bluuebunny/crossref_metadata_2025 huggingface dataset:
0798 Detriggered - a case of tenosynovitis ameliorated by CPAP
Authors: Yuan Nathaniel , Padilla Alfonso
Published: May 2022

Introduction

The influence of sleep quality and pain is bidirectional (1). Sleep loss can induce hyperalgesia through upregulated inflammatory mediators such as IL-6 and TNF (2, 3). Obstructive sleep apnea (OSA) is characterized by obstructive respiratory events, hypoxemia, sleep fragmentation, and ultimately poor quality sleep. Here we present a case of how the treatment of OSA with continuous positive airway pressure (CPAP) mitigated hand inflammation and trigger finger symptoms.

Report of Cases: A 60 year old male with prediabetes, hypertension, and BMI 30 presented to primary care with bilateral finger pain and stiffness. Hand orthopedics noted a tender left A1-pully 4th finger with 20 degree flexion contracture and a palpable right 3rd finger flexor tendon nodule causing definite triggering. He was diagnosed with trigger finger and initially treated with steroid injections and again 5 months later due to persistent symptoms. 10 months after the initial orthopedic visit, orthopedics planned for surgical intervention, but patient missed his surgery for unknown reasons.

7 months later, sleep medicine evaluated the patient for snoring and daytime fatigue. He

underwent home sleep apnea testing which revealed a respiratory event index (REI) of 36.7

which necessitated CPAP therapy. Unfortunately, the patient was then lost to follow up in sleep medicine clinic. More than a year later, the patient showed to clinic and found to have 100% CPAP compliance with residual REI of 0.7. He enthusiastically noted improvement of daytime fatigue and trigger finger symptoms when using CPAP. When he would forget to use CPAP at night or during naps, he would wake up with returned finger pain and stiffness. Per patient, the symptoms would then resolve after re-initiation of CPAP. This consistent association of CPAP and finger symptom amelioration continued even 8 months later in most recent follow up.

Conclusion

To our knowledge, this is the first report of trigger finger symptoms improving with treatment of OSA. One hypothesis is that through improved sleep quality, there is a dampening of chondrocyte proliferation of the retinacular sheath and allowing unrestricted motion of the flexor tendon (4). More studies are needed to evaluate the musculoskeletal benefits of CPAP for OSA.

Support (If Any)

1. Haack M. Scott Sutherlandj. Et al. Pain sensitivity and modulation in primary insomnia. Eur J Pain. 2012, 16: 522-533.2. Chhangani BS, Roehrs Ta et al. Pain sensitivity in sleepy pain-free normals. Sleep, 209, 32:1011-1017.3. Li, Joule Sarah Appleton. Association of Musculoskeletal Joint Pain with Obstructive Sleep Apena, Daytime Sleepiness, and Poor Sleep Quality in Men. Arthritis Care and Research Vol 69. No 5. May 2017.4. Makkouk Al Hasan et al. Trigger finger: etology, evaluation, and treatment. Curr Rev Musculoskeltal Med 2008. 1:92-96.
0801 Melatonin Induced Autoimmune Hepatitis in the Setting of the Management of REM Sleep Behavior Disorder
Authors: Moshtagh-Sisan Mahtab , Sarrami Kayvon , Patel Jay , Harris Brian , Avidan Alon
Published: May 2022

Introduction

Melatonin is a neurohormone that serves a key role in human circadian physiology. It is widely used in the United States as an over-the-counter (OTC) sleep aid for managing insomnia, circadian rhythm disorders, and parasomnias. The US Food and Drug do not regulate it as a dietary supplement. However, insufficient data currently exist about formulations and overall safety for long-term usage. While serious adverse events with melatonin are rare, we describe a patient in whom clinical, laboratory, and biopsy features of autoimmune-mediated hepatitis developed in temporal association with time-release melatonin (MLTR) therapy for the treatment of dream enactment behaviors in the setting of REM-sleep behavior disorder (RBD).

