The functional impact of BRCA1 BRCT domain variants using multiplexed DNA double-strand break repair assays.

Pathogenic variants in BRCA1 are associated with a greatly increased risk of hereditary breast and ovarian cancer (HBOC). With the increased availability and affordability of genetic testing, many individuals have been identified with BRCA1 variants of uncertain significance (VUSs), which are individually detected in the population too infrequently to ascertain a clinical risk. Functional assays can be used to experimentally assess the effects of these variants. In this study, we used multiplexed DNA repair assays of variants in the BRCA1 carboxyl terminus to functionally characterize 2,271 variants for homology-directed repair function (HDR) and 1,427 variants for cisplatin resistance (CR). We found a high level of consistent results (Pearson's r = 0.74) in the two multiplexed functional assays with non-functional variants located within regions of the BRCA1 protein necessary for its tumor suppression activity. In addition, functional categorizations of variants tested in the multiplex HDR and CR assays correlated with known clinical significance and with other functional assays for BRCA1 (Pearson's r = 0.53 to 0.71). The results of the multiplex HDR and CR assays are useful resources for characterizing large numbers of BRCA1 VUSs.

Risk factors for long post-operative hospital stays after cardiopulmonary bypass surgery in full-term neonates.

BACKGROUND: Long hospital stays for neonates following cardiac surgery can be detrimental to short- and long-term outcomes. Furthermore, it can impact resource allocation within heart centres' daily operations. We aimed to explore multiple clinical variables and complications that can influence and predict the post-operative hospital length of stay. METHODS: We conducted a retrospective observational review of the full-term neonates (<30 days old) who had cardiac surgery in a tertiary paediatric cardiac surgery centre - assessment of multiple clinical variables and their association with post-operative hospital length of stay. RESULTS: A total of 273 neonates were screened with a mortality rate of 8%. The survivors (number = 251) were analysed; 83% had at least one complication. The median post-operative hospital length of stay was 19.5 days (interquartile range 10.5, 31.6 days). The median post-operative hospital length of stay was significantly different among patients with complications (21.5 days, 10.5, 34.6 days) versus the no-complication group (14 days, 9.6, 19.5 days), p < 0.01. Among the non-modifiable variables, gastrostomy, tracheostomy, syndromes, and single ventricle physiology are significantly associated with longer post-operative hospital length of stay. Among the modifiable variables, deep vein thrombosis and cardiac arrest were associated with extended post-operative hospital length of stay. CONCLUSIONS: Complications following cardiac surgery can be associated with longer hospital stay. Some complications are modifiable. Deep vein thrombosis and cardiac arrest are among the complications that were associated with longer hospital stay and offer a direct opportunity for prevention which may be reflected in better outcomes and shorter hospital stay.

Central ECMO cannulation for severe dihydropyridine calcium channel blocker overdose.

Calcium channel blocker (CCB) toxicity carries a high mortality and is the sixth most fatal drug class reported to US poison centers. Amlodipine overdose is characterized by a life-threatening arterial vasodilation that compromises organ perfusion. The management of CCB intoxication is focused on maintaining adequate organ perfusion. In cases refractory to medical therapies, hemodynamic support with extracorporeal membrane oxygenation (ECMO) is warranted necessitating higher flows than usual to compensate for the vasodilation and requiring central cannulation. We present a case of a 12-year-old with severe dihydropyridine CCB ingestion, refractory to medical management and successfully treated with central ECMO cannulation. The patient was discharged home with no significant disability. Central ECMO cannulation may be helpful to facilitate adequate flows in vasodilatory shock such as CCB overdose.

Effectiveness of manual lymphatic drainage and intermittent pneumatic compression in lymphedema maintenance therapy.

