS: Se enviaron 327 cuestionarios, obteniendo una tasa de respuesta del 45,0%. El 95,9% indicó que recibió la medicación correctamente en su domicilio, ajustándose al tiempo estimado de entrega y en perfecto estado. El 99,3% refirió estar satisfecho con el servicio de Telefarmacia y envío a domicilio. El 76,2% prefieren, una vez finalizado el estado de alarma, la Telefarmacia y envío a domicilio de la medicación. La única variable sociodemográfica que se asoció de manera significativa con las preferencias de los pacientes por el modelo de Telefarmacia y envío a domicilio fue la distancia al domicilio del paciente. CONCLUSIONES: Se considera necesario adecuar los modelos asistenciales, debiendo incorporar a la práctica diaria el modelo de atención farmacéutica telemática, junto con el envío domiciliario de medicación, modelo válido, sustentado en la factibilidad de los envíos domiciliarios, el mantenimiento de la atención farmacéutica y la satisfacción y preferencias de los pacientes. Afortunadamente, los primeros pasos están dados y el proceso es irreversible

AIM: To assess the perceived satisfaction with the implemented Telepharmacy and home drug delivery program, as well as the preferences of patients and / or caregivers for the healthcare model of pharmaceutical care and dispensing when the "new normality" is reached. METHOD: An anonymous electronic survey was designed using the Microsoft Forms application. The target population were the patients, or caregivers, treated in the Outpatient Unit using the Telepharmacy model who received the prescribed medication in their homes between April 30 to May 18, 2020. RESULTS: 327 questionnaires were sent, obtaining a response rate of 45.0%. 95.9% indicated that they received the medication correctly at home, adjusting to the estimated delivery time and in perfect condition. 99.3% reported being satisfied with the Telepharmacy and home delivery service. 76.2% prefer, once the alarm state is over, Telepharmacy and home drug delivery of the medication. The only sociodemographic variable that was significantly associated with patient preferences for the Telepharmacy and home drug delivery model was the distance to the patient's home. CONCLUSIONS: The healthcare models should be modified, and the telematic pharmaceutical care model should be incorporated into daily practice together with the home delivery of medication. It is considered a valid model, based on the feasibility of home delivery, the maintenance of pharmaceutical care and patient satisfaction and preferences. Fortunately, the first steps are taken, and the process is irreversible

Correction to: Outcome quality standards in advanced ovarian cancer surgery.

An amendment to this paper has been published and can be accessed via the original article.

Outcome quality standards in advanced ovarian cancer surgery.

INTRODUCTION: Advanced ovarian cancer surgery (AOCS) frequently results in serious postoperative complications. Because managing AOCS is difficult, some standards need to be established that allow surgeons to assess the quality of treatment provided and consider what aspects should improve. This study aimed to identify quality indicators (QIs) of clinical relevance and to establish their acceptable quality limits (i.e., standard) in AOCS. MATERIALS AND METHODS: We performed a systematic search on clinical practice guidelines, consensus conferences, and reviews on the outcome and quality of AOCS to identify which QIs have clinical relevance in AOCS. We then searched the literature (from January 2006 to December 2018) for each QI in combination with the keywords of advanced ovarian cancer, surgery, outcome, and oncology. Standards for each QI were determined by statistical process control techniques. The acceptable quality limits for each QI were defined as being within the limits of the 99.8% interval, which indicated a favorable outcome. RESULTS: A total of 38 studies were included. The QIs selected for AOCS were complete removal of the tumor upon visual inspection (complete cytoreductive surgery), a residual tumor of < 1 cm (optimal cytoreductive surgery), a residual tumor of > 1 cm (suboptimal cytoreductive surgery), major morbidity, and 5-year survival. The rates of complete cytoreductive surgery, optimal cytoreductive surgery, suboptimal cytoreductive surgery, morbidity, and 5-year survival had quality limits of < 27%, < 23%, > 39%, > 33%, and < 27%, respectively. CONCLUSION: Our results provide a general view of clinical indicators for AOCS. Acceptable quality limits that can be considered as standards were established.

A conserved motif in three viral movement proteins from different genera is required for host factor recruitment and cell-to-cell movement.

