Clinical characteristics and outcomes of immunocompromised critically ill patients with cytomegalovirus end-organ disease: a multicenter retrospective cohort study.

BACKGROUND: Cytomegalovirus (CMV) infection in patients with cellular immune deficiencies is associated with significant morbidity and mortality. However, data on CMV end-organ disease (CMV-EOD) in critically ill, immunocompromised patients are scarce. Our objective here was to describe the clinical characteristics and outcomes of CMV-EOD in this population. METHODS: We conducted a multicenter, international, retrospective, observational study in adults who had CMV-EOD and were admitted to any of 18 intensive care units (ICUs) in France, Israel, and Spain in January 2010-December 2021. Patients with AIDS were excluded. We collected the clinical characteristics and outcomes of each patient. Survivors and non-survivors were compared, and multivariate analysis was performed to identify risk factors for hospital mortality. RESULTS: We studied 185 patients, including 80 (43.2%) with hematologic malignancies, 55 (29.7%) with solid organ transplantation, 31 (16.8%) on immunosuppressants, 16 (8.6%) with solid malignancies, and 3 (1.6%) with primary immunodeficiencies. The most common CMV-EOD was pneumonia (n = 115, [62.2%] including 55 [47.8%] with a respiratory co-pathogen), followed by CMV gastrointestinal disease (n = 64 [34.6%]). More than one organ was involved in 16 (8.8%) patients. Histopathological evidence was obtained for 10/115 (8.7%) patients with pneumonia and 43/64 (67.2%) with GI disease. Other opportunistic infections were diagnosed in 69 (37.3%) patients. Hospital mortality was 61.4% overall and was significantly higher in the group with hematologic malignancies (75% vs. 51%, P = 0.001). Factors independently associated with higher hospital mortality were hematologic malignancy with active graft-versus-host disease (OR 5.02; 95% CI 1.15-27.30), CMV pneumonia (OR 2.57; 95% CI 1.13-6.03), lymphocytes < 0.30 × 109/L at diagnosis of CMV-EOD (OR 2.40; 95% CI 1.05-5.69), worse SOFA score at ICU admission (OR 1.18; 95% CI 1.04-1.35), and older age (OR 1.04; 95% CI 1.01-1.07). CONCLUSIONS: Mortality was high in critically ill, immunocompromised patients with CMV-EOD and varied considerably with the cause of immunodeficiency and organ involved by CMV. Three of the four independent risk factors identified here are also known to be associated with higher mortality in the absence of CMV-EOD. CMV pneumonia was rarely proven by histopathology and was the most severe CMV-EOD.

CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell-targeted therapies.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.

Acute Kidney Injury Recovery Patterns in Critically Ill Patients: Results of a Retrospective Cohort Study.

OBJECTIVES: Acute kidney injury, acute kidney injury severity, and acute kidney injury duration are associated with both short- and long-term outcomes. Despite recent definitions, only few studies assessed pattern of renal recovery and time-dependent competing risks are usually disregarded. Our objective was to describe pattern of acute kidney injury recovery, change of transition probability over time and their risk factors. DESIGN: Monocenter retrospective cohort study. Acute kidney injury was defined according to Kidney Disease Improving Global Outcomes definition. Renal recovery was defined as normalization of both serum creatinine and urine output criteria. Competing risk analysis, time-inhomogeneous Markov model, and group-based trajectory modeling were performed. SETTING: Monocenter study. PATIENTS: Consecutive patients admitted in ICU from July 2018 to December 2018 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three-hundred fifty patients were included. Acute kidney injury occurred in 166 patients at ICU admission, including 64 patients (38.6%) classified as acute kidney disease according to Acute Disease Quality Initiative definition and 44 patients (26.5%) who could not be classified. Cumulative incidence of recovery was 25 % at day 2 (95% CI, 18-32%) and 35% at day 7 (95% CI, 28-42%). After adjustment, need for mechanical ventilation (subdistribution hazard ratio, 0.42; 95% CI, 0.23-0.74) and severity of the acute kidney injury (stage 3 vs stage 1 subdistribution hazard ratio, 0.11; 95% CI, 0.03-0.35) were associated with lack of recovery. Group-based trajectory modeling identified three clusters of temporal changes in this setting, associated with both acute kidney injury recovery and patients' outcomes. CONCLUSIONS: In this study, we demonstrate Acute Disease Quality Initiative to allow recovery pattern classification in 75% of critically ill patients. Our study underlines the need to take into account competing risk factors when assessing recovery pattern in critically ill patients.

