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Background: There is insufficient evidence to guide ventilatory targets in acute brain injury (ABI). Recent studies have shown associations between mechanical power (MP) and mortality in critical care populations. We aimed to describe MP in ventilated patients with ABI, and evaluate associations between MP and clinical outcomes. Methods: In this preplanned, secondary analysis of a prospective, multi-center, observational cohort study (ENIO, NCT03400904), we included adult patients with ABI (Glasgow Coma Scale ≤ 12 before intubation) who required mechanical ventilation (MV) ≥ 24h. Using multivariable log binomial regressions, we separately assessed associations between MP on hospital day (HD)1, HD3, HD7 and clinical outcomes: hospital mortality, need for reintubation, tracheostomy placement, and development of acute respiratory distress syndrome (ARDS). Results: We included 1217 patients (mean age 51.2years [SD 18.1], 66% male, mean body mass index [BMI] 26.3 [SD 5.18]) hospitalized at 62 intensive care units in 18 countries. Hospital mortality was 11% (n = 139), 44% (n = 536) were extubated by HD7 of which 20% (107/536) required reintubation, 28% (n = 340) underwent tracheostomy placement, and 9% (n = 114) developed ARDS. The median MP on HD1, HD3, and HD7 was 11.9J/min [IQR 9.2-15.1], 13J/min [IQR 10-17], and 14J/min [IQR 11-20], respectively. MP was overall higher in patients with ARDS, especially those with higher ARDS severity. After controlling for same-day pressure of arterial oxygen/fraction of inspired oxygen (P/F ratio), BMI, and neurological severity, MP at HD1, HD3, and HD7 was independently associated with hospital mortality, reintubation and tracheostomy placement. The adjusted relative risk (aRR) was greater at higher MP, and strongest for: mortality on HD1 (compared to the HD1 median MP 11.9J/min, aRR at 17J/min was 1.22, 95% CI 1.14-1.30) and HD3 (1.38, 95% CI 1.23-1.53), reintubation on HD1 (1.64; 95% CI 1.57-1.72), and tracheostomy on HD7 (1.53; 95%CI 1.18-1.99). MP was associated with the development of moderate-severe ARDS on HD1 (2.07; 95% CI 1.56-2.78) and HD3 (1.76; 95% CI 1.41-2.22). Conclusions: Exposure to high MP during the first week of MV is associated with poor clinical outcomes in ABI, independent of P/F ratio and neurological severity. Potential benefits of optimizing ventilator settings to limit MP warrant further investigation.

The dorsal visual stream, the cortical circuit that in the primate brain is mainly dedicated to the visual control of actions, is split into two routes, a lateral and a medial one, both involved in coding different aspects of sensorimotor control of actions. The lateral route, named “lateral grasping network”, is mainly involved in the control of the distal part of prehension, namely grasping and manipulation. The medial route, named “reach-to-grasp network”, is involved in the control of the full deployment of prehension act, from the direction of arm movement to the shaping of the hand according to the object to be grasped. In macaque monkeys, the reach-to-grasp network (the target of this review) includes areas of the superior parietal lobule (SPL) that hosts visual and somatosensory neurons well suited to control goal-directed limb movements toward stationary as well as moving objects. After a brief summary of the neuronal functional properties of these areas, we will analyze their cortical and thalamic inputs thanks to retrograde neuronal tracers separately injected into the SPL areas V6, V6A, PEc, and PE. These areas receive visual and somatosensory information distributed in a caudorostral, visuosomatic trend, and some of them are directly connected with the dorsal premotor cortex. This review is particularly focused on the origin and type of visual information reaching the SPL, and on the functional role this information can play in guiding limb interaction with objects in structured and dynamic environments.