Due to their minimal genomes, plant viruses are forced to hijack specific cellular pathways to ensure host colonization, a condition that most frequently involves physical interaction between viral and host proteins. Among putative viral interactors are the movement proteins, responsible for plasmodesma gating and genome binding during viral transport. Two of them, DGBp1 and DGBp2, are required for alpha-, beta- and gammacarmovirus cell-to-cell movement, but the number of DGBp-host interactors identified at present is limited. By using two different approaches, yeast two-hybrid and bimolecular fluorescence complementation assays, we found three Arabidopsis factors, eIF3g1, RPP3A and WRKY36, interacting with DGBp1s from each genus mentioned above. eIF3g1 and RPP3A are mainly involved in protein translation initiation and elongation phases, respectively, while WRKY36 belongs to WRKY transcription factor family, important regulators of many defence responses. These host proteins are not expected to be associated with viral movement, but knocking out WRKY36 or silencing either RPP3A or eIF3g1 negatively affected Arabidopsis infection by Turnip crinkle virus. A highly conserved FNF motif at DGBp1 C-terminus was required for protein-protein interaction and cell-to-cell movement, suggesting an important biological role.

Clinical efficacy and safety of anti PD-1/PD-L1 antibodies as monotherapy in patients with non-small-cell lung cancer.

OBJECTIVE: To evaluate the efficacy and safety of anti-PD-1 and anti-PD-L1 immunotherapy agents as monotherapy in patients with non-small cell  lung cancer. METHOD: This was a four-year retrospective observational study that included all patients with non-small cell lung cancer treated with  nivolumab, pembrolizumab, and atezolizumab in a third level hospital. Demographic, clinical (ECOG status, stage, PD-L1 expression  level), therapeutic (drug, start date, line of treatment and number of  cycles), efficacy (date and status at the end of follow-up) and toxicity  variables were collected. Data was extracted from the patient's electronic  medical record. Overall survival and progression-free survival rates for  different monitoring times were calculated. RESULTS: The study included 80 patients, 35 on nivolumab, 32 on  pembrolizumab and 13 on atezolizumab. The median overall survival was  not achieved. Overall survival at 6, 12, 18 and 49 months in patients  treated with nivolumab was 79.7%, 74.0%, 65.8% and 65.8%,  respectively. Median progression-free survival was 15 months. Adverse  events were observed in 85.7% of cases, the most common being asthenia (45.7%), hypothyroidism (25.7%) and cough (20.0%). For  pembrolizumab, the overall survival rate at the end of follow-up for first-  and second-line treatment was 100% and 70.9%, respectively. Median  progression-free survival was 17 months in the first-line and 24 months in  the second-line setting. Adverse events were observed in 84.4% of  subjects, the most common ones being dyspnea (31.3%), arthralgia  (28.1%) and asthenia (25.0%). The overall survival rate from 3 to 7  months remained at 75.8% for atezolizumab. Median progression-free  survival could not be determined. At 3 and 6 months, 49.5% of subjects  had made some progress. The most frequent adverse events included  toxicity (69.2%), asthenia (30.8%), and cough, dyspnea, and skin toxicity  (15.4% each). CONCLUSIONS: Subjects showed a trend toward stabilization and  chronification of the disease. A positive and considerable survival rate was observed, as compared with previous studies. Further studies are  required with larger sample sizes and longer follow-up times to confirm  these findings.