Evaluation of the effect of a laparoscopic robotized needle holder on ergonomics and skills.

BACKGROUND: Laparoscopy generates technical and ergonomics difficulties due to limited degrees of freedom (DOF) of forceps. To reduce this limitation, a new 5-mm robotized needle holder with two intracorporeal DOF, Jaimy(®), has been developed. The aim of this study was to evaluate its effects on ergonomics and skills. METHODS: Fourteen surgeons including eight senior and six residents were crossover randomized and stratified based on experience. Three suturing tasks were performed with both Jaimy(®) and a classic needle holder (NH): task 1: Peg-Board; task 2: hexagonal suture; task 3: frontal suture. Postural ergonomics of the dominant arm were evaluated with an ergonomics score (RULA score) thanks to motion capture, and muscular ergonomics with electromyography of six muscular groups (flexor and extensor carpis, biceps, triceps, deltoid, trapeze). Performance outcomes are a quantitative and qualitative score, and skills outcomes are the measurement of the number of movements and the path length travelled by the instrument. RESULTS: The RULA score showed a statistically improved posture with Jaimy(®) (p < 0.001). The cumulative muscular workload (CMW) of four muscles was not different. However, the CMW was in favor of the NH for the flexor carpi ulnaris (p < 0.001) and the triceps (p = 0.027). The number of movements was not different (p = 0.39) although the path length was shorter with Jaimy(®) (p = 0.012). The score for task 1 was in favor of the NH (p = 0.006) with a higher quantity score. Task 2 score was not different (p = 0.086): The quality part of the score was in favor of Jaimy(®) (p = 0.009) and the quantity part was higher with the NH (p = 0.04). The score for task 3 was higher with Jaimy(®) (p = 0.001). CONCLUSION: This study suggests that the use of a robotized needle holder improves both posture and the quality of laparoscopic sutures.

Adaptative damping assistance in bimanual laparoscopic surgery.

PURPOSE: Laparoscopic surgery has demonstrated various advantages for the patients' care, but also presents some difficulties for the surgeons, such as kinematic restrictions. Robotic comanipulation, in which control of instruments is shared between the robot and the surgeon, can provide adaptative damping assistance which allows stabilisation of movements. The objective of the present study was to determine the contribution of this assistance on a bimanual laparoscopic task. METHODS: Adaptative damping was studied on Peg Transfer task, performed by eighteen surgery-naive subjects. This exercise was repeated seven times without (Classic repetitions) and seven times with comanipulated robots (Robot repetitions), in a randomised order. We measured task performance, using Peg Transfer score; gesture performance, using hand oscillations and travelled distance; eye-tracking movements as an indicator of emergence of expertise. Participants' perceived workload was assessed by NASA TLX questionnaire, and difference in impression between the two conditions by UEQ questionnaire. RESULTS: Adaptative damping improved gesture performance (oscillations F(1,17) = 23.473, p < 0.001, η2 = 0.580), with a statistically significant simple effect on the tool oscillation for both non-dominant (p < 0.001) and dominant hands (p = 0.005), without influencing task performance (mean Peg Transfer score t(17) = 0.920, p = 0.382, d = 0.29), but deteriorating eye-tracking movements associated with emergence of expertise (mean fixation rate per second F(1,17) = 6.318, p = 0.022, η2 = 0.271), at the cost of a high perceived workload (NASA TLX score 59.78/100). CONCLUSION: Assistance by adaptative damping applied by comanipulated robots improved gesture performance during a laparoscopic bimanual task, without impacting task's performance without allowing the emergence of comportments associated with an expertise, and at the cost of a high perceived workload. Further research should investigate this assistance on more precise and clinical tasks performed by professionals.

