Phospholipid scramblase 1: an essential component of the nephrocyte slit diaphragm.

Blood ultrafiltration in nephrons critically depends on specialized intercellular junctions between podocytes, named slit diaphragms (SDs). Here, by studying a homologous structure found in Drosophila nephrocytes, we identify the phospholipid scramblase Scramb1 as an essential component of the SD, uncovering a novel link between membrane dynamics and SD formation. In scramb1 mutants, SDs fail to form. Instead, the SD components Sticks and stones/nephrin, Polychaetoid/ZO-1, and the Src-kinase Src64B/Fyn associate in cortical foci lacking the key SD protein Dumbfounded/NEPH1. Scramb1 interaction with Polychaetoid/ZO-1 and Flotillin2, the presence of essential putative palmitoylation sites and its capacity to oligomerize, suggest a function in promoting SD assembly within lipid raft microdomains. Furthermore, Scramb1 interactors as well as its functional sensitivity to temperature, suggest an active involvement in membrane remodeling processes during SD assembly. Remarkably, putative Ca2+-binding sites in Scramb1 are essential for its activity raising the possibility that Ca2+ signaling may control the assembly of SDs by impacting on Scramb1 activity.

Analysis of Heart Rate Variability in Individuals Affected by Amyotrophic Lateral Sclerosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) produces alterations in the autonomic nervous system (ANS), which explains the cardiac manifestations observed in patients. The assessment of heart rate variability (HRV) is what best reflects the activity of the ANS on heart rate. The Polar H7 Bluetooth® device proves to be a non-invasive and much faster technology than existing alternatives for this purpose. OBJECTIVE: The goal of this study is to determine HRV using Polar H7 Bluetooth technology in ALS patients, comparing the obtained measurements with values from healthy individuals. METHOD: The sample consisted of 124 participants: 68 diagnosed with ALS and 56 healthy individuals. Using Polar H7 Bluetooth technology and the ELITE HRV application, various HRV measurements were determined for all participants, specifically the HRV index, RMSSD, RMSSD LN, SDNN index, PNN50, LF, HF, LF/HF ratio, HR average, and HF peak frequency. RESULTS: Statistically significant differences were observed between ALS patients and healthy individuals in the HRV index, RMSSD, RMSSD LN, SDNN index, PNN50, HF, and LF, where healthy individuals exhibited higher scores. For the HR average, the ALS group showed a higher value. Values were similar when comparing men and women with ALS, with only a higher HF peak frequency observed in women. CONCLUSION: The Polar H7 Bluetooth® device is effective in determining heart rate variability alterations in ALS, being a promising prognostic tool for the disease.

A Novel Closed-Loop Electrical Brain Stimulation Device Featuring Wireless Low-Energy Ultrasound Power and Communication.

OBJECTIVES: This study aimed to indicate the feasibility of a prototype electrical neuromodulation system using a closed-loop energy-efficient ultrasound-based mechanism for communication, data transmission, and recharging. MATERIALS AND METHODS: Closed-loop deep brain stimulation (DBS) prototypes were designed and fabricated with ultrasonic wideband (UsWB) communication technology and miniaturized custom electronics. Two devices were implanted short term in anesthetized Göttingen minipigs (N = 2). Targeting was performed using preoperative magnetic resonance imaging, and locations were confirmed postoperatively by computerized tomography. DBS systems were tested over a wide range of stimulation settings to mimic minimal, typical, and/or aggressive clinical settings, and evaluated for their ability to transmit data through scalp tissue and to recharge the DBS system using UsWB. RESULTS: Stimulation, communication, reprogramming, and recharging protocols were successfully achieved in both subjects for amplitude (1V-6V), frequency (50-250 Hz), and pulse width (60-200 µs) settings and maintained for ≥six hours. The precision of pulse settings was verified with <5% error. Communication rates of 64 kbit/s with an error rate of 0.05% were shown, with no meaningful throughput degradation observed. Time to recharge to 80% capacity was <9 minutes. Two DBS systems also were implanted in the second test animal, and independent bilateral stimulation was successfully shown. CONCLUSIONS: The system performed at clinically relevant implant depths and settings. Independent bilateral stimulation for the duration of the study with a 4F energy storage and full rapid recharge were achieved. Continuous function extrapolates to six days of continuous stimulation in future design iterations implementing application specific integrated circuit level efficiency and 15F storage capacitance. UsWB increases energy efficiency, reducing storage requirements and thereby enabling device miniaturization. The device can enable intelligent closed-loop stimulation, remote system monitoring, and optimization and can serve as a power/data gateway to interconnect the intrabody network with the Internet of Medical Things.