Report of Cases: A 78-year-old female was referred to our clinic to manage disruptive dream enactment in the setting of RBD. The patient had been previously treated with Clonazepam, Diazepam, and Temazepam but remained refractory. Management with MLTR at 5 mg achieved clinical improvement and titration over a month up to 10 and 15 mg fully controlled dream enactment. Unfortunately, during this time, the patient developed swollen and erythematous joints and abdominal pain. Liver biopsy demonstrated lymphoplasmacytic infiltrate with rosette formation consistent with autoimmune hepatitis consistent with idiosyncratic drug-induced hepatitis associated with elevated liver function enzymes [AST 184 (H) (NL <39U/L), ALT 395 (H) (NL<56 U/L), Bilirubin, Direct= 0.3 (H) (NL<=0.2 mg/dL)]. Melatonin was discontinued achieving complete resolution of symptoms and normalization of liver function indicating its

causal association with hepatitis.

Conclusion

This unusual report of melatonin-induced autoimmune hepatitis is uncommon but points to intriguing immunostimulatory effects of melatonin. Our case highlights an important and sometimes overlooked attribute of melatonin that prescribers and patients must recognize. While melatonin is often viewed as a safe dietary supplement, its use, particularly among people with autoimmune disorders, should be documented and monitored with care.

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0810 Management of Narcolepsy In A Patient With Severe Chronic Iron Deficiency: The Importance of Addressing Nutritional Deficiencies In The Treatment of Narcolepsy and Hypersomnias
Authors: Baldridge Scott , Khan Yousaf , Ghildiyal Naomi , Monceaux Brittany , Asghar Sheila , Liendo Cesar , Chernyshev Oleg
Published: May 2022

Introduction

Since iron is a cofactor used in the synthesis of CNS dopamine, some of which is then converted into norepinephrine, CNS iron deficiency will have an impact on the availability of dopamine and norepinephrine. Medications for narcolepsy and hypersomnia, such as stimulants and wakefulness medications, are dependent on the availability of these neurotransmitters to achieve their clinical response. Unrecognized and untreated nutritional deficiencies may contribute to inadequate responses to treatment of these sleep disorders.

Report of Cases: A 26-year-old female with a history of iron deficiency since her pre-kindergarten health evaluation had a history of inadequate responses to stimulants and wakefulness medications. Additional labs were drawn to evaluate for nutritional deficiencies that could be contributing to the combination of fatigue and hypersomnolence. These revealed continued severe iron deficiency along with vitamin B6, B12, and D deficiencies. The treatment plan then expanded to include treatment of the nutritional deficiencies and a trial of pitolisant, which works to increase histamine levels in the brain. Sadly, pitolisant resulted in intolerable headaches, so it was discontinued.

Conclusion

This author feels that patients with hypersomnia warrant a broader approach that includes evaluating for nutritional deficiencies which may contribute to fatigue and hypersomnolence. In this case, the plan was to address the patient’s nutritional deficiencies and switch to pitolisant which mediates increased CNS histamine levels. This was unsuccessful due to the side effect of increased frequency and intensity of headaches related to pitolisant. Treating her iron deficiency with iron infusions should increase CNS synthesis of dopamine and norepinephrine. She may now have a better response to stimulants or wakefulness medications which depend on the availability of these neurotransmitters. She may also benefit from combination therapy by adding sodium oxybate to one of these medications.

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0821 Narcolepsy after West Nile Virus Meningoencephalitis infection
Authors: Tarpara Kishan , Khan Safia
Published: May 2022

Introduction

Narcolepsy is a sleep disorder characterized by hypersomnia and inappropriate intrusion of REM sleep into wakefulness. Etiology is heterogeneous, and is broadly classified into Narcolepsy Type 1 and Type 2. There is growing evidence that the pathogenesis in many cases have a post-infectious autoimmune basis. We present the case of a patient seen in our sleep clinic who was eventually diagnosed with Narcolepsy type 2 following West Nile Virus (WNV) Meningoencephalitis.