Background: To compare the effectiveness of intermittent pneumatic compression (IPC) and/or manual lymphatic drainage (MLD) associated to compression stockings in the maintenance treatment of lymphedema. Patients and methods: Patients in the maintenance phase of lymphedema therapy with MLD and compression since more than a year with stable values for weight and circumferences of ankle and calf were asked to participate in a study: Compression had to be worn daily, (1) 4 weeks IPC+MLD, (2) 4 weeks MLD alone, (3) 4 Weeks IPC alone (Order 1 and 3 was randomized). At the beginning and after each 4 weeks, circumference measurements (by hand and by machine: BT600®, Bauerfeind) were documented, pain and discomfort were assessed, and quality-of-life questionnaires were completed. Results: Of 20 participants, 18 (14 female, 4 male), mean age 59.6 years (48-89) could be evaluated. 11 subjects had bilateral, 7 unilateral, 5 primary, 13 secondary lymphedema since 2-20 years (mean 7.7), the subjects had received MLD and compression for 2-14 years (mean 6.4), 1-3 times per week (mean 1.5). The BMI ranged between 21 and 47 (mean 33.7). No differences between any phases were found for: Calf and thigh volume, circumference of calf. Only the ankle circumference was significant less (-0.22 cm) when using "both" (IPC+MLD). Compared to before the study, quality of life was better in all three phases, but with a significantly higher improvement in the phases with IPC than in the phases without. Conclusions: There were no differences in objective measurement between MLD alone, IPC alone or both, excepting the minimal significant difference in ankle circumference after IPC+MLD. QOL favored IPC application. Considering the economic consequences of these results, a change of maintenance therapy with MLD weekly over years in favor of permanent care with IPC and few appointments of MLD per year should be considered and further investigated.

Safety gaps in medical team communication: Results of quality improvement efforts in a cardiac catheterization laboratory.

OBJECTIVES: To assess closed-loop communications (readback), a fundamental aspect of effective communication, among cardiovascular teams and assess improvement efforts. BACKGROUND: Effective communication within teams is essential to assure safety and optimal outcomes. Readback of verbal physician orders is a hospital and national requirement. METHODS: Single-center observational study, where the readback responses to physician verbal orders in the catheterization laboratory were characterized over three distinct time intervals from 2015 to 2017. Performance feedback and focused education on the value of readbacks was provided to the teams in two waves, with subsequent remeasurement. Responses to verbal orders were characterized as complete (all important parameters of the order repeated for verification), partial, acknowledgement only, or no response. Changes in readback performance after quality interventions were assessed. RESULTS: During the first-observational period of 101 cases, complete readback occurred in 195 of 515 (38%) medication orders and 136 of 235 (58%) equipment orders. After initial quality improvement efforts, 102 cases were observed. In these, 298 of 480 (62%) medication orders had complete readback, and 210 of 420 (50%) equipment orders had complete readback. After additional quality improvement efforts, 168 cases were observed. In these, 506 of 723 (70%) medication orders had complete readback, and 630 of 1,061 (59%) equipment orders had complete readback. Overall, medication order readback improved over time (correlation = 0.26 [-0.30, -0.21]; p < 0.001), but equipment order readback did not (correlation = 0.02 [-0.07, 0.03]; p = 0.44). CONCLUSIONS: Closed-loop communication of physician verbal orders was used infrequently in this medical team setting and proved difficult to fully improve. This is an important safety gap.

Homeostatic feelings - a novel explanation of vein symptoms derived from an experimental patient study.

Background: Vein symptoms (VS) entail diffuse leg discomfort and pain coinciding with a perception of weighty or swollen legs. Their traditional classification as a form of venous disease may be inaccurate as they occur in patients with no or any venous disorder. We hypothesized that VS would emerge from a primordially standing associated perturbation in the lower limbs which is not necessarily connected with a venous disorder. Patients and methods: Patients were sorted into groups according to the CEAP classification, VS only (C0s), primary varicose veins (C2p), varicose veins plus oedema (C2p and C3), and venous dermatopathy (C4). Patients completed questionnaires before and one week after they were exposed to a test of stationary standing. Results: Patients (N = 127) in the four groups differed by sex, age and body weight. The VS experienced in the preceding week scored the same in all groups at 3.1 on a numeric rating scale (range 0-10; SD 1.6). During standing, lower leg volume increased and symptoms emerged to the same extent across patient groups and were reduced similarly by compression (volume by 1.7 %, symptoms by 41.7 %). The emergence of symptoms was neither correlated with leg volume increase per se, nor with limiting this increase by compression. Symptoms recorded at baseline correlated with the symptoms provoked by the stress test with bare legs while the symptoms reported at follow-up, when stockings were worn regularly, correlated with the stress test with compression. Conclusions: VS, in terms of neuropsychology, reflect a homeostatic disturbance experienced in the presence and absence of venous disease. Thus, VS are not distinctive for the presence of venous disease insofar as they may reflect dynamic homeostatic feelings resulting from a standing-related disequilibrium in the legs' internal environment.

Eosinophilic Granulomatosis With Polyangiitis: Newer Therapies.

