Mechanisms of Swallowing, Speech and Voice Disorders in Parkinson's Disease: Literature Review with Our First Evidence for the Periperal Nervous System Involvement.

The majority of patients with Parkinson's disease (PD) develop swallowing, speech, and voice (SSV) disorders. Importantly, swallowing difficulty or dysphagia and related aspiration are life-threatening conditions for PD patients. Although PD treatments have significant therapeutic effects on limb motor function, their effects on SSV disorders are less impressive. A large gap in our knowledge is that the mechanisms of SSV disorders in PD are poorly understood. PD was long considered to be a central nervous system disorder caused by the death of dopaminergic neurons in the basal ganglia. Aggregates of phosphorylated α-synuclein (PAS) underlie PD pathology. SSV disorders were thought to be caused by the same dopaminergic problem as those causing impaired limb movement; however, there is little evidence to support this. The pharynx, larynx, and tongue play a critical role in performing upper airway (UA) motor tasks and their dysfunction results in disordered SSV. This review aims to provide an overview on the neuromuscular organization patterns, functions of the UA structures, clinical features of SSV disorders, and gaps in knowledge regarding the pathophysiology underlying SSV disorders in PD, and evidence supporting the hypothesis that SSV disorders in PD could be associated, at least in part, with PAS damage to the peripheral nervous system controlling the UA structures. Determining the presence and distribution of PAS lesions in the pharynx, larynx, and tongue will facilitate the identification of peripheral therapeutic targets and set a foundation for the development of new therapies to treat SSV disorders in PD.

Focal Application of Neurotrophic Factors Augments Outcomes of Nerve-Muscle-Endplate Grafting Technique for Limb Muscle Reinnervation.

BACKGROUND: We have developed a novel muscle reinnervation technique called "nerve-muscle-endplate grafting (NMEG) in the native motor zone (NMZ)." This study aimed to augment the outcomes of the NMEG-NMZ (NN) by focal application of exogenous neurotrophic factors (ENFs) for limb reinnervation. METHODS: Adult rats were used to conduct NN plus ENF (NN/ENF) and autologous nerve grafting (ANG, technique control). The nerve innervating the left tibialis anterior (TA) muscle was resected and the denervated TA was immediately treated with NN/ENF or ANG. For NN procedure, an NMEG pedicle was taken from the lateral gastrocnemius muscle and transferred to the NMZ of the denervated TA. For ANG, the nerve gap was bridged with sural nerve. Three months after treatment, the extent of functional and neuromuscular recovery was assessed by measuring static toe spread, maximal muscle force, wet muscle weight, regenerated axons, and innervated motor endplates (MEPs). RESULTS: NN/ENF resulted in 90% muscle force recovery of the treated TA, which is far superior to ANG (46%) and NN alone (79%) as reported elsewhere. Toe spread recovered up to 89 and 49% of the control for the NN/ENF and ANG groups, respectively. The average wet muscle weight was 87 and 52% of the control for muscles treated with NN/ENF and ANG, respectively. The mean number of the regenerated axons was 88% of the control for the muscles treated with NN/ENF, which was significantly larger than that for the ANG-repaired muscles (39%). The average percentage of the innervated MEPs in the NN/ENF-treated TA (89%) was higher compared with that in the ANG-repaired TA (48%). CONCLUSION: ENF enhances nerve regeneration and MEP reinnervation that further augment outcomes of NN. The NN technique could be an alternative option to treat denervated or paralyzed limb muscles caused by traumatic nerve injuries or lesions.

Racial/ethnic disparities on inflammation and response to methylprednisolone in severe COVID-19 pneumonia.

