Survival After Severe COVID-19: Long-Term Outcomes of Patients Admitted to an Intensive Care Unit.

BACKGROUND: Understanding the long-term sequelae of severe COVID-19 remains limited, particularly in the United States. OBJECTIVE: To examine long-term outcomes of patients who required intensive care unit (ICU) admission for severe COVID-19. DESIGN, PATIENTS, AND MAIN MEASURES: This is a prospective cohort study of patients who had severe COVID-19 requiring an ICU admission in a two-hospital academic health system in Southern California. Patients discharged alive between 3/21/2020 and 12/31/2020 were surveyed approximately 6 months after discharge to assess health-related quality of life using Patient-Reported Outcomes Measurement Information System (PROMIS®)-29 v2.1, post-traumatic stress disorder (PTSD) and loneliness scales. A preference-based health utility score (PROPr) was estimated using 7 PROMIS domain scores. Patients were also asked their attitude about receiving aggressive ICU care. KEY RESULTS: Of 275 patients admitted to the ICU for severe COVID-19, 205 (74.5%) were discharged alive and 132 (64%, median age 59, 46% female) completed surveys a median of 182 days post-discharge. Anxiety, depression, fatigue, sleep disturbance, ability to participate in social activities, pain interference, and cognitive function were not significantly different from the U.S. general population, but physical function (44.2, SD 11.0) was worse. PROPr mean score of 0.46 (SD 0.30, range -0.02 to 0.96 [<0 is worse than dead and 1 represents perfect health]) was slightly lower than the U.S. general population, with an even distribution across the continuum. Poor PROPr was associated with chronic medical conditions and receipt of life-sustaining treatments, but not demographics or social vulnerability. PTSD was suspected in 20% and loneliness in 29% of patients. Ninety-eight percent of patients were glad they received life-saving treatment. CONCLUSION: Most patients who survive severe COVID-19 achieve positive outcomes, with health scores similar to the general population at 6 months post-discharge. However, there is marked heterogeneity in outcomes with a substantial minority reporting severely compromised health.

The Internal Superior Laryngeal Nerve in Humans: Evidence for Pure Sensory Function.

OBJECTIVES: To determine if the internal branch of the superior laryngeal nerve (iSLN) provides direct motor innervation to the interarytenoid muscle, a laryngeal adductor critical for airway protection. We studied the iSLN-evoked motor response in the interarytenoid and other laryngeal muscles. If the iSLN is purely sensory, there will be no detectable short latency motor response upon supramaximal stimulation, indicating the absence of a direct efferent conduction path. STUDY DESIGN: Intraoperative case series. METHODS: In seven anesthetized patients undergoing laryngectomy for unilateral laryngeal carcinoma, the iSLN of the unaffected side was electrically stimulated intraoperatively with 0.1-ms pulses of progressive intensities until supramaximal stimulation was reached. Electromyographic responses were measured in the ipsilateral interarytenoid, thyroarytenoid, and cricothyroid muscles. RESULTS: None of the subjects exhibited short-latency interarytenoid motor responses to iSLN stimulation. Supramaximal electrical stimulation of the intact iSLN evoked ipsilateral motor responses with long latencies: 18.7-38.5 ms in the interarytenoid (n = 6) and 17.8-24.9 ms in the thyroarytenoid (n = 5). Supramaximal stimulation of the recurrent laryngeal nerve evoked ipsilateral motor responses with short latencies: 1.6-3.9 ms in the interarytenoid (n = 6) and 1.6-2.7 ms in the thyroarytenoid (n = 6). CONCLUSION: The iSLN provides no functional efferent motor innervation to the interarytenoid muscles. The iSLN exclusively evokes an interarytenoid motor response via afferent activation of central neural circuits that mediate the laryngeal reflex arc. These findings suggest that the role of the iSLN in vital laryngopharyngeal functions, such as normal swallowing and protection of the airway from aspiration, is purely sensory. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E207-E211, 2021.

Substantia Nigra Volume Dissociates Bradykinesia and Rigidity from Tremor in Parkinson's Disease: A 7 Tesla Imaging Study.