The superior parietal lobule (SPL) integrates somatosensory, motor, and visual signals to dynamically control arm movements. During reaching, visual and gaze signals are used to guide the hand to the desired target location, while proprioceptive signals allow to correct arm trajectory, and keep the limb in the final position at the end of the movement. Three SPL areas are particularly involved in this process: V6A, PEc, PE. Here, we evaluated the influence of eye and arm position upon single neuron activity of these areas during the holding period at the end of arm reaching movements, when the arm is motionless and gaze and hand positions are aligned. Two male macaques (Macaca fascicularis) performed a foveal reaching task while single unit activity was recorded from areas V6A, PEc, and PE. We found that at the end of reaching movements the neurons of all these areas were modulated by both eye position and static position of the arm. V6A and PEc showed a prevalent combination of gaze and proprioceptive input, while PE seemed to encode these signals more independently. Our results demonstrate that all these SPL areas combine gaze and proprioceptive input to provide an accurate monitoring of arm movements.SIGNIFICANCE STATEMENTThis study shows that the SPL areas V6A, PEc and PE combine eye and static arm positions signals to build an estimate of the limb posture at the end of a reaching movement. The degree of integration of gaze and proprioceptive information changes from a joint processing of these signals in the caudal-most areas V6A and PEc (Brodmann area 7), to a more independent encoding in PE (Brodmann area 5). Our results support the existence of a functional trend in the SPL, with the anterior part dealing mainly with limb representation based on proprioception and the posterior one linking gaze and arm position signals for encoding reaching.

Objective. Motor decoding is crucial to translate the neural activity for brain-computer interfaces (BCIs) and provides information on how motor states are encoded in the brain. Deep neural networks (DNNs) are emerging as promising neural decoders. Nevertheless, it is still unclear how different DNNs perform in different motor decoding problems and scenarios, and which network could be a good candidate for invasive BCIs. Approach. Fully-connected, convolutional, and recurrent neural networks (FCNNs, CNNs, RNNs) were designed and applied to decode motor states from neurons recorded from V6A area in the posterior parietal cortex (PPC) of macaques. Three motor tasks were considered, involving reaching and reach-to-grasping (the latter under two illumination conditions). DNNs decoded nine reaching endpoints in 3D space or five grip types using a sliding window approach within the trial course. To evaluate decoders simulating a broad variety of scenarios, the performance was also analyzed while artificially reducing the number of recorded neurons and trials, and while performing transfer learning from one task to another. Finally, the accuracy time course was used to analyze V6A motor encoding. Main results. DNNs outperformed a classic Naïve Bayes classifier, and CNNs additionally outperformed XGBoost and Support Vector Machine classifiers across the motor decoding problems. CNNs resulted the top-performing DNNs when using less neurons and trials, and task-to-task transfer learning improved performance especially in the low data regime. Lastly, V6A neurons encoded reaching and reach-to-grasping properties even from action planning, with the encoding of grip properties occurring later, closer to movement execution, and appearing weaker in darkness. Significance. Results suggest that CNNs are effective candidates to realize neural decoders for invasive BCIs in humans from PPC recordings also reducing BCI calibration times (transfer learning), and that a CNN-based data-driven analysis may provide insights about the encoding properties and the functional roles of brain regions.

To evaluate the epidemiology, incidence rate, incidence proportion, and prevalence of Achilles tendon ruptures (ATRs) in professional footballers and their performance after the injury.Professional male footballers participating in Serie A in 11 consecutive seasons (2008/2009-2018/2019) were screened to identify ATRs through the online football archive transfermarkt.com. Exposure in matches and training was calculated. The number of matches played in the 5 seasons before and after ATRs was obtained, when possible, together with transfers to a different team or participation in lower Divisions.Eleven ATRs were found in 11 footballers with a mean age of 29.8 ± 4.4 years; 72% of ATR involved the nondominant leg; 58% occurred during matches and 42% during training, with no peculiar distribution along the playing season. The overall incidence proportion was 0.17% (0.11% during matches and 0.06% during training). The overall incidence rate was 0.007 injuries per 1000 hours of play (0.051 during matches and 0.003during training; P0.0001). All players returned to play soccer after a mean of 170 ± 35 days after ATRs and participated in an official match after a mean of 274 ± 98 days. However, 2 seasons after ATRs, 3 footballers were playing in a lower Division; 1 played less than 10 matches (compared with25 matches in the 5 seasons before an ATR) and 1 had retired.An overall ATR rate of 0.007 per 1000 hours of soccer play and an incidence proportion of 0.17% were reported. All footballers return to play; however, up to 40% players decreased the level of play by reducing the number of games or participating in a lower Division 2 seasons after an ATR.