BACKGROUND: Racial/ethnic minorities are at higher risk for severe COVID-19. This may be related to social determinants that lead to chronic inflammatory states. The aims of the study were to determine if there are racial/ethnic disparities with inflammatory markers and association of methylprednisolone to in hospital survival. METHODS: This was a secondary analysis of a retrospective cohort study of patients ≥ 18 years of age and admitted for severe COVID-19 pneumonia between March and June 2020 in 13 Hospitals in New Jersey, United States. Patients who received other formulation of corticosteroids were not included. Area under the receiver operating characteristics curves were performed to test for discriminatory ability of each inflammatory makers. Univariate and multivariate Cox regression assessed the association of variables to in hospital survival. RESULTS: Propensity matched sample (n = 759) between no methylprednisolone (n = 380) and methylprednisolone (n = 379) had 338 Whites, 102 Blacks, 61 Asian/Indians, and 251 non-Black non-White Hispanics. Compared to CRP, area under receiving operating characteristic curve for d-dimer in Hispanics (0.742) was statistically different (DeLong Test P = 0.0041). Multivariate cox regression showed that different variables in Blacks [age ≥ 60 years (HR = 3.71, P = 0.0281), mechanical ventilation (HR = 5.07, P = 0.0281) and creatinine ≥ 1.5 mg/dL (HR = 3.61, P = 0.0007)], Whites [cancer (HR = 1.68, P = 0.0213), qSOFA score of 1 (HR = 1.81, P = 0.0213), qSOFA score of 2 (HR = 5.16, P < 0.0001), qSOFA score of 3 (HR = 11.81, P < 0.0001) and creatinine ≥ 1.5 mg/dL (HR = 2.16, P = 0.0006)], Hispanics [hypertension (HR = 2.52, P = 0.0007), cancer (HR = 2.99, P = 0.0244 and D-dimer ≥ 2 mcg/mL (HR = 2.22, P = 0.0077)], and Asian/Indians [ chronic kidney disease (HR = 6.36, P = 0.0031) and CRP > 20 mg/L (HR = 5.02, P = 0.0032)] were statistically significant for mortality. Low dose and high dose methylprednisolone were significantly associated with prolonged survival in Whites [low dose (HR = 0.37, P < 0.0001) and high dose (HR = 0.48, P < 0.0183)] and Asian/Indians [low dose (HR = 0.13, P = 0.0101) and high dose (HR = 0.15, P = 0.01)]. However, high dose was not associated with improved survival compared to low dose. Methylprednisolone was not associated with prolonged survival in Blacks and Hispanics. CONCLUSION: Racial/Ethnic disparities with inflammatory markers preclude the use of one marker as a predictor of survival. Methylprednisolone is associated with prolonged survival in Asian/Indians and Whites.

Methylprednisolone, venous thromboembolism, and association with heparin to 30 days in hospital survival in severe Covid-19 pneumonia.

BACKGROUND: Mortality in severe COVID-19 pneumonia is associated with thrombo-inflammation. Corticosteroids are given to attenuate the inflammation, but they are associated with thrombosis. The aims of this study were to determine the risk of venous thromboembolism between no methylprednisolone and methylprednisolone (dose versus duration) and to evaluate any synergistic dose-dependent association of heparin and methylprednisolone to 30 days in hospital survival. METHODS: This was a secondary analysis of a retrospective cohort. Patients included in this study were ≥ 18 years of age and admitted for severe COVID-19 pneumonia between March and June 2020 in 13 hospitals in New Jersey, United States. A propensity score analysis between administration of methylprednisolone and no methylprednisolone was fitted for 11 variables and Youden Index Method was used to determine cut-off between low dose and high dose methylprednisolone. Multivariate cox regression was to assess risk. RESULTS: In 759 patients, the incidence of venous thromboembolism was 9% of patients who received methylprednisolone and 3% of patients who did not receive methylprednisolone with a [RR 2.92 (95% CI 1.54, 5.55 P < 0.0001)]. There was a higher incidence of mechanical ventilation in the methylprednisolone group. The median d-dimer between patients with venous thromboembolism was higher compared to those without (P < 0.0003). However, the d-dimer was not statistically significant between those who had venous thromboembolism between methylprednisolone and no methylprednisolone groups (P = 0.40). There was no higher risk in high dose versus low dose [RR = 0.524 (95% CI 0.26, 1.06 P 0.4)]; however, the risk for venous thromboembolism between methylprednisolone for > 7 days and ≤ 7 days was statistically significant (RR 5.46 95% CI 2.87, 10.34 P < 0.0001). Patients who received low dose methylprednisolone and therapeutic heparin had a trend towards higher risk of mortality compared to prophylactic heparin (HR 1.81 95% CI 0.994 to 3.294) (P = 0.0522). There was no difference in 30 days in hospital survival between high dose methylprednisolone with prophylactic or therapeutic heparin (HR 0.827 95% CI 0.514 to 1.33) (P = 0.4335). CONCLUSION: Methylprednisolone for > 7 days had a higher association of venous thromboembolism. There was no added benefit of therapeutic heparin to methylprednisolone on mechanically ventilated patients.