Report of Cases: · The patient is a 44 year old Hispanic woman who had no prior sleep difficulties before 2013, when she was diagnosed with WNV meningitis. Lumbar puncture results from the time of infection are not available, as this evaluation occurred in the Dominican Republic. Subsequent lumbar punctures have shown the presence of anti-WNV IgG antibodies in her CSF. MRI and MRA brain were unremarkable.

· She also has a history of migraine, fibromyalgia, depression, and adrenal insufficiency.

· She presented with sleep complaints, including sleep onset insomnia, symptoms of sleep

disordered breathing, and excessive daytime sleepiness.

· She underwent home sleep apnea test in 12/2020 which revealed mild obstructive sleep

apnea. Overall AHI was 7.9/hour without significant hypoxemia. She was subsequently started on CPAP therapy with good adherence, but she continued to have significant daytime sleepiness, notably with an Epworth Sleepiness Scale score of 21/24.

· She subsequently underwent overnight polysomnogram and multiple sleep latency test in our sleep laboratory.

· Overnight PSG confirmed mild obstructive sleep apnea (AHI 12.0) along with short REM

latency (10.5 minutes). Next day MSLT showed mean sleep latency of 2.3 minutes, for 5

attended naps, with 2 SOREMPs, which was diagnostic of Narcolepsy type 2.

Conclusion

This case demonstrates the onset of narcolepsy after WNV meningoencephalitis.

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0829 Workup of Nocturnal Hypoxemia Leads to Diagnosis of Patent Foramen Ovale
Authors: Stanton Crystal , Francis Natalie , Bashir Ahsan , Freire Amado
Published: May 2022

Introduction

Patent foramen ovale (PFO) in adults often remains asymptomatic until clinical manifestations such as cryptogenic stroke, migraine headache, air embolism, hypoxemia, or platypnea-orthodeoxia syndrome occur. In this case, prior workup of cryptogenic stroke failed to identify a PFO that was diagnosed after further investigation of polycythemia which revealed nocturnal hypoxemia on polysomnogram.

Report of Cases: A 60-year-old male with history of recurrent venous thromboembolic events (VTE), secondary polycythemia, and cryptogenic strokes was referred for a polysomnogram during the evaluation of polycythemia. Over the span of six years, he had multiple cryptogenic strokes and VTEs in the setting of polycythemia and normal hypercoagulability labs. Further evaluation suggested secondary polycythemia after serum erythropoietin and JAK2 mutation testing were negative. The patient was a never smoker without evidence of malignancy or renal disease leading to suspicion that his polycythemia was due to hypoxemia despite normal oxygen saturations during point of care evaluations. He frequently reported shortness of breath during

appointments.

During a polysomnogram, the patient was found to have a total apnea-hypopnea index of fewer

than 5 events per hour but demonstrated hypoxemia with 49.7% of total sleep time spent

below an oxygen saturation of 90%. He was referred to pulmonology for further evaluation that

showed normal resting oxygen saturation, no desaturation on a six-minute walk test, mild

restrictive defect on pulmonary function testing, and a normal chest computed tomography

with angiography. Prior transthoracic echocardiogram had demonstrated an atrial septal

aneurysm without communication between the atrial chambers. No evidence suggestive of a

right-to-left shunt was found on lateral imaging of the brain during a ventilation-perfusion scan.

Further evaluation of the aneurysmal atrial septum on transesophageal echocardiogram with an

agitated saline bubby study demonstrated a patent foramen ovale with a right-to-left shunt. In

the setting of hypoxia leading to secondary polycythemia, the patient was scheduled for PFO

closure.

Conclusion

Hypoxemia out of proportion to sleep-disordered breathing on polysomnogram should prompt further evaluation. Despite multiple prior strokes, our patient’s PFO had gone undiagnosed until polycythemia prompted a polysomnogram that demonstrated isolated nocturnal hypoxemia and prompted a further workup. Clinically significant hypoxemia is an indication for PFO closure.