The dexterous control of our grasping actions relies on the cooperative activation of many brain areas. In the parietal lobe, 2 grasp-related areas collaborate to orchestrate an accurate grasping action: dorsolateral area AIP and dorsomedial area V6A. Single-cell recordings in monkeys and fMRI studies in humans have suggested that both these areas specify grip aperture and wrist orientation, but encode these grasping parameters differently, depending on the context. To elucidate the causal role of phAIP and hV6A, we stimulated these areas, while participants were performing grasping actions (unperturbed grasping). rTMS over phAIP impaired the wrist orientation process, whereas stimulation over hV6A impaired grip aperture encoding. In a small percentage of trials, an unexpected reprogramming of grip aperture or wrist orientation was required (perturbed grasping). In these cases, rTMS over hV6A or over phAIP impaired reprogramming of both grip aperture and wrist orientation. These results represent the first direct demonstration of a different encoding of grasping parameters by 2 grasp-related parietal areas.

Purpose An ongoing pandemic of COVID-19 that started in Hubei, China has resulted in massive strain on the healthcare infrastructure in Lombardy, Italy. The management of these patients is still evolving. Materials and methods This is a single-center observational cohort study of critically ill patients infected with COVID-19. Bedside clinicians abstracted daily patient data on history, treatment, and short-term course. We describe management and a proposed severity scale for treatment used in this hospital. Results 44 patients were enrolled; with incomplete information on 11. Of the 33 studied patients, 91% were male, median age 64; 88% were overweight or obese. 45% were hypertensive, 12% had been taking an ACE-inhibitor. Noninvasive ventilation was performed on 39% of patients for part or all or their ICU stay with no provider infection. Most patients received antibiotics for pneumonia. Patients also received lopinivir/ritonavir (82%), hydroxychloroquine (79%), and tocilizumab (12%) according to this treatment algorithm. Nine of 10 patients survived their ICU course and were transferred to the floor, with one dying in the ICU. Conclusions ICU patients with COVID-19 frequently have hypertension. Many could be managed with noninvasive ventilation, despite the risk of aerosolization. The use of a severity scale augmented clinician management., Highlights • COVID-19 is a global pandemic that has recently devastated Italy • Hospitals in Italy have experience strain on resources and used non-intensivists to manage critically ill patients. • Investigators created a severity scale for communicating with non-intensivist for triage and management • Hospitals should consider adapting or revising a severity scale when utilizing non-intensivist physicians.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS, as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID. This article is protected by copyright. All rights reserved.

Summary The protocol provides an extensive guide to apply the generalized linear model framework to neurophysiological recordings. This flexible technique can be adapted to test and quantify the contributions of many different parameters (e.g., kinematics, target position, choice, reward) on neural activity. To weight the influence of each parameter, we developed an intuitive metric (“w-value”) that can be used to build a “functional fingerprint” characteristic for each neuron. We also provide suggestions to extract complementary useful information from the method. For complete details on the use and execution of this protocol, please refer to Diomedi et al. (2020)., Graphical abstract, Highlights • GLM applied to neuronal discharges reveals parameters that modulate their activity • Applying regularizers helps to discard minority parameters and reduces noise • Each neuron can be characterized by the weight assigned to each parameter tested • Results are well suited for population analyses (i.e., clustering, correlation, etc), The protocol provides an extensive guide to apply the generalized linear model framework to neurophysiological recordings. This flexible technique can be adapted to test and quantify the contributions of many different parameters (e.g., kinematics, target position, choice, reward) on neural activity. To weight the influence of each parameter, we developed an intuitive metric (“w-value”) that can be used to build a “functional fingerprint” characteristic for each neuron. We also provide suggestions to extract complementary useful information from the method.

Several investigations at a single-cell level demonstrated that the medial posterior parietal area V6A is involved in encoding reaching and grasping actions in different visual conditions. Here, we looked for a “low-dimensional” representation of these encoding processes by studying macaque V6A neurons tested in three different tasks with a dimensionality reduction technique, the demixed principal component analysis (dPCA), which is very suitable for neuroprosthetics readout. We compared neural activity in reaching and grasping tasks by highlighting the portions of population variance involved in the encoding of visual information, target position, wrist orientation and grip type. The weight of visual information and task parameters in the encoding process was dependent on the task. We found that the distribution of variance captured by visual information in the three tasks did not differ significantly among the tasks, whereas the variance captured by target position and grip type parameters were significantly higher with respect to that captured by wrist orientation regardless of the number of conditions considered in each task. These results suggest a different use of relevant information according to the type of planned and executed action. This study shows a simplified picture of encoding that describes how V6A processes relevant information for action planning and execution.