Epidemiology, clinical aspects, outcomes and prognostic factors associated with Trichosporon fungaemia: results of an international multicentre study carried out at 23 medical centres.

BACKGROUND: Trichosporon fungaemia (TF) episodes have increased in recent years and mortality rates remain high despite the advances in the management of sepsis. New concepts about its clinical course, treatment and microbiology need to be investigated for the better management of this infection. OBJECTIVES: To describe the aetiology, natural history, clinical management and prognostic factors of TF. METHODS: TF episodes documented between 2005 and 2018 in 23 South American centres were retrospectively investigated by using a standard clinical form. Molecular identification, antifungal susceptibility testing and biofilm production were also performed. RESULTS: Eighty-eight TF episodes were studied. Patients had several underlying conditions, including haematological diseases (47.7%), post-operative status (34%), solid organ transplants (n = 7, 7.9%), among others. Seventy-three (82.9%) patients had a central venous catheter (CVC) at TF diagnosis. The 30 day mortality rate was 51.1%. Voriconazole-based therapy was given to 34 patients (38.6%), with a 30 day mortality rate of 38.2%. Multivariate predictors of 30 day mortality were age (OR 1.036), mechanical ventilation (OR 8.25) and persistent neutropenia (OR 9.299). CVC removal was associated with over 75% decreased risk of 30 day mortality (OR 0.241). Microbiological analyses revealed that 77.7% of the strains were identified as Trichosporon asahii, and voriconazole showed the strongest in vitro activity against Trichosporon spp. Most of the strains (63%) were considered medium or high biofilm producers. CONCLUSIONS: Older age, mechanical ventilation and persistent neutropenia were associated with poor prognosis. CVC may play a role in the pathogenicity of TF and its removal was associated with a better prognosis.

Nerve growth factor and basic fibroblast growth factor promote reinnervation by nerve-muscle-endplate grafting.

INTRODUCTION: This study was designed to test whether exogenous application of nerve growth factor (NGF) and basic fibroblast growth factor (FGF-2) to muscles reinnervated with nerve-muscle-endplate band grafting (NMEG) could promote specific outcomes. METHODS: The right sternomastoid muscle in adult rats was experimentally denervated and immediately reinnervated by implanting an NMEG pedicle from the ipsilateral sternohyoid muscle. A fibrin sealant containing NGF and FGF-2 was focally applied to the implantation site. Maximal tetanic force, muscle weight, regenerated axons, and motor endplates were analyzed 3 months after treatment. RESULTS: Mean tetanic force, wet muscle weight, and number of regenerated axons in the treated muscles were 91%, 92%, and 84% of the contralateral controls, respectively. The majority of endplates (86%) in the treated muscles were reinnervated by regenerated axons. DISCUSSION: Focal administration of NGF and FGF-2 promotes efficacy of the NMEG technique. Muscle Nerve 57: 449-459, 2018.

Immunohistochemical Detection of Motor Endplates in the Long-Term Denervated Muscle.