PURPOSE OF REVIEW: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic disseminated vasculitis associated with extravascular granulomas in patients suffering from asthma and tissue eosinophilia. Current therapies to achieve remission and prevent relapse include glucocorticoids and immunosuppressants like cyclophosphamide. RECENT FINDINGS: With the right treatment, clinical prognosis is favorable, so concerted efforts have been made in recent years to find new alternatives for treating severe EGPA. Monoclonal antibodies such as omalizumab, rituximab, and mepolizumab are among these new options. This review summarizes the pathogenesis and clinical manifestations of EGPA and critically examines current and emerging therapies.

Nutritional Assessment Tools for the Identification of Malnutrition and Nutritional Risk Associated with Cancer Treatment.

Malnutrition and muscle wasting are common features of cancer cachexia that may interfere with the patient's response to cancer treatment, survival, and quality of life. An accurate nutritional screening at the time of diagnosis and throughout the patient's treatment fosters better control of the disease. Several screening tools have proven to be useful for this purpose. Nevertheless, nutritional evaluation is not a routine practice in this clinical setting and procedures must be standardized. Nutritional risk screening (NRS), malnutrition screening tool (MST), and patient-generated subjective global assessment (PG-SGA) are the most common screening tools, and each one possesses some benefits when screening patients for malnutrition; however, weight loss over a specific time period, dietary intake and anorexia must also be considered. The body mass index-adjusted weight loss grading system predicts survival. We recommend the application of MST or NRS, followed by PG-SGA, food intake determination, measurement of body weight, and its changes as well as body composition, biochemical nutritional markers, muscle function, and physical performance.

Toe elevation manoeuvre to assess venous reflux in comparison to manual calf compression and release.

BACKGROUND: In the daily office setting, flow and reflux in leg veins is assessed to investigate patients with chronic venous disease. Valsalva manoeuvre and manual calf compression and release are frequent manoeuvres used to elicit blood flow in leg veins. Toe elevation manoeuvre (TEM) was proposed as a further alternative to provoke blood flow in veins. We compared both methods. PATIENTS AND METHODS: Patients consulting a venous office referring no previous treatment on their leg veins were evaluated with duplex ultrasound in the standing position. Age, body mass index, C of CEAP, venous clinics severity score, diameter of great saphenous vein and reflux duration at proximal thigh following TEM and manual calf compression and release were assessed. RESULTS: In total, 53 legs were evaluated with both manoeuvres, applied in a randomised sequence. Reflux >0.5s was found in 40 legs (group "reflux") and no reflux in 13 legs (group "no reflux"). No significant difference was found following manual calf compression and release or TEM (2.11s vs. 2.31s in "reflux-group" and 0.11s vs. 0.13s in "no-reflux-group"), but good correlation was found between both with Pearson's test (r=0.72). CONCLUSIONS: Both manoeuvres showed a good correlation with respect to reflux detection and reflux duration. The advantage of TEM is the easy and painless performance, low fatigability and independence from examiner.

Biodegradation of p-cresol and sulfide removal by a marine-denitrifying consortium.

The simultaneous removal of sulfide and p-cresol was carried out by using a marine-denitrifying consortium collected in the coastal zone of Sonora, Mexico. Different experimental conditions were used to evaluate the capacity of the consortium to simultaneously eliminate nitrate, sulfide, and p-cresol. For instance, the first set of assays was conducted at different sulfide concentrations (20, 50, and 100 mg S(2À) L(À1) ), with a fixed concentration of p-cresol (45 mg C L(À1) ). The second set of assays was developed at different concentrations of p-cresol (45, 75, and 100 mg C L(-1) ), in the presence of 20 mg S(2À) L(À1) . In all cases, the concentration of nitrate was stoichiometrically added for the complete oxidization of the substrates. The results showed removal efficiencies up to 92% for p-cresol and nitrate at 20 and 50 mg S(2À) L(À1) ; whereas at 100 mg S(2À) L(À1) removal efficiencies were 77% and 59% for p-cresol and nitrate, respectively. On the other hand, sulfide (20 mg L(À1) ) was completely removed under different concentrations of p-cresol tested, with a partial accumulation of nitrite according to the increment of p-cresol concentration. The results obtained indicate that the marine consortium was able to simultaneously remove the pollutants studied.

The covert symphony: cellular and molecular accomplices in breast cancer metastasis.