BACKGROUND: In postmortem analysis of late stage Parkinson's disease (PD) neuronal loss in the substantial nigra (SN) correlates with the antemortem severity of bradykinesia and rigidity, but not tremor. OBJECTIVE: To investigate the relationship between midbrain nuclei volume as an in vivo biomarker for surviving neurons in mild-to-moderate patients using 7.0 Tesla MRI. METHODS: We performed ultra-high resolution quantitative susceptibility mapping (QSM) on the midbrain in 32 PD participants with less than 10 years duration and 8 healthy controls. Following blinded manual segmentation, the individual volumes of the SN, subthalamic nucleus, and red nucleus were measured. We then determined the associations between the midbrain nuclei and clinical metrics (age, disease duration, MDS-UPDRS motor score, and subscores for bradykinesia/rigidity, tremor, and postural instability/gait difficulty). RESULTS: We found that smaller SN correlated with longer disease duration (r = -0.49, p = 0.004), more severe MDS-UPDRS motor score (r = -0.42, p = 0.016), and more severe bradykinesia-rigidity subscore (r = -0.47, p = 0.007), but not tremor or postural instability/gait difficulty subscores. In a hemi-body analysis, bradykinesia-rigidity severity only correlated with SN contralateral to the less-affected hemi-body, and not contralateral to the more-affected hemi-body, possibly reflecting the greatest change in dopamine neuron loss early in disease. Multivariate generalized estimating equation model confirmed that bradykinesia-rigidity severity, age, and disease duration, but not tremor severity, predicted SN volume. CONCLUSIONS: In mild-to-moderate PD, SN volume relates to motor manifestations in a motor domain-specific and laterality-dependent manner. Non-invasive in vivo 7.0 Tesla QSM may serve as a biomarker in longitudinal studies of SN atrophy and in studies of people at risk for developing PD.

Sensory dysphagia: A case series and proposed classification of an under recognized swallowing disorder.

BACKGROUND: Although sensory feedback is a vital regulator of deglutition, it is not comprehensively considered in the standard dysphagia evaluation. Difficulty swallowing secondary to sensory loss may be termed "sensory dysphagia" and may account for cases receiving diagnoses of exclusion, like functional or idiopathic dysphagia. METHODS AND RESULTS: Three cases of idiopathic dysphagia were suspected to have sensory dysphagia. The patients had (1) effortful swallowing, (2) globus sensation, and (3) aspiration. Endoscopic sensory mapping revealed laryngopharyngeal sensory loss. Despite normal laryngeal motor function during voluntary maneuvers, laryngeal closure was incomplete during swallowing. The causes of sensory loss were identified: cranial neuropathy from Chiari malformation, immune-mediated neuronopathy, and nerve damage from prior traumatic intubation. CONCLUSIONS: Sensory loss may cause dysphagia without primary motor dysfunction. Sensory dysphagia should be classified as a distinct form of swallowing motility disorder to improve diagnosis. Increasing awareness and developing appropriate assessment tools may advance dysphagia care.

Applying Machine Learning Algorithms for Automatic Detection of Swallowing from Sound.

Despite the severe consequences of dysfunctional swallowing, there is no simple method of monitoring swallowing outside of clinical settings. People who cannot swallow cannot eat safely, resulting in profound changes in quality of life and risk of death from aspiration pneumonia. A non-invasive swallowing detector may have widespread impact in both clinical care and research. Detection of swallowing from laryngeal sounds could become an ideal assessment tool because sounds are simple to record, quantifiable, and amenable to software analysis. The focus of this paper is to achieve high accuracy binary swallowing detection from sound recordings. A dataset with 2500 swallow sound samples and 1700 mixed laryngeal noise samples from 15 healthy adults was used to train and test three supervised machine learning algorithms. A decision tree, support vector machine (SVM), and neural network trained with the scaled conjugate gradient (SCG) method had areas under the receiver operating characteristic (ROC) curve of 0.970, 0.961, and 0.971 and average accuracies of 93.2 percent, 86.2 percent, and 93.7 percent respectively. While further work needs to be done to further optimize these algorithms and validate their efficacy, these initial results suggest machine learning strategies may be helpful to improve accuracy of swallowing detection.

Prototype and Chimera-Type Galectins in Placentas with Spontaneous and Recurrent Miscarriages.