BACKGROUND: We have demonstrated that the native motor zone (NMZ) within a muscle is an ideal target for performing nerve-muscle-endplate band grafting (NMEG) to restore motor function of a denervated muscle. This study was designed to determine spatiotemporal alterations of the myofibers, motor endplates (MEPs), and axons in the NMZ of long-term denervated muscles for exploring if NMEG-NMZ technique would have the potential for delayed reinnervation. METHODS: Sternomastoid (SM) muscles of adult female Sprague-Dawley rats (n = 21) were experimentally denervated and denervation-induced changes in muscle weight, myofiber size, MEPs, and intramuscular nerve axons were evaluated histomorphometrically and immunohistochemically at the end of 3, 6, and 9 months after denervation. The values obtained from the ipsilateral normal side served as control. RESULTS: The denervated SM muscles exhibited a progressive reduction in muscle weight (38%, 31%, and 19% of the control) and fiber diameter (52%, 40%, and 28% of the control) for 3-, 6-, and 9-month denervation, respectively. The denervated MEPs were still detectable even 9 months after denervation. The mean number of the denervated MEPs was 79%, 65%, and 43% of the control in the 3-, 6-, and 9-month denervated SM, respectively. Degenerated axons in the denervated muscles became fragmented. CONCLUSIONS: Persistence of MEPs in the long-term denervated SM suggests that some surgeries targeting the MEPs such as NMEG-NMZ technique should be effective for delayed reinnervation. However, more work is needed to develop strategies for preservation of muscle mass and MEPs after denervation.

Outcomes of Muscle Reinnervation with Direct Nerve Implantation into the Native Motor Zone of the Target Muscle.

Background Our recent work has demonstrated that the native motor zone (NMZ) within a given skeletal muscle is the best site for muscle reinnervation. This study was designed to explore the outcomes of direct nerve implantation (DNI) into the NMZ of denervated sternomastoid (SM) muscle in a rat model. Methods The right SM muscle was experimentally denervated by transecting its innervating nerve. The proximal stump of the severed SM nerve was immediately implanted into a small muscle slit made in the NMZ of the muscle where denervated motor endplates were concentrated. The outcomes of DNI-NMZ reinnervation were evaluated 3 months after surgery. Specifically, the degree of functional recovery was examined with muscle force measurement. The extent of nerve regeneration and endplate reinnervation was assessed using histological and immunohistochemical methods. Results This study showed that the mean muscle force of the treated muscles was 64% of the contralateral control. Reinnervated SM muscles weighed 71% of the weight of the control muscles. Abundant regenerated axons were identified in the NMZ of the target muscle. The mean number and area of the regenerated axons in the treated muscles was computed to be 62% and 51% of the control muscles, respectively. On average, 66% of the denervated endplates in the treated muscles were reinnervated by regenerated axons. Conclusion Our results suggest that the NMZ within a muscle is an ideal site for endplate reinnervation and satisfactory functional recovery. Further studies are needed to promote the efficacy of DNI-NMZ technique for muscle reinnervation.

Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson's Disease Patients.

Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.

The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation.

We conducted a study of patients with multiple myeloma (MM) undergoing allogeneic transplantation to evaluate outcome parameters. Fifty-seven consecutive patients with MM received an allogeneic transplantation between 2004 and 2011 at our institution. Patients who had received at least 1 prior autologous transplantation were included. Twenty-six patients underwent allogeneic transplantation for consolidation after a response to their first autograft, and 30 patients received an allogeneic transplantation as salvage therapy. Donor source was evenly distributed between related and unrelated. The median follow-up was 52 months. Thirty-two (57.1%) patients achieved a complete response (CR). At 5 years, 49.2% of all patients were in CR. Sixteen patients received either donor lymphocyte infusions or immune suppression withdrawal for disease progression, with a 62.5% response rate. The 5-year overall survival (OS) for all patients was 59%. The 5-year OS for the 30 patients in the consolidation group was 82% compared with 38% for those in the salvage group. In multivariate analysis, 3 factors remained significantly associated with OS. These include being in the salvage group (hazard ratio [HR], 4.05; P = .0196), acute graft-versus-host disease (aGVHD) (HR, 2.99; P = .034), and chronic graft-versus-host disease (cGVHD), which was highly protective, with a 5-year OS of 78.8% for patients with cGVHD versus 42.6% for patients without cGVHD (HR .17, P = .008). Our data show that allogeneic transplantation for MM can lead to sustained remissions. aGVHD is significantly deleterious to OS and progression-free survival, whereas cGVHD is strongly favorable, supporting an important role for the graft-versus-myeloma effect.