Robust trocar identification and its application in robotic minimally invasive surgery.

BACKGROUND: In minimally invasive surgery (MIS), instruments pass through trocars which are installed through the incision points. This forms a fulcrum effect and imposes significant constraint. For robotic manipulative operations, the real-time trocar information is a prerequisite. Systems acquire this knowledge either with a prior registration procedure or through coordinated control of their joints. METHODS: A robust and real-time trocar identification algorithm based on least square (LS) algorithm was proposed in the context of human-robot co-manipulation scenario. RESULTS: Both in vitro and in vivo experiments were performed to verify the effectiveness of the proposed algorithm. The estimated trocar coordinates expressed in the robot base frame were further leveraged to implement an instrument gravity compensation function. CONCLUSIONS: An LS based approach can be employed to robustly estimate the real-time trocar information so as to implement more practical robotic functions.

The stability investigation of variable viscosity control in the human-robot interaction.

BACKGROUND: For many co-manipulative applications, variable damping is a valuable feature provided by robots. One approach is implementing a high viscosity at low velocities and a low viscosity at high velocities. This, however, is proven to have the possibility to alter human natural motion performance. METHODS: We show that the distortion is caused by the viscosity drop resulting in robot's resistance to motion. To address this, a method for stably achieving the desired behaviour is presented. It involves leveraging a first-order linear filter to slow the viscosity variation down. RESULTS: The proposition is supported by a theoretical analysis using a robotic model. Meanwhile, the user performance in human-robot experiments gets significantly improved, showing the practical efficiency in real applications. CONCLUSIONS: This paper discusses the variable viscosity control in the context of co-manipulation. An instability problem and its solution were theoretically shown and experimentally evidenced through human-robot experiments.

Simultaneous Control of 2DOF Upper-Limb Prosthesis With Body Compensations-Based Control: A Multiple Cases Study.

Controlling several joints simultaneously is a common feature of natural arm movements. Robotic prostheses shall offer this possibility to their wearer. Yet, existing approaches to control a robotic upper-limb prosthesis from myoelectric interfaces do not satisfactorily respond to this need: standard methods provide sequential joint-by-joint motion control only; advanced pattern recognition-based approaches allow the control of a limited subset of synchronized multi-joint movements and remain complex to set up. In this paper, we exploit a control method of an upper-limb prosthesis based on body motion measurement called Compensations Cancellation Control (CCC). It offers a straightforward simultaneous control of the intermediate joints, namely the wrist and the elbow. Four transhumeral amputated participants performed the Refined Rolyan Clothespin Test with an experimental prosthesis alternatively running CCC and conventional joint-by-joint myoelectric control. Task performance, joint motions, body compensations and cognitive load were assessed. This experiment shows that CCC restores simultaneity between prosthetic joints while maintaining the level of performance of conventional myoelectric control (used on a daily basis by three participants), without increasing compensatory motions nor cognitive load.

Sinusoidal Obstruction Syndrome in Critically Ill Patients in the Era of Defibrotide: A Retrospective Multicenter Study.

Sinusoidal obstruction syndrome (SOS) is a life-threatening liver complication of high- dose chemotherapy. Defibrotide is the only available therapeutic option approved for SOS. The prognosis of SOS in patients requiring intensive care unit (ICU) admission remains unknown. The primary objective of this study was to assess the outcome of SOS patients in ICU. This retrospective study was conducted between 2007 and 2019 in 13 French ICUs. Seventy-one critically ill adult patients with SOS defined according to European Society for Blood and Marrow Transplantation criteria and treated with defibrotide were included. The main reasons for ICU admission were respiratory failure and acute kidney injury. Mechanical ventilation, vasopressors, and renal replacement therapy were required in 59%, 52%, and 49% of patients, respectively. Twenty-three percent of patients experienced a bleeding event during defibrotide treatment. Hospital mortality was 54%, mainly related to multiorgan failure. Older age (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00 to 1.04), mechanical ventilation (HR, 1.99; 95% CI, 1.00 to 3.99), renal replacement therapy (HR, 2.55; 95% CI, 1.32 to 4.91) were independent predictors of hospital mortality. Defibrotide prophylaxis (HR, 0.35; 95% CI, 0.13 to 0.92) was associated with better outcomes. Critically ill patients with SOS have a high mortality rate in the ICU, especially if organ support is required. Additional studies assessing the impact of defibrotide prophylaxis are warranted.