Clustering analysis reveals different profiles associating long-term post-COVID symptoms, COVID-19 symptoms at hospital admission and previous medical co-morbidities in previously hospitalized COVID-19 survivors.

PURPOSE: To identify subgroups of COVID-19 survivors exhibiting long-term post-COVID symptoms according to clinical/hospitalization data by using cluster analysis in order to foresee the illness progress and facilitate subsequent prognosis. METHODS: Age, gender, height, weight, pre-existing medical comorbidities, Internal Care Unit (ICU) admission, days at hospital, and presence of COVID-19 symptoms at hospital admission were collected from hospital records in a sample of patients recovered from COVID-19 at five hospitals in Madrid (Spain). A predefined list of post-COVID symptoms was systematically assessed a mean of 8.4 months (SD 15.5) after hospital discharge. Anxiety/depressive levels and sleep quality were assessed with the Hospital Anxiety and Depression Scale and Pittsburgh Sleep Quality Index, respectively. Cluster analysis was used to identify groupings of COVID-19 patients without introducing any previous assumptions, yielding three different clusters associating post-COVID symptoms with acute COVID-19 symptoms at hospital admission. RESULTS: Cluster 2 grouped subjects with lower prevalence of medical co-morbidities, lower number of COVID-19 symptoms at hospital admission, lower number of post-COVID symptoms, and almost no limitations with daily living activities when compared to the others. In contrast, individuals in cluster 0 and 1 exhibited higher number of pre-existing medical co-morbidities, higher number of COVID-19 symptoms at hospital admission, higher number of long-term post-COVID symptoms (particularly fatigue, dyspnea and pain), more limitations on daily living activities, higher anxiety and depressive levels, and worse sleep quality than those in cluster 2. CONCLUSIONS: The identified subgrouping may reflect different mechanisms which should be considered in therapeutic interventions.

A New Technique of Pars Plana Vitrectomy With Microinterventional Nucleus Disassembly to Reduce the Energy of Fragmatome Lensectomy for Posteriorly Dislocated Crystalline Lens Removal.

PURPOSE: To describe a novel technique of lens disassembly in posteriorly dislocated crystalline lens removal. METHODS: A microinterventional microfilament loop device was introduced through the sclerotomy created for the fragmatome to cleave the lens into smaller, manageable pieces. RESULTS: Five cases were performed with this technique with improved visual acuity and no complications. CONCLUSION: The use of microinterventional nucleus disassembly during pars plana vitrectomy for retained lens material is a novel approach with potential advantages including decreased operating time and reduced complications secondary to excessive production of ultrasound energy.

Sensitization symptoms are associated with psychological and cognitive variables in COVID-19 survivors exhibiting post-COVID pain.

OBJECTIVE: To investigate the association between demographic, clinical, psychological, cognitive, and health-related variables and the Central Sensitization Inventory (CSI) in previously hospitalized COVID-19 survivors exhibiting "de novo" post-COVID pain. METHODS: Seventy-seven (n = 77) COVID-19 survivors with "de novo" post-COVID pain completed demographic (age, height, and weight), clinical (duration and intensity of the pain), psychological (depressive/anxiety levels and sleep quality), cognitive (catastrophizing and kinesiophobia levels), and health-related quality of life variables as well as the CSI. A multivariable correlation analysis was conducted to determine the association between variables, and a stepwise multiple linear regression model was performed to identify CSI predictors. RESULTS: Patients were assessed a mean of 6.0 (SD 0.8) months after hospital discharge. Twenty-six (33.7%) individuals showed indications of sensitization-associated symptoms (CSI score ≥40 points). The CSI score was positively associated with pain intensity (r: 0.371), anxiety (r: 0.784), depressive (r: 0.709), catastrophizing (r: 0.620), and kinesiophobia (r: 0.359) levels (all, p < 0.001). The stepwise regression analysis revealed that 60.2% of CSI was explained by anxiety levels and pain intensity. CONCLUSION: This study found that psychological and cognitive variables were associated with the CSI score in previously hospitalized COVID-19 survivors with "de novo" post-COVID pain. Anxiety levels and the intensity of pain symptoms were independently associated with CSI score suggesting a significant overlap with psychological construct. The "de novo" post-COVID pain association with CSI may indicate changes in the pain processing important for managing the pain.