In the treatment of knee periprosthetic joint infection with a two-stage protocol, static spacers allow for the local delivery of high doses of antibiotics and help to preserve soft tissue tension. Articulated spacers were introduced to better preserve flexion after the reimplantation. The aim of this systematic review is to provide a comprehensive data collection of the results of these different spacers. An in-depth search on the main clinical databases was performed concerning the studies reporting data on the topic. A total of 87 studies and 4250 spacers were included. No significant differences were found both in pooling data analysis and meta-analysis of comparative studies about infection recurrences, complications, and clinical scores. Mean active knee flexion at last follow-up after total knee reimplantation was found to be significantly higher using articulated spacers (91.6° ± 7° for static spacers vs. 100.3° ± 9.9° for articulated spacers; p < 0.001). Meta-analysis also recognized this strong significant difference (p < 0.001). This review has confirmed that articulated spacers do not appear to be inferior to static spacers regarding all clinical outcomes, while they are superior in terms of active flexion. However, the low quality of the studies and the risk for selection bias with complex patients preferentially treated with static spacers need to be accounted for.

Background The treatment of shoulder prosthetic joint infections (PJIs) requiring removal of the prosthesis is not well defined. This article aims to systematically review and compare the results of the literature in single-stage and two-stage protocols in the treatment of shoulder PJI. Methods An in-depth search on PubMed/Scopus/Web of Science databases and cross-referencing search was carried out concerning the articles reporting detailed data on the topic. Results A total of 486 shoulder PJIs were included: 137 treated with single-stage and 349 with two-stage procedure. A similar distribution between early and not-early infections (19.1% vs 80.9%) was found between the two groups. The overall rate of success in terms of PJI eradication was significantly higher in the single-stage group (95.6% vs 85.7%, p Discussion The single-phase protocol showed a higher success rate in eradicating the infection and a lower complication rate. However, the low number of patients included, the low quality of the articles, the lack of data on clinical severity and bacteriological virulence suggest caution in conclusions.

Cryptococcal meningoencephalitis is the most common infective complication observed in patients with CD4 lymphocytopenia, including sarcoidosis. T-cell immunity is well characterized in HIV-related infections and data regarding immunity in cryptococcosis animal models is now available; on the contrary, little is known about the immune status in non-HIV-related infections. We report on reduced production of new T cells observed in a patient with sarcoidosis, CD4 lymphocytopenia, and cryptococcal-related meningoencephalitis. Although T cells presented with an intact proliferative capacity, they were oligoclonally expanded showing an effector memory phenotype. However, the deleterious activity of effector memory cells could have been controlled by the expansion of the regulatory T cell subset with the highest suppressive capability. This information provides a better understanding of the immune response to Cryptococcus occurring in non-HIV-associated cases, the predisposition to infection, and the role of different cell subtypes in controlling the disease in humans.

BACKGROUND: The aim was to describe the incidence and risk factors of barotrauma in patients with the Coronavirus disease 2019 (COVID-19) on invasive mechanical ventilation, during the outbreak in our region (Lombardy, Italy). METHODS: The study was an electronic survey open from March 27th to May 2nd, 2020. Patients with COVID-19 who developed barotrauma while on invasive mechanical ventilation from 61 hospitals of the COVID-19 Lombardy Intensive Care Unit network were involved. RESULTS: The response rate was 38/61 (62%). The incidence of barotrauma was 145/2041 (7.1%; 95%-CI: 6.1-8.3%). Only a few cases occurred with ventilatory settings that may be considered non-protective such as a plateau airway pressure >35 cmH2O (2/113 [2%]), a driving airway pressure >15 cmH2O (30/113 [27%]), or a tidal volume >8 mL/kg of ideal body weight and a plateau airway pressure >30 cmH2O (12/134 [9%]). CONCLUSIONS: Within the limits of a survey, patients with COVID-19 might be at high risk for barotrauma during invasive (and allegedly lung-protective) mechanical ventilation.