Objetivo: Evaluación de la efectividad y seguridad de inmunoterapia anti- PD-1 y anti-PD-L1 en monoterapia para pacientes con cáncer de pulmón no microcítico.Método: Estudio observacional retrospectivo que incluyó a pacientes con cáncer de pulmón no microcítico tratados con nivolumab,  pembrolizumab y atezolizumab, durante 4 años en un hospital de tercer  nivel. Se recogieron variables demográficas, clínicas (clasificación en la  escala del Eastern Cooperative Oncology Group, estadio de la enfermedad, determinación y valor de PD-1), de tratamiento (fármaco, fecha de inicio,  línea de tratamiento y número de ciclos), de efectividad (fecha y estado a  fin de seguimiento) y de toxicidad. Los datos se extrajeron de la historia  clínica informatizada. Se calcularon las tasas de supervivencia global y de  supervivencia libre de progresión para diferentes tiempos de seguimiento.Resultados: Se incluyeron 80 pacientes, 35 con nivolumab, 32 con pembrolizumab y 13 con atezolizumab. No se alcanzaron medianas de supervivencia global. En los pacientes tratados con nivolumab, la  supervivencia a los 6, 12, 18 y 49 meses fue del 79,7%, 74,0%, 65,8% y  65,8%, respectivamente. La mediana de supervivencia libre de progresión  fue de 15 meses. El 85,7% presentó toxicidad, siendo astenia (45,7%),  hipotiroidismo (25,7%) y tos (20,0%) las más frecuentes. Para  pembrolizumab, la tasa de supervivencia global al final del seguimiento fue del 100% en primera línea y del 70,9% en segunda línea de tratamiento.  La mediana de supervivencia libre de progresión fue de 17 meses en  primera línea y 24 meses en segunda línea de tratamiento. El 84,4%  presentó toxicidad, siendo disnea (31,3%), artralgias (28,1%) y astenia  (25,0%) las más frecuentes. Para atezolizumab la tasa de supervivencia  global se mantuvo en 75,8% desde los 3 hasta los 7 meses. No se alcanzó  la mediana de supervivencia libre de progresión; a los 3 y 6 meses, el  49,5% había progresado. El 69,2% presentó toxicidad, siendo astenia  (30,8%) y tos, disnea y toxicidad cutánea (15,4%, para cada una) las más frecuentes.Conclusiones: Se observa una tendencia de la muestra a la estabilización y cronificación de la enfermedad, hallándose una positiva y  considerable tasa de supervivencia, en comparación con estudios previos. Se precisa ampliar el tamaño muestral y el tiempo de seguimiento  para confirmar dicha tendencia.

Hexanoic Acid Treatment Prevents Systemic MNSV Movement in Cucumis melo Plants by Priming Callose Deposition Correlating SA and OPDA Accumulation.

Unlike fungal and bacterial diseases, no direct method is available to control viral diseases. The use of resistance-inducing compounds can be an alternative strategy for plant viruses. Here we studied the basal response of melon to Melon necrotic spot virus (MNSV) and demonstrated the efficacy of hexanoic acid (Hx) priming, which prevents the virus from systemically spreading. We analysed callose deposition and the hormonal profile and gene expression at the whole plant level. This allowed us to determine hormonal homeostasis in the melon roots, cotyledons, hypocotyls, stems and leaves involved in basal and hexanoic acid-induced resistance (Hx-IR) to MNSV. Our data indicate important roles of salicylic acid (SA), 12-oxo-phytodienoic acid (OPDA), jasmonic-isoleucine, and ferulic acid in both responses to MNSV. The hormonal and metabolites balance, depending on the time and location associated with basal and Hx-IR, demonstrated the reprogramming of plant metabolism in MNSV-inoculated plants. The treatment with both SA and OPDA prior to virus infection significantly reduced MNSV systemic movement by inducing callose deposition. This demonstrates their relevance in Hx-IR against MNSV and a high correlation with callose deposition. Our data also provide valuable evidence to unravel priming mechanisms by natural compounds.

Dissecting the multifunctional role of the N-terminal domain of the Melon necrotic spot virus coat protein in RNA packaging, viral movement and interference with antiviral plant defence.

The coat protein (CP) of Melon necrotic spot virus (MNSV) is structurally composed of three major domains. The middle S-domain builds a robust protein shell around the viral genome, whereas the C-terminal protruding domain, or P-domain, is involved in the attachment of virions to the transmission vector. Here, we have shown that the N-terminal domain, or R-domain, and the arm region, which connects the R-domain and S-domain, are involved in different key steps of the viral cycle, such as cell-to-cell movement and the suppression of RNA silencing and pathogenesis through their RNA-binding capabilities. Deletion mutants revealed that the CP RNA-binding ability was abolished only after complete, but not partial, deletion of the R-domain and the arm region. However, a comparison of the apparent dissociation constants for the CP RNA-binding reaction of several partial deletion mutants showed that the arm region played a more relevant role than the R-domain in in vitro RNA binding. Similar results were obtained in in vivo assays, although, in this case, full-length CPs were required to encapsidate full-length genomes. We also found that the R-domain carboxyl portion and the arm region were essential for efficient cell-to-cell movement, for enhancement of Potato virus X pathogenicity, for suppression of systemic RNA silencing and for binding of small RNAs. Therefore, unlike other carmovirus CPs, the R-domain and the arm region of MNSV CP have acquired, in addition to other essential functions such as genome binding and encapsidation functions, the ability to suppress RNA silencing by preventing systemic small RNA transport.