Low handgrip strength is associated with higher liver enzyme concentrations in US adolescents.

BACKGROUND: Increasing evidence highlights the role of muscular strength as a protective factor for cardiometabolic health in adolescents. However, it is not known the relationship between liver enzyme concentrations, liver disease risk factors, and muscular strength among young populations. The aim of this study was to determine the association between muscle strength and liver enzymes and chronic liver disease risk among US adolescents. METHODS: Data from the NHANES cross-sectional study (2011-2014) was used. A total of 1270 adolescents were included in the final analysis (12-17 years old). Absolute handgrip strength (kg) was normalized according to body composition parameters by body weight [NHSw], whole-body fat [NHSf], and trunk fat [NHSt]). RESULTS: In boys, handgrip strength was inversely associated with higher values of aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (GGT) for all estimations of muscle strength (NHSw, NHSf, and NHSt) (p < 0.050). Likewise, boys with high and intermediate NHSw, NHSf, and NHSt presented lower AST and GGT than their counterparts with low handgrip strength (p < 0.050). CONCLUSIONS: Our findings highlight the importance of muscular strength during adolescence since they could help in developing better liver enzyme profiles among adolescent population. IMPACT: Our research suggests that US adolescents with low handgrip strength have higher values of liver enzymes as well as a higher prevalence of chronic liver disease. These findings are clinically meaningful and highlight the importance of muscular strength during adolescence since they could help in developing better liver enzyme profiles among young populations.

Immediate Effects of Dry Needing or Manual Pressure Release of Upper Trapezius Trigger Points on Muscle Activity During the Craniocervical Flexion Test in People with Chronic Neck Pain: A Randomized Clinical Trial.

OBJECTIVE: To compare the effects of dry needling or manual pressure release on an active trigger point in the upper trapezius on craniocervical flexion test performance, pressure pain thresholds, and cervical range of motion in chronic neck pain. DESIGN: A parallel randomized clinical trial. SETTING: Physical therapy service. SUBJECTS: Individuals with chronic neck pain. METHODS: Subjects were randomized to receive dry needling (n = 25) or manual trigger point pressure release (n = 25) on upper trapezius active trigger points. Surface electromyography from the upper trapezius, splenius capitis, sternocleidomastoid, and scalene muscles during performance of the craniocervical flexion test was assessed before and immediately after the intervention as the primary outcome. Neck pain intensity, range of motion, and pressure pain thresholds were the secondary outcomes. RESULTS: A decrease in sternocleidomastoid activity at all stages of the craniocervical flexion test (time effect, P < 0.001) was found in both groups after the interventions, with no significant between-group difference. Pressure pain thresholds measured over the cervical spine and second metacarpal increased after dry needling when compared with manual trigger point pressure release (P < 0.05). Pain intensity decreased immediately after both treatments with moderate to large effect sizes, whereas cervical range of motion increased for both groups but with small effect sizes. CONCLUSION: A single session of dry needling or manual pressure release over upper trapezius active trigger points promotes limited effects on muscle performance during the craniocervical flexion test, pressure pain thresholds, and cervical range of motion in patients with chronic neck pain.

Serological Biomarkers at Hospital Admission Are Not Related to Long-Term Post-COVID Fatigue and Dyspnea in COVID-19 Survivors.