Background COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established. Methods We performed retrospective analyses of data from patients receiving off-label use of exogenous natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality. Results Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive. Conclusions Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration did not cause acute decompensation, may reduce mortality and mechanical ventilation duration in COVID-19 ARDS patients. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous sub-bronchial lavage with surfactant as treatment for patients with COVID-19 ARDS.

Rationale: Treatment with noninvasive ventilation (NIV) in coronavirus disease (COVID-19) is frequent. Shortage of intensive care unit (ICU) beds led clinicians to deliver NIV also outside ICUs. Data about the use of NIV in COVID-19 is limited. Objectives: To describe the prevalence and clinical characteristics of patients with COVID-19 treated with NIV outside the ICUs. To investigate the factors associated with NIV failure (need for intubation or death). Methods: In this prospective, single-day observational study, we enrolled adult patients with COVID-19 who were treated with NIV outside the ICU from 31 hospitals in Lombardy, Italy. Results: We collected data on demographic and clinical characteristics, ventilatory management, and patient outcomes. Of 8,753 patients with COVID-19 present in the hospitals on the study day, 909 (10%) were receiving NIV outside the ICU. A majority of patients (778/909; 85%) patients were treated with continuous positive airway pressure (CPAP), which was delivered by helmet in 617 (68%) patients. NIV failed in 300 patients (37.6%), whereas 498 (62.4%) patients were discharged alive without intubation. Overall mortality was 25%. NIV failure occurred in 152/284 (53%) patients with an arterial oxygen pressure (PaO2)/fraction of inspired oxygen (Fi O2) ratio 60% and close to 75% in full-treatment patients. C-reactive protein, PaO2/Fi O2, and platelet counts were independently associated with increased risk of NIV failure. Clinical trial registered with ClinicalTrials.gov (NCT04382235).

Background: Excessive sedation has been associated with poor outcome in critically-ill patients with acute respiratory Distress Syndrome (ARDS). The on-going pandemic has seen many critically-ill COVID-19 with ARDS, yet the incidence of excessive sedation and its association to delirium in these patients has to date not been assessed. We aimed at comparing the incidence and outcome of excessive sedation and delirium in two cohorts of critically-ill patients. Methods: This was an international, dual center retrospective analysis of prospectively collected data from two cohorts of critically ill patients, with and without COVID-19 disease, pertaining to two different hospital settings. Depth of sedation was monitored through processed EEG and delirium through the Confusion Assessment Method for the ICU(CAM-ICU). The main outcomes were the incidence of excessive sedation and delirium between the two cohorts, and secondary outcomes were length of ICU and hospital stay and mechanical ventilation duration.Results: Fifty-seven non-COVID-19 and 21 COVID-19 patients were included, 38(49%) of whom had ARDS. Twenty-seven(47.3%) non-COVID-19 and 11(52.3%) COVID-19 patients fulfilled the criteria for excessive sedation. Excessively sedated patients were older(p=0.034) and had delirium more frequently(pnon-COVID-19 patients when compared to COVID-19 patients. Despite this, COVID-19 patients remained ventilated for a longer period of time, had a longer ICU and H-LOS. Conclusion: Besides age, excessive sedation might represent an important risk factor for delirium in COVID-19 and non-COVID-19 critically ill patients, which may lead to an increased ICU-LOS, H-LOS and MV duration. The use of continuous EEG-based monitoring for quantification of sedation depth, along with frequent delirium assessment in critically-ill COVID-19 patients is warranted along with larger prospective trials aimed at verifying weather the use of EEG-based monitoring leads to improved outcome.

Background. COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established. Methods. We performed retrospective analyses of data from patients receiving off-label use of natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality. Results. Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi and lung retention for up to 2 hours. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive. Conclusions. Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration does not cause acute decompensation, and it could be related to improved survival and reduction of mechanical ventilation duration. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous surfactant delivery.