Galectins are galactose binding proteins and, in addition, factors for a wide range of pathologies in pregnancy. We have analyzed the expression of prototype (gal-1, -2, -7, -10) and chimera-type (gal-3) galectins in the placenta in cases of spontaneous abortions (SPA) and recurrent abortions (RA) in the first trimester. Fifteen placental samples from healthy pregnancies were used as a control group. Nine placentas were examined for spontaneous abortions, and 12 placentas for recurrent abortions. For differentiation and evaluation of different cell types of galectin-expression in the decidua, immunofluorescence was used. For all investigated prototype galectins (gal-1, -2, -7, -10) in SPA and RA placenta trophoblast cells the expression is significantly decreased. In the decidua/extravillous trophoblast only gal-2 expression was significantly lowered, which could be connected to its role in angiogenesis. In trophoblasts in first-trimester placentas and in cases of SPA and RA, prototype galectins are altered in the same way. We suspect prototype galectins have a similar function in placental tissue because of their common biochemical structure. Expression of galectin 3 as a chimera type galectin was not found to be significantly altered in abortive placentas.

HIV-associated dementia in the Dominican Republic: a consequence of stigma, domestic abuse and limited health literacy.

A 38-year-old Dominican woman presented at an infectious disease clinic in Santo Domingo, with subacute dementia and psychomotor slowing. Based on physical findings and laboratory results, she was diagnosed with AIDS and HIV-associated dementia (HAD). She subsequently began combined antiretroviral therapy (cART). Psychiatric complications later emerged: the patient developed suicidal ideation and her partner expressed homicidal thoughts. After extensive interviewing, it was revealed that the patient had known her HIV-positive serostatus for years. However, several factors, including HIV stigma, mental illness stigma, domestic abuse and limited health literacy, had prevented her from seeking treatment and from disclosing her status to her partner. This patient's HIV was unmanaged as a consequence of social and educational circumstance, which resulted in severe sequelae, namely HAD. Compounded barriers to care can lead to the presentation of disease complications that are rarely seen today in countries with widespread access to antiretroviral therapy.

Comparative analyses on expression of galectins1-4, 7-10 and 12 in first trimester placenta, decidua and isolated trophoblast cells in vitro.

INTRODUCTION: Galectins are members of the mammalian ß-galactoside-binding proteins, which recognize Galß1-4GlcNAc sequences of several cell surface oligosaccharides. Plenty of galectins are already described in human tissue, especially in placenta. Here, gal-1-4, 7-10 and gal-12 were investigated systematically in trophoblast and decidua cells of first trimester placentas. MATERIAL AND METHODS: Within this study, 15 first trimester placentas after induced abortion (7th-14th week of gestation) were examined with immunohistology and immunofluorescence based on a scoring system. Moreover, isolated and cultivated trophoblast cells from the first trimester were analyzed and evaluated for expression of gal-1-4, gal-7-10 and gal-12 at mRNA and protein level with real-time RT-Polymerase chain Reaction/PCR (Taq-Man). Double immunofluorescence with trophoblast specific markers identified galectin expressing cells at the feto-maternal interface. RESULTS: We could detect immunohistochemical staining of galectins 1-4, 7-10 and 12 in first trimester placenta: all examined galectins were found in the cytotrophoblast (CTB) and syncytiotrophoblast (SCT). Gal-1, -2, -3, -4, -7, -8, -9, -10 and -12 were identified in extravillous trophoblast cells (EVT) in immunohistology and immunoflourescence. The expression of gal-1, -9, -10, and gal-12 increased after 96h incubation in vitro without stimulation at mRNA level, while gal-2, -3, -4, -7 and -8 were decreased. DISCUSSION AND CONCLUSION: This study describes a systematic analysis of the expression of gal-1-4, gal-7-10 and gal-12 in first trimester placentas and isolated trophoblast cells. Expression levels at mRNA level and the change within 96h cultivation in vitro indicate a possible influence on syncytium building of trophoblast cell on expression of galectins. Therefore, an interaction of galectins in vitro in syncytium building is possible.

Trophoblastic cell lines ACH1P and AC-1M32 react with a distinctive cytokine pattern toward Listeria monocytogenes and show morphologic differences.