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0831 Identifying Sleep-Related Breathing Disorders in Underserved Demographics Using Commercial Portable Monitoring Devices: A Case Report
Authors: Tchopev Zahari , Carrizales Alex , Cunico Jorey , Mysliwiec Vincent , Peterson Alan , Kim David , Hansen Shana , Powell Tyler , Brock Matthew
Published: May 2022

Introduction

An estimated twenty-five percent of American women are at high risk of having obstructive sleep apnea (OSA). However, male sex is the predominantly reported risk factor. Women are less likely to report “classic” symptoms such as snoring that prompt referral for sleep evaluation. This dichotomy potentially represents a disparity in clinical evaluation and treatment of OSA in women. Consumer digital health devices are frequently used to monitor sleep in people with and without sleep disturbances. They are generally highly sensitive yet have lower specificity when compared with formal actigraphy or polysomnography. They may be used in conjunction with physician evaluation to guide decision-making.

Report of Cases: A 33 year-old female with a pertinent past medical history of obesity (BMI 37.83 kg/m ), depression, chronic pain, and anxiety was referred to our sleep center with a multi-year history of excessive daytime fatigue and non-restorative sleep that persisted despite healthy habits counseling and unremarkable lab evaluation. She ultimately presented her primary care

physician with biometric data collected by her Garmin watch and Oura ring. This data, which

included a reported low SpO of 83%, motivated a referral to Sleep Medicine. Her presentation Epworth Sleepiness Scale (ESS) score and Insomnia Severity Index (ISI) were 14 and 17, respectively. Polysomnography revealed an AHI of 32.6/hr, oxygen nadir of 79%, ODI of 28.7/hr, and a 97.2% sleep efficiency. PLMS index was 23.2/hour but did not contribute

to sleep fragmentation and there was increased proportion of stage N3 sleep (28.2%). Severe

OSA was treated with APAP. The two month follow-up ESS and ISS improved to 9 and 4, respectively. Device data revealed greater than 6 hours of consistent nightly use with a residual AHI of 3.1/hr. She subjectively stated APAP “has been a life changer” personally and professionally, as well as spousal report of resolution of snoring. Her consumer devices similarly reported improved sleep measures.

Conclusion

Minorities and women may be underserved in evaluation, diagnosis, and treatment of OSA. Portable monitoring using readily available consumer biometric devices may be a viable strategy for patients to further identify high risk features and prompt referral by primary care.

Support (If Any)

This work was supported by the Defense Health Agency, Defense Medical Research and Development Program, Clinical Research Intramural Initiative for Military Women’s Health (DM170708; Mysliwiec) and the Air Force Research Laboratory, Wright Patterson Air Force Base, Ohio (FA8650-18-2-6953; Peterson).
0832 Nocturnal Tachypnea with Non-Invasive Ventilation; A case report
Authors: Elballat Mohammad , Anderson William , Patel Kevin
Published: May 2022

Introduction

We present a case of nocturnal tachypnea secondary to suspected auto-triggering in a patient on Bilevel device. Auto-triggering is a patient-ventilator asynchrony in which a ventilator breath is triggered in the absence of inspiratory muscle activity. This phenomenon was mostly described in postcardiac surgery and in brain dead patients on mechanical ventilation. Detecting this asynchrony is important as it can lead to patient discomfort, poor compliance and hypocarbia that can lead to apneic events.

Report of Cases: An 82-year-old male with history of chronic atrial fibrillation, coronary artery disease (s/p bypass surgery) and Ischemic cardiomyopathy (EF 25-30%). He had moderate obstructive sleep apnea with central apnea. He was started on AutoPAP then was upgraded to BPAP (IPAP 16/EPAP 9 cmH2O). His wife reported episodes of nocturnal tachypnea and increased daytime somnolence. This was confirmed by the compliance reports from his BPAP device, and a portable sleep study obtained while using the BPAP (respiratory rate > 40 breaths/minute).