To study disease activity during pregnancy and obstetric outcomes in patients with juvenile idiopathic arthritis (JIA) upon different subsets and with focus on medication use. Retrospective observational study of 22 pregnancies in 16 JIA patients (95.5% Caucasian) who were followed between 2010 and 2018. Disease activity, flares and medications were recorded before conception, during each trimester and postpartum period. Pregnancies occurred in 10 (45.5%) oligoarticular extended (OLA-E), 6 (27.3%) in polyarticular (PLA), 4 in (18.2%) systemic (SYS), 1 (4.5%) in oligoarticular persistent (OLA-P) and 1 (4.5%) in enthesitis-related arthritis (ERA) JIA patients. The median age at disease diagnosis and at conception was 5.5 and 28 years (respectively). The median disease duration was 20 years. Nineteen (95%) pregnancies started in a period of stable disease remission. Among the 22 pregnancies, 20 ended with a live birth (90.9%). No spontaneous miscarriages occurred; two voluntary interruption of pregnancy were performed. There were 7 flares in 6/20 pregnancies (35%) and 8 flares (8/22, 36.4%) occurred in postpartum period, all of them in OLA-E and PLA patients. Seven patients (35%) were taking biological disease-modifying anti-rheumatic drugs (bDMARDs) at conception, and 6 of them stopped this treatment at positive pregnancy test. Five patients resumed bDMARDs either during pregnancy (3 exposed during the third trimester) or puerperium due to a flare. Four preterm deliveries (20%) were recorded, all in patients who had a flare during pregnancy. The preconception counselling should include the evaluation of disease subset, as OLA-E and PLA may flare more than other subsets, especially if bDMARDs are discontinued at positive pregnancy test. Continuation of bDMARDs during pregnancy should be considered to minimize the risk of adverse pregnancy outcomes, particularly preterm delivery. Key Points • In our cohort, all the flares during pregnancy and 75% of postpartum flares were observed in patients who withdrew bDMARDs and cDMARDs at the beginning of pregnancy. • Flares were observed only in PLA and OLA-E patients. • Preterm delivery occurred in 20% of the pregnancies; all of these patients had a disease flare during pregnancy.

A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24-72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0-2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10. In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.

Background/Purpose To analyse complement variations during SLE pregnancies, considering pregnancies with Adverse Pregnancy Outcome (APO) and with flares. Methods Monocentric, retrospective study of 98 SLE patients with 134 pregnancies (including 3 twin pregnancies) prospectively followed by multidisciplinary team (1987–2015). Hypocomplementemia was defined according to the normality range calculated in healthy pregnancies by Reggia et al.1 Results APO occurred in 22 (16%) and flares in 11 (8%) pregnancies. The variation of mean C3 and C4 levels are shown in table 1. Notably, both in pregnancies with flares and with APO, there was no increase of C3 between the 2nd and the 3rd trimester and of C4 between the 1st and the 3rd trimester. In pregnancies with flares the mean levels of C3 and C4 were lower than in pregnancies without flares during the 2nd and the 3rd trimester; the mean levels of C4 were also lower in the flare group during pre-conceptional visit. In pregnancies with APO, the variation of C4 levels between the 2nd and the 3rd trimester was lower than in pregnancies without APO (-3.18 vs 0.27; p=0.01). The frequency of low C4 was higher in pregnancies with flare at pre-conceptional visit, 1st trimester and 3rd trimester (6/7 vs 25/103 p=0.002; 8/9 vs 56/106 p=0.04; 9/11 vs 33/96 p=0.003), as compared with pregnancies without flares. Conclusions In our cohort, low C4 at pre-conceptional visit seems to predict flares during pregnancies. Lower increase of C4 levels between the 2nd and the 3rd trimester could predict an APO. Reference Reggia R., Ziglioli T., Andreoli L., et al. Primary anti-phospholipid syndrome: any role for serum complement levels in predicting pregnancy complications?. Rheumatology 2012;51:2186–2190

Summary The activity of neurons of the medial posterior parietal area V6A in macaque monkeys is modulated by many aspects of reach task. In the past, research was mostly focused on modulating the effect of single parameters upon the activity of V6A cells. Here, we used Generalized Linear Models (GLMs) to simultaneously test the contribution of several factors upon V6A cells during a fix-to-reach task. This approach resulted in the definition of a representative “functional fingerprint” for each neuron. We first studied how the features are distributed in the population. Our analysis highlighted the virtual absence of units strictly selective for only one factor and revealed that most cells are characterized by “mixed selectivity.” Then, exploiting our GLM framework, we investigated the dynamics of spatial parameters encoded within V6A. We found that the tuning is not static, but changed along the trial, indicating the sequential occurrence of visuospatial transformations helpful to guide arm movement., Graphical Abstract, Highlights • The parietal cortex integrates a variety of sensorimotor inputs to guide reaching • GLM disentangled the effect of various reaching parameters upon cell activity • V6A neurons were not functionally clustered, but characterized by mixed selectivity • Spatial selectivity was dynamic and reached its peak during the movement phase, Neuroscience; Behavioral Neuroscience; Biocomputational Method