OBJECTIVE: The aim of this study was to investigate the association between serological biomarkers at the acute phase of infection at hospital admission with the development of long-term post-COVID fatigue and dyspnea. METHODS: A cohort study including patients hospitalized due to COVID-19 in one urban hospital of Madrid (Spain) during the first wave of the outbreak (from March 20 to June 30, 2020) was conducted. Hospitalization data, clinical data, and eleven serological biomarkers were systematically collected at hospital admission. Patients were scheduled for an individual telephone interview after hospital discharge for collecting data about the presence of post-COVID fatigue and dyspnea. RESULTS: A total of 412 patients (age: 62 years, standard deviation: 15 years; 47.5% women) were assessed with a mean of 6.8 and 13.2 months after discharge. The prevalence of post-COVID fatigue and dyspnea was 72.8% and 17.2% at 6 months and 45.4% and 13.6% at 12 months after hospital discharge, respectively. Patients exhibiting post-COVID fatigue at 6 or 12 months exhibited a lower hemoglobin level, higher lymphocyte count, and lower neutrophil and platelets counts (all, p < 0.05), whereas those exhibiting post-COVID dyspnea at 6 or 12 months had a lower platelet count and lower alanine transaminase, aspartate transaminase, and lactate dehydrogenase (LDH) levels (all, p < 0.05) than those not developing post-COVID fatigue or dyspnea, respectively. The multivariate regression analyses revealed that a lower platelet count and lower LDH levels were associated but just explaining 4.5% of the variance, of suffering from post-COVID fatigue and dyspnea, respectively. CONCLUSION: Some serological biomarkers were slightly different in patients exhibiting post-COVID fatigue or dyspnea, but they could not explain the long-COVID problems in those patients.

Fatigue and Dyspnoea as Main Persistent Post-COVID-19 Symptoms in Previously Hospitalized Patients: Related Functional Limitations and Disability.

BACKGROUND: Multicentre studies focussing on specific long-term post-COVID-19 symptoms are scarce. OBJECTIVE: The aim of this study was to determine the levels of fatigue and dyspnoea, repercussions on daily life activities, and risk factors associated with fatigue or dyspnoea in COVID-19 survivors at long term after hospital discharge. METHODS: Age, gender, height, weight, symptoms at hospitalization, pre-existing medical comorbidity, intensive care unit admission, and the presence of cardio-respiratory symptoms developed after severe acute respiratory syndrome coronavirus 2 infection were collected from patients who recovered from COVID-19 at 4 hospitals in Madrid (Spain) from March 1 to May 31, 2020 (first COVID-19 wave). The Functional Impairment Checklist was used for evaluating fatigue/dyspnoea levels and functional limitations. RESULTS: A total of 1,142 patients (48% women, age: 61, standard deviation [SD]: 17 years) were assessed 7.0 months (SD 0.6) after hospitalization. Fatigue was present in 61% patients, dyspnoea with activity in 55%, and dyspnoea at rest in 23.5%. Only 355 (31.1%) patients did not exhibit fatigue and/or dyspnoea 7 months after hospitalization. Forty-five per cent reported functional limitations with daily living activities. Risk factors associated with fatigue and dyspnoea included female gender, number of pre-existing comorbidities, and number of symptoms at hospitalization. The number of days at hospital was a risk factor just for dyspnoea. CONCLUSIONS: Fatigue and/or dyspnoea were present in 70% of hospitalized COVID-19 survivors 7 months after discharge. In addition, 45% patients exhibited limitations on daily living activities. Being female, higher number of pre-existing medical comorbidities and number of symptoms at hospitalization were risk factors associated to fatigue/dyspnoea in COVID-19 survivors 7 months after hospitalization.

Prevalence of Neuropathic Component in Post-COVID Pain Symptoms in Previously Hospitalized COVID-19 Survivors.

Objectives: To investigate the prevalence of neuropathic pain symptoms and to analyze the correlation between neuropathic symptoms with pain-related, psychological, and cognitive variables in COVID-19 survivors exhibiting "de novo" post-COVID pain. Methods: Seventy-seven (n = 77) previously hospitalized COVID-19 survivors presenting with post-COVID pain completed demographic (such as age, height, and weight), pain-related (the duration and intensity of pain), psychological (depressive/anxiety levels), and cognitive (catastrophizing and kinesiophobia) variables. The Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaire was also assessed. After conducting multivariable correlation analyses, a stepwise multiple linear regression model was performed to identify S-LANSS predictors. Results: Participants were assessed a mean of 6.0 (SD 0.8) months after hospital discharge. Nineteen (24.6%) exhibited neuropathic pain symptoms (S-LANSS score≥12 points). The S-LANSS score was positively associated with the duration of post-COVID pain (r: 0.262), anxiety levels (r: 0.275), and kinesiophobia level (r: 0.291) (all, P < 0.05). The stepwise regression analysis revealed that 12.8% of the S-LANSS variance was just explained by kinesiophobia. Conclusion: This study found that almost 25% of previously hospitalized COVID-19 survivors with "de novo" post-COVID pain reported a neuropathic pain component. The presence of neuropathic pain symptomatology was associated with more anxiety and kinesiophobia, but only kinesiophobia level was significantly associated explaining 12.8% of the variance of the S-LANSS score.