Breast cancer has emerged as the most commonly diagnosed cancer and primary cause of cancer-related deaths among women worldwide. Although significant progress has been made in targeting the primary tumor, the effectiveness of systemic treatments to prevent metastasis remains limited. Metastatic disease continues to be the predominant factor leading to fatality in the majority of breast cancer patients. The existence of a prolonged latency period between initial treatment and eventual recurrence in certain patients indicates that tumors can both adapt to and interact with the systemic environment of the host, facilitating and sustaining the progression of the disease. In order to identify potential therapeutic interventions for metastasis, it will be crucial to gain a comprehensive framework surrounding the mechanisms driving the growth, survival, and spread of tumor cells, as well as their interaction with supporting cells of the microenvironment. This review aims to consolidate recent discoveries concerning critical aspects of breast cancer metastasis, encompassing the intricate network of cells, molecules, and physical factors that contribute to metastasis, as well as the molecular mechanisms governing cancer dormancy.

Reflux origin of the insufficient small saphenous vein by duplex ultrasound determination and consequences for therapy considering the saphenopopliteal junction type.

OBJECTIVE: The reflux pathophysiology of the saphenofemoral junction (SFJ) of the insufficient great saphenous vein (GSV) has already been investigated and stratified. These results are still lacking for the small saphenous vein (SSV). The aim of the study was to analyze the pathophysiology of the saphenopopliteal junction (SPJ) in case of refluxing SSV. METHODS: The study included 1142 legs investigated between April 1, 2019, and February 15, 2023, with chronic venous insufficiency scheduled for endoluminal thermal ablation of the insufficient SSV. Preoperatively, a standardized duplex ultrasound assessment of the SPJ including the cranial extension of the SSV and the Giacomini vein, respectively, was performed to determine the origin of reflux. Having in mind, that the draining type according to Cavezzi is relevant to the treatment planning, after having scanned 152 legs, the protocol was extended to this feature: Cavezzi type A1 or A2 was recorded on 990 legs. RESULTS: In 984 cases (86%), saphenopopliteal reflux from the popliteal vein into the insufficient SSV was detected, and in 181 cases of these (16%), simultaneous refluxing blood from the cranial extension or Giacomini vein was found. In 119 cases (10%), reflux resulted only from the cranial extension or Giacomini vein with a competent SPJ, and in 39 cases (3%), the reflux source was diffusely from side branches and/or perforating veins. Cavezzi's junction types A1 (independent junction of SSV and muscle veins) and A2 (muscle veins join into SSV, draining together into the popliteal vein through the SPJ) were found in 65% and 35% of cases, respectively. CONCLUSIONS: The insufficient SSV shows a high frequency of axial reflux from the deep into the saphenous vein with an indication for high ligation or thermal ablation at the level of the SPJ or immediately distal to the inflow of muscular veins depending on the junction type. In 14%, based on this study, we observed a competent junction of the SSV without indication for ligation or thermal destruction of the SPJ.

Clinical effects of hydration, supplementary vitamins, and trace elements during end-of-life care for cancer patients.

Introduction: Introduction: current data regarding the decision on rehydration of patients with terminal-stage cancer remain controversial. Objective: the present study was to evaluate the effect of intravenous hydration and supplementary vitamins and trace elements on clinical symptoms and biochemical parameters in palliative cancer patients. Methods: a randomized clinical trial including 72 palliative cancer patients aged 18 years and older was performed at the National Cancer Institute in Mexico. Patients were divided into two groups: intervention and control, both receiving intravenous saline solution weekly for 4 weeks, but the former was also supplemented with vitamins and trace elements. Symptoms were assessed at baseline and 4 weeks after with the Edmonton Symptom Assessment Scale. Same measurements applied to biochemical parameters. Results: the mean age of the patients was 58.75 years. The most frequent cancer diagnoses were gastrointestinal (32 %). In the between-groups analysis significant improvements were found for the intervention group in anorexia (p = 0.024), pain (p = 0.030), chloride (p = 0.043), phosphorus (p = 0.001), potassium (p = 0.006), and total proteins (< 0.0001). Conclusion: we highlight the improvement in the control of most symptoms and some biochemical parameters in the intervention group receiving vitamins and oligoelements along with intravenous hydration. Further studies are needed.