PROBLEM: The differential reaction of cytotrophoblast and syncytiotrophoblast towards infection with listeria monocytogenes (LM) is pivotal to its pathogenicity. In this study we tested the cytokine signature upon infection with listeria monocytogenes (LM) in an in vitro model. METHOD OF STUDY: We compared two related trophoblastic cell lines (AC-1M32 and ACH1P). The cell line ACH1P showed syncytium formation, whereas AC-1M32 did not fuse, as demonstrated with immunfluorescence E-Cadherin staining. In a Multi-Analyte ELISArray we tested for concentrations of TNFα, IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17A, IL-8, MCP1, MIP-1a, MIP-1b, MDC, Eotaxin, IFNγ, G-CSF, TGFß1 after 8 and 24 hours. RESULTS: Compared to unstimulated cells, the syncytial cell line ACH1P showed a significant induction of Interleukin-6 (IL-6), Monocyte Chemotactic Protein-1 (MCP-1) and transforming growth factor ß-1 (TGFß1). Incubating AC-1M32 with LM, however, showed significantly reduced IL-6 levels and a massively increased (~300fold) TGFß1 secretion compared to unstimulated controls. CONCLUSIONS: A functional anti-LM immune response was only induced by the syncytium-forming cell line ACH1P. Using the two sister cell lines AC-1M32 and ACH1P in an in vitro LM-stimulation assay might facilitate research in the area of placental listeria infection.

Glycodelin A induces a tolerogenic phenotype in monocyte-derived dendritic cells in vitro.

PROBLEM: Successful mammalian pregnancy requires a delicate immunological balance at the feto-maternal interface that allows the semi-allogeneic fetus to grow, while protecting mother and child from environmental pathogens. As in other mucosal tissues, antigen-recognition and -handling by professional antigen-presenting cells such as dendritic cells (DC) determine the course of the subsequent immune response. DC at the feto-maternal interface help shape this immunological equilibrium. Endometrial tissue secretes high quantities of glycodelin A (GdA) during the so-called fertile window (i.e. the time of implantation of the blastocyst). METHOD OF STUDY: We investigated the effect of GdA on monocyte-derived DC (moDC) regarding surface marker expression, endopinocytotic activity, cytokine profile as well as lymphoproliferative activity. RESULTS: Upon pretreatment with GdA and subsequent maturation with tumor necrosis factor-alpha and interleukin (IL)-1beta, moDC displayed a reduced expression of costimulatory molecules, an unchanged major histocompatibility complex-II expression and persistence of DC-SIGN positive cells. GdA-pretreated moDC had a higher endopinocytotic activity, an increased IL-10 production and a dose-dependent reduction in lymphoproliferative activity. GdA incubation alone did not alter the immature phenotype. CONCLUSION: Our results suggest a model in which the human endometrium secretes high quantities of GdA during implantation and thereby helps to shape the unique immunological interaction between mother and fetus via decidual DC.

Distribution and maturity of dendritic cells in diseases of insufficient placentation.

PROBLEM: The immunological equilibrium at the feto-maternal interphase contributes towards late gestational diseases like growth restriction (IUGR) pre-eclampsia (PE) and hemolysis, elevated liver enzymes, low platelets (HELLP)-syndrome. The state of activation of decidual dendritic cells (DC) has emerged as one of the central players influencing this immunological equilibrium. METHOD OF STUDY: Paraffin-embedded tissue sections from 27 pregnancies were immunostained for DC markers DEC-205, DC-SIGN, DC-LAMP and costained for DC-SIGN/CD56 and DC-SIGN/ vascular endothelial growth factor receptor (VEGFR) -1 and -2. We investigated placental tissue of IUGR fetuses and of patients who developed PE or HELLP-syndrome as well as placental tissue derived from normal pregnancies. RESULTS: We found that expression of DEC-205 and DC-SIGN was significantly upregulated in HELLP placentas, whereas expression of DC-LAMP was abrogated almost entirely. Costaining showed an interaction between DC-SIGN(+) DC and natural killer cells as well as costaining of VEGFR-1 and -2 and DC-SIGN. Pre-eclamptic and IUGR placentas showed no significant change in any of the investigated markers compared to normal controls. CONCLUSION: Our data suggest a participation of DC-mediated immunological mechanisms in HELLP syndrome.