Up to 40% of patients treated with tumor necrosis factor alpha inhibitors (TNFi) do not respond to therapy. Testing drug bioavailability and/or anti-drug antibody (ADAb) levels may justify dosage adjustment or switch to different drugs, enabling a personalized medicine approach. We report a multicenter cross-sectional study on different methods [ELISA and a cell based functional assay (reporter gene assay – RGA)] for drug/ADAb detection, and on the relationship between drug bioavailability and ADAb. 163 patients with rheumatoid arthritis (RA) treated with infliximab (IFX; n = 67), adalimumab (ADL; n = 49) or etanercept (ETA; n = 47) were tested for drug and ADAb levels. Furthermore, we report prospective data from additional 70 patients (59 RA and 11 juvenile idiopathic arthritis - JIA) tested for drug and ADAb levels at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment with ADL or ETA only. IFX-treated patients were not included because of the increasing use of IFX biosimilars. Stringent inclusion criteria were used in order to avoid unwanted variables in both studies; none of the patients used TNFi before the study, and TNFi was used only in combination with methotrexate. Clinical response was defined according to EULAR response criteria. The two assays performed comparably in the comparison study. Accordingly, ELISA was selected for the prospective study because of its feasibility in the clinical setting. The cross-sectional study found ADAb in IFX and ADL treated groups only, that were associated with a decrease in pharmacological drug availability in the blood. Comparable results were found for the ADL-treated group in the prospective study which also showed a relationship between drug/ADAb levels and the loss of clinical response. Altogether our findings support drug and anti-drug Ab monitoring in the real-world clinical setting thus enabling individualized treatment and reducing disability in chronic inflammatory arthritis.

Background:The burden of anterior cruciate ligament (ACL) injury in professional soccer players is particularly relevant as it represents a potentially career-threatening injury.Hypothesis:Our hypotheses were that (1) injury incidence rate would be similar to that reported in the literature, (2) we would identify a uniform distribution of the injuries along the season, and (3) injury incidence rate would be similar in high-ranked and lower ranked teams, based on final placement in the league.Study Design:Descriptive epidemiological study.Level of Evidence:Level 4.Methods:Professional male soccer players participating in the Serie A championship league in 7 consecutive seasons (2011-2012 to 2017-2018) were screened to identify ACL injuries through the online football archive transfermarkt.com . Exposure in matches and training were calculated.Results:There were 84 ACL injuries found (mean player age, 25.3 ± 4.2 years). Overall, 25% of ACL injuries were reruptures (15%) or contralateral injuries (10%). ACL incidence rate was 0.4215 per 1000 hours of play during Serie A matches, 0.0305 per 1000 hours of training (rate ratio [RR], 13.8; 95% CI, 8.4-22.7; P < 0.0001), and 0.0618 per 1000 hours of total play. Injury distribution had a bimodal peak, with the highest number of events in October and March. Alternatively, training injuries peaked in June and July. A significantly higher incidence rate was found for the teams ranked from 1st to 4th place compared with those ranked 5th to 20th (0.1256 vs 0.0559 per 1000 hours of play; RR, 2.2; 95% CI, 1.4-3.6; P = 0.0003). A similar finding was found for injury incidence proportion (3.76% vs 1.64%; P = 0.0003).Conclusion:The overall incidence rate of ACL injuries in Italian Serie A was 0.062 per 1000 hours, with a 14-fold risk in matches compared with training. Relevantly, 25% were second injuries. Most injuries occurred in October and March, and an almost 2-fold incidence rate and incidence proportion were noted in those teams ranked in the first 4 positions of the championship league.Clinical Relevance:Knowing the precise epidemiology of ACL injury in one of the most competitive professional football championship leagues could help delineate fields of research aimed to investigate its risk factors.