Understanding entrance-air-kerma as a quality-control metric for dual-energy x-ray absorptiometry.

PURPOSE: The low exposures, unique x-ray beam geometry, and scanning design in dual-energy x-ray absorptiometry (DXA) make measurement and quality-control strategies different from traditional x-ray equipment. This study examines the dependence of measured entrance-air-kerma (EAK) on both dose sensor type and scan length. The feasibility of using EAK to compare scanner output between different scan modes, individual scanners, and scanner platforms was also established. Finally, the congruence between measured and vendor-reported EAK was analyzed. METHODS: Four Hologic DXA scanners at two institutions and all four available scan modes were tested. EAK was measured directly by three types of Radcal dose sensors: 60-cc pancake ion-chamber (IC), 180-cc pancake IC, and solid-state detector. The coefficient of variation (COV) was used to assess the dependence of EAK on scan length. Variations in EAK between the types of dose sensors as well as measured versus vendor-reported values were evaluated using Bland-Altman analysis: mean ±95% prediction interval (PI): 1.96σ. RESULTS: Dose sensor variations in EAK were minimal, with a -3.5 ± 3.5% (mean ±95% PI) percent difference between the two sizes of IC's. The solid-state detector produced highly similar measurements to the 180-cc IC. These small differences were consistent across all scanners and all scan modes tested. Neither measured nor vendor-reported EAK values were found to show relevant dependence on scan length, with all COV values ≤4%. Differences between measured and reported EAK were higher at -6 ± 48%. Likely errors in vendor-reported EAK calculations were also identified. CONCLUSION: It is feasible to quantify DXA scanner stability using EAK as a quality-control metric with a variety of solid-state and IC dose sensors, and the scan length used is not critical. Although vendor-reported EAK was consistent among scanners of the same platform, measured EAK varied significantly from scanner to scanner. As a result, measured and reported EAK may not always be comparable.

Sucrose detection and discrimination estimated by the analysis of psychometric functions with linear and non-linear models.

Sucrose detection and discrimination thresholds were determined by conducting two alternative forced-choice tests with aqueous solutions. The standard models probit and logit, and non-linear were fitted to the empirical psychometric functions. 0, 7 and 15 g/L sucrose solutions were used as standard stimuli in the detection and discrimination experiments (two levels) respectively. Comparison stimuli consisted of aqueous sucrose solutions with concentrations from 0.5 to 25 g/L. Observed absolute threshold was around 2.96 g/L and the difference limen for 7 and 15 g/L standard stimuli was around 2.98 g/L and 5.29 g/L, respectively. Calculated Weber fractions for 7 and 15 g/L standard stimuli were 0.42 and 0.35, respectively. Judges' performance in the discrimination experiment was similar to that observed in the detection experiment. Goodness of fit for probit and logit models was similar. The non-linear model showed a lower average error and demonstrated an excellent predictive ability.

[The expected cost of cancer in Chile]. / El costo esperado de cáncer en Chile.

BACKGROUND: Cancer is a public health priority in Chile. AIM: To estimate the expected annual cost of cancer in Chile, due to direct costs of health services, working allowances and indirect costs for productivity losses. MATERIAL AND METHODS: We undertook an ascendent costing methodology to calculate direct costs. We built diagnostic, treatment and follow-up cost baskets for each cancer type. Further, we estimated the expenditure due to sick leave subsidies. Both estimates were performed either for the public or private sector. Costs related to productivity loss were estimated using the human capital approach, incorporating disease related absenteeism premature deaths. The time frame for all estimates was one year. RESULTS: The annual expected costs attributed to cancer was $1,557 billion of Chilean pesos. The health services expected annual costs were $1,436 billion, 67% of which are spent on five cancer groups (digestive, hematologic, respiratory, breast and urinary tract). The expected costs of sick leave subsidies and productivity loss were $48 and $71 billion, respectively. CONCLUSIONS: Cancer generates costs to the health system, which obliges health planners to allocate a significant proportion of the health budget to this disease. The expected costs estimated in this study are equivalent to 8.9% of all health expenditures and 0.69% of the Gross Domestic Product. This study provides an updated reference for future research, such as those aimed at evaluating the current health policies in cancer.