Introducción: Introducción: los datos actuales sobre la decisión de rehidratación de pacientes con cáncer en fase terminal siguen siendo controvertidos. Objetivo: el presente estudio fue evaluar el efecto de la hidratación intravenosa y la suplementación con vitaminas y oligoelementos sobre los síntomas clínicos y parámetros bioquímicos en pacientes con cáncer paliativo. Métodos: en el Instituto Nacional del Cáncer de México se realizó un ensayo clínico aleatorizado que incluyó a 72 pacientes con cáncer paliativo de 18 años o más. Los pacientes se dividieron en dos grupos: intervención y control, ambos recibieron solución salina intravenosa semanalmente durante 4 semanas, pero el primero también se complementó con vitaminas y oligoelementos. Los síntomas se evaluaron al inicio del estudio y 4 semanas después con la escala de evaluación de síntomas de Edmonton. Mismas medidas aplicadas a los parámetros bioquímicos. Resultados: la edad media de los pacientes fue de 58,75 años. El diagnóstico de cáncer más frecuente fue el gastrointestinal (32 %). En el análisis entre grupos se encontraron mejoras significativas para el grupo de intervención en anorexia (p = 0,024), dolor (p = 0,030), cloro (p = 0,043), fósforo (p = 0,001), potasio (p = 0,006) y proteínas totales (< 0,0001). Conclusión: destacamos la mejoría en el control de la mayoría de los síntomas y algunos parámetros bioquímicos en el grupo de intervención que recibió vitaminas y oligoelementos junto con hidratación endovenosa. Se necesitan más estudios.

Nutritional status in patients with COVID-19 and cancer: the experience of the National Cancer Institute in Mexico.

INTRODUCTION: Background: nutritional status might vary according to different underlying illnesses such as cancer or infectious diseases, including COVID-19. In this context, data from developing countries remain scarce. Objectives: the objective of this study was to assess the nutritional status and outcomes of Mexican cancer patients diagnosed with COVID-19 at a tertiary care center. Methods: this was a retrospective study including 121 consecutive cancer patients diagnosed with COVID-19 at the National Cancer Institute, Mexico City, during four months. Results: the most frequent oncological diagnoses were gynecological (19 %) and hematological (17 %). Most patients were overweight (35 %). In the univariate analysis, ≥ 65 years, intubation, hypoalbuminemia, high creatinine, lymphopenia, nutrition-impact symptoms, and ECOG 2-4 were statistically associated with lower survival. The median survival of the cohort was 41 days. Conclusions: to our best knowledge, this is the first study of its kind performed in Mexico, and as other studies from other regions, our results might aid in identifying cancer patients most at risk for severe COVID-19, and could be potentially useful to enhance public health messaging on self-isolation and social distancing among Mexican cancer patients.

INTRODUCCIÓN: Antecedentes: el estado nutricional puede variar según las diferentes enfermedades subyacentes, como el cáncer o las enfermedades infecciosas, por ejemplo, la COVID-19. En este contexto, los datos de los países en desarrollo siguen siendo escasos. Objetivos: el objetivo de este estudio fue evaluar el estado nutricional y los resultados de pacientes mexicanos con cáncer diagnosticados de COVID-19 en un centro de atención terciaria. Métodos: se trata de un estudio retrospectivo que incluyó a 121 pacientes consecutivos con cáncer diagnosticados de COVID-19 en el Instituto Nacional del Cáncer de la Ciudad de México durante cuatro meses. Resultados: los diagnósticos oncológicos más frecuentes fueron los ginecológicos (19 %) y hematológicos (17 %). La mayoría de los pacientes tenían sobrepeso (35 %) y obesidad (31 %). En el análisis univariado, ≥ 65 años, intubación, hipoalbuminemia, creatinina alta, linfopenia, síntomas de impacto nutricional y ECOG 2-4 se asociaron estadísticamente con una menor supervivencia. La mediana de supervivencia de la cohorte fue de 41 días. Conclusiones: hasta donde sabemos, este es el primer estudio de este tipo realizado en México y, al igual que otros estudios de otras regiones, nuestros resultados podrían ayudar a identificar a los pacientes con cáncer y mayor riesgo de COVID-19 grave; también podrían ser potencialmente útiles para mejorar los mensajes de salud sobre el autoaislamiento y el distanciamiento social entre los pacientes mexicanos con cáncer.

Cytokine markers of B lymphocytes in minor salivary gland infiltrates in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterised by the clinical presence of sicca syndrome. SS compromises the dysfunction of exocrine glands due to the presence of focal, mononuclear cell infiltrates that surround the ducts and replace the secretory units. Abnormal expression of different cytokines and chemokines such as B-cell activating factor, CXC Motif Chemokine Ligand 13, interleukin 6 (IL-6), IL-22, and FMS-like tyrosine kinase 3 ligand as well as that of their corresponding receptors has been implicated in the inflammatory process. The severity of glandular infiltration has been suggested to be associated with the presence of extra-glandular systemic manifestations, contributing to a clinical spectrum of the most severe disease. This review describes several cytokines and chemokines associated with B lymphocytes expressed in the minor salivary gland, their chemical structures, and their roles in SS as possible early predictors of lymphoma development and disease progression.