Phase 1 study of concomitant tumor treating fields and temozolomide chemoradiation for newly diagnosed glioblastoma.

Background: Glioblastoma (GBM) is the most common and aggressive primary brain tumor and has limited effective therapies. Tumor treating fields (TTF; Optune Gio®) is an FDA-approved device with data supporting a significant survival benefit and minimal toxicity when added to maintenance chemotherapy. Uptake in clinical practice is not universal and might improve if a shorter duration of treatment is feasible. This phase 1 trial was designed to determine the safety and preliminary efficacy of TTF concomitant to chemoradiation. Methods: Patients with newly diagnosed, histologically confirmed GBM were eligible. Following surgery, patients were treated with TTF concomitant to standard chemoradiation. The device continued through 2 monthly cycles of maintenance temozolomide with imaging and clinical assessments at regular intervals to assess toxicity and response. The primary endpoint was the safety and tolerability of combined modality treatment based upon the incidence and severity of adverse events. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results: Thirteen patients were enrolled. Dermatologic adverse events were frequent but limited to grade 1/2. There was only 1 serious adverse event possibly related to TTF and no patients were unable to complete the prescribed course of multimodality treatment due to TTF-associated toxicity. Twelve patients were evaluable for median and 6-month progression-free survival which were 8.5 months (mo) and 66.7%, respectively. Median and 12 mo overall survival were 16.0 mo and 83.3%, respectively. Conclusions: TTF can be safely delivered in conjunction with chemoradiation. The potential for a finite TTF course merits further evaluation.

Incidence of renal artery pseudoaneurysm following open and minimally invasive partial nephrectomy: a systematic review and comparative analysis.

PURPOSE: Partial nephrectomy is performed for renal masses as a means of preserving renal function. Renal artery pseudoaneurysm is a potential complication of partial nephrectomy. We determined the incidence of renal artery pseudoaneurysm after open and minimally invasive partial nephrectomy, and performed a comparative analysis. MATERIALS AND METHODS: We queried the Ovid Medline® and PubMed® databases to locate published reports of renal artery pseudoaneurysm after partial nephrectomy. Studies were included in comparative analysis if they were in English and showed the total number of procedures performed and perioperative complications. RESULTS: Included studies represented a total of 5,229 patients, of whom 2,494 and 2,735 underwent open and minimally invasive partial nephrectomy, respectively. A total of 25 and 52 renal artery pseudoaneurysms were reported after open and minimally invasive procedures (weighted 1.00% and 1.96%, respectively). The difference between these 2 values was statistically significant (p ≤ 0.001). Patients diagnosed with renal artery pseudoaneurysm presented a mean of 14.9 days after surgery and 87.3% of them had gross hematuria at presentation. Almost all patients with renal artery pseudoaneurysm were treated with percutaneous angioembolization with 96% success. CONCLUSIONS: Although it is rare, the risk of renal artery pseudoaneurysm after partial nephrectomy is significant and should be high on the differential for a patient who presents postoperatively with gross hematuria. The incidence of renal artery pseudoaneurysm is higher after minimally invasive partial nephrectomy than after an open approach. Angioembolization for renal artery pseudoaneurysm after partial nephrectomy offers an excellent success rate and minimal patient morbidity.