Synthetic generation of DSC-MRI-derived relative CBV maps from DCE MRI of brain tumors.

PURPOSE: Perfusion MRI with gadolinium-based contrast agents is useful for diagnosis and treatment response evaluation of brain tumors. Dynamic susceptibility contrast (DSC) MRI and dynamic contrast enhanced (DCE) MRI are two gadolinium-based contrast agent perfusion imaging techniques that provide complementary information about the tumor vasculature. However, each requires a separate administration of a gadolinium-based contrast agent. The purpose of this retrospective study was to determine the feasibility of synthesizing relative cerebral blood volume (rCBV) maps, as computed from DSC MRI, from DCE MRI of brain tumors. METHODS: One hundred nine brain-tumor patients underwent both DCE and DSC MRI. Relative CBV maps were computed from the DSC MRI, and blood plasma volume fraction maps were computed from the DCE MRIs. Conditional generative adversarial networks were developed to synthesize rCBV maps from the DCE MRIs. Tumor-to-white matter ratios were calculated from real rCBV, synthetic rCBV, and plasma volume fraction maps and compared using correlation analysis. Real and synthetic rCBV in white and gray matter regions were also compared. RESULTS: Pearson correlation analysis showed that both the tumor rCBV and tumor-to-white matter ratios in the synthetic and real rCBV maps were strongly correlated (ρ = 0.87, P < .05 and ρ = 0.86, P < .05, respectively). Tumor plasma volume fraction and real rCBV were not strongly correlated (ρ = 0.47). Bland-Altman analysis showed a mean difference between the synthetic and real rCBV tumor-to-white matter ratios of 0.20 with a 95% confidence interval of ±0.47. CONCLUSION: Realistic rCBV maps can be synthesized from DCE MRI and contain quantitative information, enabling robust brain-tumor perfusion imaging of DSC and DCE parameters with a single gadolinium-based contrast agent administration.

"Safe incision" in calcaneal sliding osteotomies reduces the incidence of sural nerve injury.

PURPOSE: The purpose of this study was to demonstrate whether application of the so-called safe incision when performing calcaneal sliding osteotomies reduces the risk of sural nerve injury. METHODS: Patients who underwent either medial or lateral sliding calcaneal osteotomies between 2010 and 2018 were analysed retrospectively. A thorough neurological examination was performed, and the location of the surgical wound and the type of wound closure were recorded. The European Foot and Ankle Surgery (EFAS) score and 12-item Short Form Survey (SF-12) were also documented. RESULTS: A total of 57 patients were included, of which 20 (35.1%) had a sural nerve injury. Five patients had a neurapraxia (8.8%), while 15 patients had a permanent injury (26.3%). Respecting the "safe incision" decreased sural nerve injury (p = 0.02). The type of osteotomy and closure was not significant. No significant differences were found in the functional tests between the different techniques, or between patients who presented sural nerve injury and those who did not. CONCLUSION: Sural nerve injury after calcaneal sliding osteotomies is higher than previously reported in the scientific literature, with an incidence of 35.1% (20/57 patients). Respecting the so-called safe zone (oblique incision that runs through the point that is > 1/3 of the distance from the tip of the lateral malleolus to the posteroinferior margin of the calcaneus) clearly decreases the incidence of sural nerve injury. Finally, the majority of patients remained asymptomatic despite the neurological injury.

Advances in Xmipp for Cryo-Electron Microscopy: From Xmipp to Scipion.

Xmipp is an open-source software package consisting of multiple programs for processing data originating from electron microscopy and electron tomography, designed and managed by the Biocomputing Unit of the Spanish National Center for Biotechnology, although with contributions from many other developers over the world. During its 25 years of existence, Xmipp underwent multiple changes and updates. While there were many publications related to new programs and functionality added to Xmipp, there is no single publication on the Xmipp as a package since 2013. In this article, we give an overview of the changes and new work since 2013, describe technologies and techniques used during the development, and take a peek at the future of the package.