Factors associated with coinfections in invasive aspergillosis: a retrospective cohort study.

OBJECTIVES: To describe the coinfections in invasive aspergillosis (IA), to identify factors associated with coinfections, and to evaluate the impact of coinfection on mortality. PATIENTS AND METHODS: We conducted a monocentric retrospective study of consecutive putative, probable, or proven IA that occurred between 1997 and 2017. All coinfections, with an onset within 7 days before or after the first sign of aspergillosis, were identified. Factors associated with coinfections and mortality were analysed by multivariable analysis. RESULTS: Among the 690 patients with IA included in the study, the median age was 57 years (range 7 days to 90 years). A coinfection was diagnosed in 272/690 patients (39.4%, 95%CI 35.8-43.2). The location of this coinfection was pulmonary only in 131/272 patients (48%), bloodstream only in 66/272 patients (24%) and other/multiple sites in 75/272 patients (28%). Coinfections were bacterial (110/272 patients, 40%), viral (58/272, 21%), fungal (57/272, 21%), parasitic (5/272, 2%) or due to multiple types of pathogens (42/272, 15%). Factors associated with a coinfection in adjusted analysis were: allogeneic haematopoietic stem-cell transplantation (OR 2.3 (1.2-4.4)), other haematological malignancies (OR 2.1 (1.2-3.8)), other underlying diseases (OR 4.3 (1.4-13.6)), lymphopenia (OR 1.7 (1.1-2.5)), C-reactive protein >180 mg/L (OR 1.9 (1.2-3.0)), fever (OR 2.4 (1.5-4.1)), tracheal intubation (OR 2.6 (1.5-4.7)), isolation of two or more different Aspergillus species (OR 2.7 (1.1-6.3)), and the presence of non-nodular lesions on chest computed tomography (OR 2.2 (1.3-3.7) and OR 2.2 (1.2-4.0)). Coinfections were independently associated with a higher mortality at week 12 (adjusted HR 1.5 (1.1-1.9), p < 0.01). CONCLUSIONS: Coinfections are frequent in IA patients and are associated with higher mortality.

Precisely positioning the tip of an instrument inserted through an orifice with a free wrist robot: application to prostate biopsies.

PURPOSE: Robots with a spherical unactuated wrist can be used for minimally invasive surgery. With such a robot, positioning the wrist center controls the instrument tip position when assuming that the insertion site behaves like a lever with a fixed and known fulcrum. In practice, this assumption is not always respected. In this paper we first study the practical consequences of this problem in terms of tip precision positioning. We then propose a robotic control scheme that improves the precision compared to the fixed point assumption approach. METHODS: In the first part of the paper, data recorded during robot-assisted transrectal needle positioning for prostate biopsies (nine patients) are exploited to quantify the positioning error induced by the use of a fixed point hypothesis in the positioning process. In the second part of the paper advanced control techniques allow for the online identification of a locally linear system that describes a model characterized by anisotropy and center displacement. A laboratory apparatus is used to demonstrate the resulting improvement on tip positioning precision. RESULTS: Errors obtained by processing the clinical data reach 7.5 mm at the tip in average. Errors obtained with the laboratory apparatus drop from 2.4 mm in average to 0.8 mm when using real-time model update.

Anasarca, Fever, Thrombocytopenia, Organomegaly, and Multiorgan Failure in a 24-Year-Old Pregnant Woman.