Conclusion

Vignaux et al estimated the incidence of auto-triggering with NIV to be 13%. This phenomenon can be caused by a major circuit leak or secondary to cardiogenic oscillations. Effect of cardiogenic oscillation on the pulmonary air flow was described by West and Hugh-Jones in 1961. Our patient had dilated cardiomyopathy with hyperdynamic circulation which we believe was the major cause of his auto-triggering asynchrony. Changes in intracardiac volume and cardiac movements during systole resulted in intrapulmonary flow oscillations exceeding the set flow-trigger threshold leading to the tachypnea. In our patient, the events resolved after cardiac resynchronization procedure that improved the overall cardiac function and adjusting the trigger sensitivity.

Support (If Any)

[1]Kondili E, Prinianakis G, Georgopoulos D.; Patient ventilator interaction, Br J Anaesth. 2003; 91: 106-119 [2] Richard Arbour; Cardiogenic Oscillation and Ventilator Autotriggering in Brain-Dead Patients: A Case Series. Am J Crit Care 1 September 2009; 18 (5): 496–488. doi: https://doi.org/10.4037/ajcc2009690 [3] Imanaka, Hideaki MD; Nishimura, Masaji MD; Takeuchi, Muneyuki MD; Kimball, William R. MD, PhD; Yahagi, Naoki MD; Kumon, Keiji MD Auto-triggering caused by cardiogenic oscillation during flow-triggered mechanical ventilation, Critical Care Medicine: February 2000 - Volume 28 - Issue 2 - p 402-407 [4]Vignaux L, Vargas F, Roeseler J, Tassaux D, Thille AW, Kossowsky MP, et al. Patient-ventilator asynchrony during non-invasive ventilation for acute respiratory failure: a multicenter study. Intensive Care Med 2009;35(5):840–846
0837 Average Volume-Assured Pressure Support (AVAPS) after CPAP Failure in A Pediatric Patient with Severe Obstructive Sleep Apnea and Sleep-Related Hypoventilation
Authors: Tu Xinhang , Peng Victor , Lasso-Pirot Anayansi , Diaz-Abad Montserrat
Published: May 2022

Introduction

Obstructive sleep apnea (OSA) has become an increasingly pervasive sleep disorder in the pediatric population. Current mainstream treatments include adenotonsillectomy and positive airway pressure therapy. Average volume-assured pressure support (AVAPS) is a relatively new mode of non-invasive ventilation, which has been increasingly used in the treatment of respiratory failure and hypoventilation syndromes. Here we present a case of a pediatric patient with severe OSA and sleep-related hypoventilation who was successfully treated with AVAPS after failure of CPAP therapy.

Report of Cases: A four year old boy with history of severe OSA, severe obesity, asthma, and allergic rhinitis underwent polysomnography one year after adenotonsillectomy and nasal turbinate reduction due to continued symptoms of sleep-disordered breathing. Results showed elevated residual apnea-hypopnea index (AHI = 30.4 events/hour), sleep-related hypoventilation (T ETCO2≥50 = 228.3 minutes), and sleep-related hypoxemia (T≤90% = 7 minutes). Therefore the patient underwent repeated adenotonsillectomy and turbinate reduction, with post-operative course complicated by pulmonary edema requiring intubation. He was extubated and weaned to

nocturnal CPAP. Following discharge, CPAP titration failed to control AHI at maximal pressure

(AHI 54.5 on 20 cm H2O, T≤90% = 15.3 minutes). The patient was then started on AVAPS

with auto-titrating EPAP (AVAPS-AE, settings Pmax 20 cm H2O, PS 2-10 cm H2O, EPAP 5-10

cm H2O, RR auto, room air) with subsequent improvement of snoring and witnessed apneas, as

well as reduction of daytime sleepiness. Afterwards, AVAPS-AE titration confirmed resolution of obstructive sleep apnea, sleep-related hypoxemia, and sleep-related hypoventilation (AHI =

2.5, T≤90% = 1.2 minutes, T ETCO2 ≥50 = 6.5 minutes.) The patient has since remained stable on AVAPS-AE until age ten, with the most recent AVAPS titration demonstrating continued resolution of sleep-disordered breathing.

Conclusion

AVAPS was an effective treatment for a pediatric patient with severe OSA and sleep-related hypoventilation who had failed CPAP therapy.