Reinnervation of Paralyzed Limb Muscle by Nerve-Muscle-Endplate Grafting Technique.

BACKGROUND: We have developed a novel reinnervation technique called nerve-muscle-endplate grafting in the native motor zone (NMEG-NMZ). However, it remains unknown whether the NMEG-NMZ is effective for limb reinnervation. OBJECTIVE: To evaluate the efficacy of the NMEG-NMZ in limb muscle reinnervation. METHODS: Forty-five adult rats were divided into 3 groups: NMEG, end-to-end anastomosis (EEA, technique control), and denervation control (DC). The left tibialis anterior muscle was denervated by resecting its nerve. For NMEG-NMZ, the denervated tibialis anterior was reinnervated by transferring a NMEG pedicle from the lateral gastrocnemius muscle. Three months after surgery, static toe spread analysis was performed for all rats and muscle force was measured for the rats treated with NMEG and EEA. Muscle weight, myofiber morphology, regenerated axons, and reinnervated motor endplates in the treated muscles were also quantified and compared with those in the DC group. RESULTS: NMEG-NMZ technique resulted in better muscle force recovery (79% of the control) compared with EEA (51% of the control, P = .048). Toe spread analysis in NMEG-NMZ reinnervated muscles showed static sciatic index = -16.8, whereas -41.4 in EEA, P < .0001). The average weight of the NMEG-NMZ reinnervated muscles (86%) was greater than those of the EEA treated (71%) and DC (26%) muscles (all P < .0001). The mean count of the regenerated axons in the muscles with NMEG-NMZ was 76% of the control, which was larger than that in the muscles with EEA (46%), P < .0001. CONCLUSION: NMEG-NMZ technique has unique advantages and is superior to EEA for muscle reinnervation and functional recovery.

Histopathologic findings in laparoscopic sleeve gastrectomy: is routine full pathologic evaluation indicated?

BACKGROUND: Laparoscopic sleeve gastrectomy (SG) is the most commonly performed bariatric surgery. The resected gastric segment is routinely sent for pathology evaluation. No formal national recommendation exists that mandates pathology review. We proposed to study the largest histopathologic series in SG patients yet reported. OBJECTIVE: The primary objective of our study was to determine whether a subgroup of patients who underwent bariatric surgery in the northeastern Unites States is more susceptible to having clinically significant pathologic findings that may benefit from routine histopathologic evaluation of the gastric sleeve specimen. SETTING: University hospital. METHODS: A retrospective electronic chart review of patients who underwent SG at a single large academic institution was performed. Patient demographics, body mass index, and histopathologic reports of the gastric specimens obtained during SG were analyzed. RESULTS: The records of 3543 patients were reviewed. A total of 1076 patients had abnormal pathologies, including gastritis (938), follicular gastritis (98), intestinal metaplasia (25), gastrointestinal stromal tumor (12), leiomyoma (1), lymphoma (1), and other malignancy (1). Black and Hispanic patients had a higher incidence of developing gastrointestinal stromal tumor and intestinal metaplasia. A higher incidence of Helicobacter pylori infection among specimens with abnormal pathologies was noted. CONCLUSIONS: The findings of this study call into question the routine use of pathology workup in gastric specimens after SG. Our data suggest that such analysis may be warranted in certain subtypes of patients such as older Black and Hispanic patients in the northeastern United States.

Propranolol for infantile haemangiomas: initiating treatment on an outpatient basis.