TAFRO syndrome is a distinct idiopathic multicentric Castleman disease characterized by the association of thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. We report the first case occurring in a Caucasian pregnant woman. At 34 weeks of gestation, our patient presented with all clinical and biological symptoms compatible with a TAFRO syndrome. Tough quick cesarean section was performed as symptoms got worse with onset of multiorgan failure requiring mechanical ventilation for acute respiratory distress, continuous renal replacement, and vasopressors. Nine days after ICU admission, steroid boluses were started and allowed spectacular clinical and biological improvement. As systemic inflammatory manifestations are important, TAFRO syndrome can be mistaken with severe autoimmune diseases, systemic infections, hematological malignancies, or hemophagocytic lymphohistiocytosis.

Prostate biopsies assisted by comanipulated probe-holder: first in man.

PURPOSE: A comanipulator for assisting endorectal prostate biopsies is evaluated through a first-in-man clinical trial. This lightweight system, based on conventional robotic components, possesses six degrees of freedom. It uses three electric motors and three brakes. It features a free mode, where its low friction and inertia allow for natural manipulation of the probe and a locked mode, exhibiting both a very low stiffness and a high steady-state precision. METHODS: Clinical trials focusing on the free mode and the locked mode of the robot are presented. The objective was to evaluate the practical usability and performance of the robot during clinical procedures. A research protocol for a prospective randomized clinical trial has been designed. Its specific goal was to compare the accuracy of biopsies performed with and without the assistance of the comanipulator. RESULTS: The accuracy is compared between biopsies performed with and without the assistance of the comanipulator, across the 10 first patients included in the trial. Results show a statistically significant increase in the precision.

Robot guidance of an ultrasound probe toward a 3D region of interest detected through X-ray mammography.

PURPOSE: This research is situated in the context of breast cancer detection where the standard procedure is the succession of an initial mammography (MX) examination and a supplementary ultrasound (US) scan. One major difficulty of this procedure results from the fact that breast geometry changes between both examinations due to different patient's positions. The proposed system facilitates this combined examination by keeping the breast geometry and by adding a US probe guidance robot to the mammography system. METHODS: A comanipulation system is set up where the robot and user simultaneously manipulate the probe toward the target previously localized in MX images. Calibration procedures and robot control are detailed. RESULTS: A test protocol was presented to conduct two tests that are both related to the medical application. The first tests aim at evaluating robot guidance for localizing a lesion which was previously defined in the X-ray images. The second tests aim at quantifying robot influence when scanning a target lesion. The studied task consists of a pointing/scanning exercise, where the US beam intersects a breast lesion. CONCLUSIONS: The experiments show a significant increase in examination quality when using robot guidance as compared to the nonassisted examination.

Differential gene retention as an evolutionary mechanism to generate biodiversity and adaptation in yeasts.

The evolutionary history of the characters underlying the adaptation of microorganisms to food and biotechnological uses is poorly understood. We undertook comparative genomics to investigate evolutionary relationships of the dairy yeast Geotrichum candidum within Saccharomycotina. Surprisingly, a remarkable proportion of genes showed discordant phylogenies, clustering with the filamentous fungus subphylum (Pezizomycotina), rather than the yeast subphylum (Saccharomycotina), of the Ascomycota. These genes appear not to be the result of Horizontal Gene Transfer (HGT), but to have been specifically retained by G. candidum after the filamentous fungi-yeasts split concomitant with the yeasts' genome contraction. We refer to these genes as SRAGs (Specifically Retained Ancestral Genes), having been lost by all or nearly all other yeasts, and thus contributing to the phenotypic specificity of lineages. SRAG functions include lipases consistent with a role in cheese making and novel endoglucanases associated with degradation of plant material. Similar gene retention was observed in three other distantly related yeasts representative of this ecologically diverse subphylum. The phenomenon thus appears to be widespread in the Saccharomycotina and argues that, alongside neo-functionalization following gene duplication and HGT, specific gene retention must be recognized as an important mechanism for generation of biodiversity and adaptation in yeasts.