Support (If Any)

None.
0861 Sleepy in the Mountains
Authors: Moshtagh-Sisan Mahtab , Zeidler Michelle , De Cruz Sharon
Published: May 2022

Introduction

Central sleep apnea (CSA) is a rare disorder caused by a reduction of airflow and ventilatory effort during sleep. CSA is rarely idiopathic and associated with medical conditions including heart failure, opioid medications, treatment emergent and high-altitude periodic breathing. At higher altitudes, hypoxemia induces periodic breathing with periods of deep and rapid breathing alternating with central apnea. Patients with high-altitude periodic breathing experience fragmented sleep, poor sleep quality, excessive daytime sleepiness, morning headaches and witnessed apnea. We discuss a patient with obstructive sleep apnea (OSA) who developed new-onset central sleep apnea after relocating to a higher altitude location.

Report of Cases: A 75-year-old male with a history of moderate obstructive sleep apnea well controlled on CPAP for eight years, with no known cardiovascular or pulmonary disease, presented with new-onset excessive daytime sleepiness. He had recently relocated to an area in the Colorado mountains (7000 ft elevation) from his previous home in Los Angeles (sea level). His residual apneahypopnea index (r-AHI) displayed on his CPAP machine increased to 7-14/hr from his normal of 1-2/hr after his relocation. Review of his compliance data revealed his central apnea index was elevated, contributing to his high r-AHI. A one-night nocturnal oximeter was mailed to the patient to use while on CPAP. Data revealed oxygen desaturation to less than 88% for about 2 hours of the night, worse during the early morning hours. The patient was advised to undergo a polysomnography and adaptive servo-ventilation titration if significant central sleep apnea was present. The patient declined due to concern about the COVID-19 pandemic. Supplemental nocturnal oxygen was initiated at 2L/min with normalization of the r-AHI.

Conclusion

Patients with OSA who experience worsening symptoms or increased r-AHI despite excellent compliance with PAP therapy should be considered for repeat polysomnography or titration study. While it is expected that high-altitude central sleep apnea will improve with acclimatization, nocturnal supplemental oxygen in addition to PAP therapy is indicated for patients with high-altitude central sleep apnea to diminish hypoxemia and improve residual AHI and sleep quality.

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Barriers to positive airway pressure adherence among veterans with sleep apnea: a mixed methods study
Authors: Goldstein Lizabeth A , Purcell Natalie , Sarmiento Kathleen F , Neylan Thomas C , Maguen Shira
Published: May 2022

Rates of adherence to positive airway pressure (PAP) for sleep apnea are suboptimal. Though previous studies have identified individual factors associated with PAP nonadherence, few projects have investigated a wide range of possible barriers directly from the patient perspective. We examined the range of factors that patients identify as barriers to optimal use of PAP as well as the solutions most commonly offered by providers. We employed a mixed methods design including semistructured interviews and medical record review at a US Department of Veterans Affairs Medical Center. Thirty patients identified as nonadherent to PAP participated. Patients were asked to report on current sleep problems, reasons for nonadherence, and solutions proposed by providers. Chart review was used to identify untreated apnea severity, Epworth Sleepiness Scale score, therapy hours, and residual apnea severity. Patients described physical and psychological barriers to adherent use at approximately equal rates: Mask leaks and dry throat/nose were common physical barriers, and anxiety/claustrophobia and worsening insomnia were common psychological barriers. Untreated apnea severity, residual apnea severity, and daytime sleepiness were not associated with therapy hours. Solutions offered by providers most frequently addressed physical barriers, and solutions to psychological barriers were rarely proposed. The most common solution offered by providers was trying different masks. We recommend individualized assessment of each patient’s barriers to use as well as increased involvement of behavioral health providers in sleep medicine clinics.
Inhibition of vascular endothelial growth factor alleviates neovascular retinopathy with regulated neurotrophic/proinflammatory cytokines through the modulation of DBI‐TSPO signaling
Authors: Gao Shuang , Li Na , Wang Yanuo , Lin Zhongjing , Zhu Yanji , Xu Jianmin , Zhang Qiong , Zhu Caihong , Zhou Yingming , Zhou Jia , Shen Xi
Published: May 2022