INTRODUCTION: Propranolol was recently discovered to be an effective treatment for infantile haemangiomas, and varying doses and monitoring regimens have been proposed. Adverse events, although uncommon, have been reported. MATERIALS AND METHODS: This was a retrospective chart review of infants with haemangiomas who were started on propranolol at a dose of 3 milligrams per kilogram per day on an outpatient basis. After a baseline cardiac evaluation including an electrocardiogram and an echocardiogram, treatment was initiated during 6 hours of observation. RESULTS: A total of 15 patients were identified; however, only 13 returned for at least one follow-up visit. This cohort was followed up for a median of 2.8 months with a range from 0.2 to 10.0. No hypotension, hypoglycaemia, bronchospasm, or clinically significant bradycardia occurred during treatment. All patients had clinical improvement of their haemangiomas. CONCLUSIONS: This study suggests that initiating treatment during outpatient observation may be a reasonable alternative to inpatient admission. In addition, expensive testing may not be necessary during pre-treatment screening when the physical examination is normal.

Hydroxychloroquine, azithromycin and methylprednisolone and in hospital survival in severe COVID-19 pneumonia.

Introduction: Severe COVID-19 pneumonia has two phases that are not mutually exclusive. Repurposed drugs target only one phase and the association of combination therapy to survival is unknown. Objective: To determine the association of hydroxychloroquine, azithromycin, and methylprednisolone versus methylprednisolone only to in hospital survival. Methods: This is a secondary analysis of a retrospective cohort of patients admitted for severe covid-19 in 13 hospitals in New Jersey, United States from March-June 2020. Propensity score match with 11 variables was constructed between those who received no methylprednisolone and methylprednisolone. Multivariate Cox regression was used for risk of in hospital mortality. Measurements and main results: There were 759 patients, 380 in no methylprednisolone and 379 with methylprednisolone. Multivariate Cox regression shows that methylprednisolone, hydroxychloroquine, and azithromycin had prolonged survival compared to methylprednisolone alone [HR 0.45 (95% CI 0.22,0.91 p < 0.03)]. In patients who received hydroxychloroquine and azithromycin, those who also received high dose methylprednisolone were associated with worse survival compared to those who received low dose methylprednisolone (HR = 1.642; 95% CI 1.053 to 2.562; p = 0.0287). Nursing home residents [HR 2.77 (95% CI 1.67, 4.59 p < 0.0001)], coronary artery disease [HR 2.93 (95% CI 1.31, 3.15 p = 0.001), and invasive mechanical ventilation [HR 3.02 (95% CI 1.71,5.34 p = 0.0001)] were independently associated with worse survival. Conclusion: Combination therapy was associated with improved survival compared to monotherapy. However, nursing home residents, coronary artery disease, and mechanical ventilation were independently associated with mortality. Larger randomized controlled studies are needed to confirm conclusions.

Morphometric and Immunohistochemical Characteristics of the Adult Human Soft Palate Muscles.

The soft palate is the only structure that reversibly separates the respiratory and gastrointestinal systems. Most species can eat and breathe at the same time. Humans cannot do this and malfunction of the soft palate may allow food to enter the lungs and cause fatal aspiration pneumonia. Speech is the most defining characteristic of humans and the soft palate, along with the larynx and tongue, plays the key roles. In addition, palatal muscles are involved in snoring and obstructive sleep apnea. Considering the significance of the soft palate, its function is insufficiently understood. The objectives of this study were to document morphometric and immunohistochemical characteristics of adult human soft palate muscles, including fiber size, the fiber type, and myosin heavy chain (MyHC) composition for better understanding muscle functions. In this study, 15 soft palates were obtained from human autopsies. The palatal muscles were separated, cryosectioned, and stained using histological and immunohistochemical techniques. The results showed that there was a fast type II predominance in the musculus uvulae and palatopharyngeus and a slow type I predominance in the levator veli palatine. Approximately equal proportions of type I and type II fibers existed in both the palatoglossus and tensor veli palatine. Soft palate muscles also contained hybrid fibers and some specialized myofibers expressing slow-tonic and embryonic MyHC isoforms. These findings would help better understand muscle functions.

Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production.