EMA Review of Daratumumab (Darzalex) for the Treatment of Adult Patients Newly Diagnosed with Multiple Myeloma.

The use of daratumumab in combination with established regimens for the treatment of newly diagnosed multiple myeloma has recently been authorized by the European Medicines Agency based on results from three separate phase III randomized, active controlled, open-label studies that have confirmed enhanced efficacy and tolerability in both transplant-ineligible (MMY3008 and MMY3007) and transplant-eligible (MMY3006) patients, without compromising transplant ability. Trial MMY3008 showed an improvement in progression-free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone; the median PFS had not been reached in the daratumumab arm and was 31.9 months in the control arm (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.43-0.73; p < .0001). Trial MMY3007 showed an improvement in PFS when daratumumab was added to bortezomib, melphalan, and prednisone compared with bortezomib, melphalan, and prednisone; PFS had not been reached in the daratumumab arm and was 18.1 months in the control arm (HR, 0.5; 95% CI, 0.38-0.65; p < .0001). In trial MMY3006, daratumumab added to bortezomib, thalidomide, and dexamethasone was compared with bortezomib, thalidomide, and dexamethasone as induction and consolidation treatment prior to autologous stem cell transplant. The stringent complete response rate at day 100 after transplant in the daratumumab group was 29% compared with 20% in the control group (odds ratio, 1.60; 1.21-2.12 95% CI; p = .0010). Overall adverse events were manageable, with an increased rate of neutropenia and infections in the daratumumab arms. Regulatory assessment of efficacy and safety results from trials MMY3006, MMY3007, and MMY3008 confirmed a positive benefit-risk ratio leading to an approval of the extensions of indication. IMPLICATIONS FOR PRACTICE: A set of extensions of indication was recently approved for daratumumab (Darzalex) in the setting of newly diagnosed multiple myeloma in combination with established regimens. Results of the MMY3006, MMY3007, and MMY3008 trials have shown enhanced efficacy and a favorable side effect profile of several daratumumab-based combinations in patients both ineligible and eligible for transplant, without compromising transplant ability. The combinations of daratumumab with either lenalidomide and low-dose dexamethasone or bortezomib, melphalan, and prednisone were approved for transplant-ineligible patients. The combination of daratumumab with bortezomib, thalidomide, and dexamethasone was approved for transplant-eligible patients. These combinations are expected to improve the survival outlook for patients with multiple myeloma, without an unacceptable risk of increase in adverse events, and updated information on progression-free survival and overall survival is expected from the above trials.

Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study.

OBJECTIVES: To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/ß-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). METHODS: This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. RESULTS: Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). CONCLUSIONS: Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

[Factors influencing the choice of a career in primary care among medical students in Central America]. / Factores que influyen en la elección de una carrera en atención primaria entre los estudiantes de medicina en América Central.

OBJECTIVES: To identify the preferred specialties, salary perception and other factors that influence the choice of a career in primary care among last-year medical students or social service students in Central America. METHODS: A cross-sectional, multicenter study using a survey that investigated demographic information, preferred specialty, salary perception, and other factors that influence the choice of a specialty. RESULTS: A total of 1 722 students from 31 universities participated and identified as future specialties: surgery (11.7%), gynecology/obstetrics (10.3%), pediatrics (9.9%) and internal medicine (6.6%). General medicine was preferred by 3.8% and family medicine by 1.1%. On grouping them, the greatest interest was observed for medical specialties (49.7%), followed by surgical specialties (31.7%). Primary care registered an interest of 17.1%. Surgical specialties were perceived as having the highest income (USD 36 000); primary care was perceived as having the lowest income (USD 24 000). Income (23.6%), future work (19.7%) and "making a difference in people" (8.9%) were the main factors involved in the choice. "Working with people with low access" was significantly associated with preference for primary care. Preference for other specialties was influenced by "perceived prestige" and "enjoying life" (P < 0.05). Most participants who chose primary care were studying at a public university (P < 0.05), highlighting the role of public institutions of higher education. CONCLUSIONS: There is a combination of facilitating factors and barriers that affect the low interest in primary care careers. There is a need for strategies from academia and the government sector, as well as the definition of public policies, that support the choice of primary care.