Diazepam binding inhibitor (DBI)‐translocator protein (18kDa) (TSPO) signaling in the retina was reported to possess coordinated macroglia‐microglia interactions. We investigated DBI‐TSPO signaling and its correlation with vascular endothelial growth factor (VEGF), neurotrophic or inflammatory cytokines in neovascular retinopathy, and under hypoxic conditions. The vitreous expression of DBI, VEGF, nerve growth factor (NGF), and interleukin‐1beta (IL‐1β) were examined in proliferative diabetic retinopathy (PDR) patients with or without anti‐VEGF therapy and nondiabetic controls. Retinal DBI‐TSPO signaling and the effect of the anti‐VEGF agent were evaluated in a mouse model of oxygen‐induced retinopathy (OIR). Interactions between Müller cell‐derived VEGF and DBI, as well as cocultured microglial cells under hypoxic conditions, were studied, using Western blot, real‐time RT‐PCR, enzyme‐linked immunosorbent assay (ELISA), flow cytometry, and immunofluorescent labeling. Results showed that vitreous levels of DBI, VEGF, NGF, and IL‐1β were significantly higher in PDR patients compared with controls, which further changed after anti‐VEGF therapy. A statistical association was found between vitreous DBI and VEGF, NGF, IL‐1β, and age. The application of the anti‐VEGF agent in the OIR model induced retinal expression of DBI and NGF, and attenuated inflammation and microglial cell activation. Inhibition of Müller cell‐derived VEGF could increase its DBI expression under hypoxic conditions, while the DBI‐TSPO signaling pathway is essential for anti‐VEGF agents exerting anti‐inflammatory and neuroprotective effects, as well as limiting inflammatory magnitude, promoting its neurotrophin production and anti‐inflammatory (M2) polarization in microglial cells. These findings suggest the beneficial effect of anti‐VEGF therapy on inflammation and neurotrophy of retinal glial cells through modulation of the DBI‐TSPO signaling pathway.
A new preclinical model of western diet‐induced progression of non‐alcoholic steatohepatitis to hepatocellular carcinoma
Authors: Green Christopher D. , Weigel Cynthia , Brown Ryan D. R. , Bedossa Pierre , Dozmorov Mikhail , Sanyal Arun J. , Spiegel Sarah
Published: May 2022

Non‐alcoholic steatohepatitis (NASH) results from the accumulation of excessive liver lipids leading to hepatocellular injury, inflammation, and fibrosis that greatly increase the risk for hepatocellular carcinoma (HCC). Despite the well‐characterized clinical and histological pathology for NASH‐driven HCC in humans, its etiology remains unclear and there is a deficiency in pre‐clinical models that recapitulate the progression of the human disease. Therefore, we developed a new mouse model amenable to genetic manipulations and gene targeting that mimics the gradual NASH to HCC progression observed in humans. C57BL/6NJ mice were fed a Western high‐fat diet and sugar water (HFD/SW) and monitored for effects on metabolism, liver histology, tumor development, and liver transcriptome for up to 54 weeks. Chronic HFD/SW feeding led to significantly increased weight gain, serum and liver lipid levels, liver injury, and glucose intolerance. Hepatic pathology progressed and mice developed hepatocellular ballooning, inflammation, and worse fibrosis was apparent at 16 weeks, greatly increased through 32 weeks, and remained elevated at 54 weeks. Importantly, hepatocellular cancer spontaneously developed in 75% of mice on HFD/SW, half of which were HCC, whereas none of the mice on the chow diet developed HCC. Chronic HFD/SW induced molecular markers of de novo lipogenesis, endoplasmic reticulum stress, inflammation, and accumulation of p62, all of which also participate in the human pathology. Moreover, transcriptome analysis revealed activation of HCC‐related genes and signatures associated with poor prognosis of human HCC. Overall, we have identified a new preclinical model that recapitulates known hallmarks of NASH‐driven HCC that can be utilized for future molecular mechanistic studies of this disease.
Determinants and Clinical Significance of Musculoskeletal Symptoms in Patients With Chronic Graft-Versus-Host Disease
Authors: Zelic Kerep Ana , Pirsl Filip , Steinberg Seth , Mitchell Sandra , Curtis Lauren , Holtzman Noa , Goklemez Sencer , Bilic Ervina , Cowen Edward , Pichard Dominique , Joe Galen , Comis Leora , Im Annie , Berger Ann , Parsons-Wandell Laura , Pulanic Drazen , Baird Kristin , Gress Ronald , Pavletic Steven
Published: May 2022