Background: Natural killer (NK) cells are part of the innate arm of the immune system; as such NK cells can be activated rapidly to target virus-infected cells and tumor cells without prior sensitization. The human NK-92MI cell line is among the most widely used NK cell in preclinical research studies and has also been approved for clinical applications. Previous studies have shown that osteoblasts (OSB) confer drug resistance in multiple myeloma (MM) and other cancers that metastasize to the bone marrow. Aim: We evaluated here how OSB, which are bone forming cells and a key cellular component of the bone marrow microenvironment, modulate the cytotoxic activity of NK-92MI cells against the MM.1S multiple myeloma cell line. Methods: The osteoblastic niche was recapitulated with either the osteoblastic cell line hFOB 1.19 (hFOB) or primary osteoblasts (P-OSB) derived from surgical resections. Time-lapse imaging was utilized to quantify changes in MM.1S cell viability under different conditions, including: (1) Co-culture of MM.1S with NK92MI cells, (2) triple-culture of hFOB or P-OSB with MM.1S and NK-92MI, and (3) MM.1S or NK-92MI cells primed with OSB-derived supernatant. Cytokine analysis was conducted to quantify potential secreted factors associated with the protective effects of OSB. Results: The physical presence of OSB hindered the activity of NK-92MI cells, resulting in the increased viability of MM.1S compared to co-cultures which lacked OSB. This observation was accompanied by reduced perforin and granzyme A secretion from NK-92MI cells. Contact of OSB and NK-92MI cells also induced interleukin 6 (IL-6) and interleukin 10 (IL-10) production; two cytokines which are known to impair the NK cell immunity against MM and other cancers. OSB supernatant also conferred cytoprotection to MM.1S, suggesting a dual mechanism by which OSB may modulate both NK and MM cells. Conclusions: We demonstrated here that OSB can negatively impact the activity of NK cells against MM. As NK cells and their chimeric antigen receptor-modified versions become more widely used in the clinic, our results suggest that understanding the role of OSB as potential immunoregulators of the NK cell-mediated cytotoxic response in the bone marrow tumor microenvironment may provide new opportunities for enhancing the effectiveness of this potent immunotherapeutic approach.

Vancomycin-resistant enterococcal bacteraemia and daptomycin: are higher doses necessary?

BACKGROUND: The MIC corresponding to daptomycin susceptibility for vancomycin-resistant enterococci (VRE) is ≤ 4 mg/L. Based on the concentration-dependent killing properties of daptomycin, there may be concern about achieving adequate concentrations when the MIC approaches the upper end of the susceptible range (3-4 mg/L). Higher doses of daptomycin may be needed to treat VRE isolates with higher MICs. METHODS: We conducted a single-centre retrospective chart review of adult cases with VRE bacteraemia who received daptomycin as initial therapy. The primary outcome was time to microbiological cure (TMC) between standard doses (≤ 6 mg/kg) and high doses (> 6 mg/kg) of daptomycin and whether TMC differed based on MICs. The secondary outcome evaluated the daptomycin MIC distribution and assessed whether recent exposure to vancomycin was associated with higher daptomycin MICs. RESULTS: Forty-six cases were included in the primary analysis and 60.9% of patients were neutropenic. The two dose groups differed in the baseline characteristics of age, body mass index, blood culture source and catheter removal. Median TMC was 2 days for both dose groups. There was no significant difference in TMC between MIC subgroups of ≤ 2 mg/L versus >2 and ≤ 4 mg/L. For the secondary analysis 227 VRE isolates were evaluated and 62% had daptomycin MICs of 3-4 mg/L. Each daptomycin MIC group had a similar incidence of prior vancomycin exposure. CONCLUSIONS: Based on this retrospective review we did not observe a difference in TMC based on daptomycin dose and MIC; however, there were various limitations to this study, and the study was not powered to detect a difference in TMC. Also, prior vancomycin exposure did not appear to influence daptomycin MICs. The frequency of daptomycin MICs of 3-4 mg/L reported in this study is higher than those reported in the literature.