Comparative proteomic analysis of melon phloem exudates in response to viral infection.

Phloem vasculature is the route that most plant viruses use to spread widely around the plant. In addition, phloem sap transports signals that trigger systemic defense responses to infection. We investigated the proteome-level changes that occur in phloem sap during virus infection using the 2D-DIGE technique. Total proteins were extracted from phloem exudates of healthy and Melon necrotic spot virus infected melon plants and analyzed by 2D-DIGE. A total of 1046 spots were detected but only 25 had significant changes in abundance. After mass spectrometry, 19 different proteins corresponding to 22 spots were further identified (13 of them up-accumulated and 9 down-accumulated). Most of them were involved in controlling redox balance and cell death. Only two of the differentially altered proteins had never been described to be present in the phloem before: a carboxylesterase and the fumarylacetoacetate hydrolase 1, both considered negative regulators of cell death. RT-PCR analysis of phloem sap RNAs revealed that the transcripts corresponding to some of the identified protein could be also loaded into the sieve elements. The impact of these proteins in the host response against viral infections and the potential involvement in regulating development, growth and stress response in melon plants is discussed. BIOLOGICAL SIGNIFICANCE: Despite the importance of phloem as an integrative pathway for resource distribution, signaling and plant virus transport little is known about the modifications induced by these pathogens in phloem sap proteome. Only one previous study has actually examined the phloem sap proteome during viral infection using conventional two-dimensional electrophoresis. Since the major limitation of this technique has been its low sensitivity, the authors only identified five phloem proteins with altered abundance. To circumvent this issue we use two-dimensional difference in-gel electrophoresis (2D DIGE) technique, which combined with DeCyder Differential Analysis Software allows a more accurate and sensitive quantitative analysis than with conventional 2D PAGE. We identified 19 different proteins which accumulation in phloem sap was altered during a compatible plant virus infection including redox and hypersensitivity response-related proteins. Therefore, this work would help to understand the basic processes that occur in phloem during plant-virus interaction.

A model for transport of a viral membrane protein through the early secretory pathway: minimal sequence and endoplasmic reticulum lateral mobility requirements.

Viral movement proteins exploit host endomembranes and the cytoskeleton to move within the cell via routes that, in some cases, are dependent on the secretory pathway. For example, melon necrotic spot virus p7B, a type II transmembrane protein, leaves the endoplasmic reticulum (ER) through the COPII-dependent Golgi pathway to reach the plasmodesmata. Here we investigated the sequence requirements and putative mechanisms governing p7B transport through the early secretory pathway. Deletion of either the cytoplasmic N-terminal region (CR) or the luminal C-terminal region (LR) led to ER retention, suggesting that they are both essential for ER export. Through alanine-scanning mutagenesis, we identified residues in the CR and LR that are critical for both ER export and for viral cell-to-cell movement. Within the CR, alanine substitution of aspartic and proline residues in the DSSP ß-turn motif (D7 AP10 A) led to movement of discrete structures along the cortical ER in an actin-dependent manner. In contrast, alanine substitution of a lysine residue in the LR (K49 A) resulted in a homogenous ER distribution of the movement protein and inhibition of ER-Golgi traffic. Moreover, the ability of p7B to recruit Sar1 to the ER membrane is lost in the D7 AP10 A mutant, but enhanced in the K49 A mutant. In addition, fluorescence recovery after photobleaching revealed that K49 A but not D7 AP10 A dramatically diminished protein lateral mobility. From these data, we propose a model whereby the LR directs actin-dependent mobility toward the cortical ER, where the cytoplasmic DSSP ß-turn favors assembly of COPII vesicles for export of p7B from the ER.