Musculoskeletal symptoms in chronic graft-versus-host disease (cGVHD) are rare manifestations contributing to disease burden. This study assesses the frequency of muscle cramps, joint and muscle aches, and muscle weakness in a cohort of patients severely affected by cGVHD. Three hundred thirty-four patients participated in the NCI natural history study of cGVHD (NCT00092235) from October 2004 to March 2017. Five-point Lee cGVHD Symptom Scale was dichotomized (less symptom bother—0, 1, 2; severe symptom bother—3, 4) and tested for associations with: Short Form 36 (SF36), 2-minute walk test, grip strength, joint range of motion, and human activity profile, clinical and laboratory data. Seventy-five point four percent of patients reported joint and muscle aches (36.8% severe, Lee Symptom Scale score 3–4), 74.3% muscle cramps (33.5% severe), and 82.34% muscle weakness (45.51% severe), which were associated with reduced functional capacity (SF36 Physical Component Scale, P < 0.0001). Muscle cramps were associated with limited joint movement (P < 0.0001) and skin manifestations (skin thickening, P = 0.0008; itchy skin, P = 0.0003). Muscle cramps did not show association with potential causative agents, such as concomitant calcineurin inhibitors therapy, statins, or use of antidiabetic drugs. Joint and muscle aches showed associations with multiple variables (including strong associations with mood symptoms and fatigue, P < 0.0001). Muscle weakness was not associated with steroid dose, but was significantly associated with depression (P < 0.0001) and anxiety (P = 0.0009). This study documents a high frequency of musculoskeletal symptoms in a cohort of adult patients with cGVHD. The multivariable logistic regression models showed that a joint set of factors were moderately well associated with musculoskeletal symptoms in this study.
Calcium Channel Antagonists for Mood Disorders
Authors: Dubovsky Steven L. , Marshall Dori
Published: May 2022

Purpose

Development of new thymoleptic medications has primarily centered on anticonvulsants and antipsychotic drugs. Based on our studies of intracellular calcium ion signaling in mood disorders, we were interested in the use of novel medications that act on this mechanism of neuronal activation as potential mood stabilizers.

Method

We reviewed the dynamics of the calcium second messenger system and the international body of data demonstrating increased baseline and stimulated intracellular calcium levels in peripheral cells of patients with bipolar mood disorders. We then examined studies of the effect of established mood stabilizers on intracellular calcium ion levels and on mechanisms of mobilization of this second messenger. After summarizing studies of calcium channel blocking agents, whose primary action is to attenuate hyperactive intracellular calcium signaling, we considered clinical experience with this class of medications and the potential for further research.

Findings

Established mood stabilizers normalize increased intracellular calcium ion levels in bipolar disorder patients. Most case series and controlled studies suggest an antimanic and possibly mood stabilizing effect of the calcium channel blocking medications verapamil and nimodipine, with fewer data on isradipine. A relatively low risk of teratogenicity and lack of cognitive adverse effects or weight gain suggest possible applications in pregnancy and in patients for whom these are considerations.

Implications

Medications that antagonize hyperactive intracellular signaling warrant more interest than they have received in psychiatry. Further experience will clarify the applications of these medications alone and in combination with more established mood stabilizers.
DNA Damage Repair Proteins, HSP27, and Phosphorylated-HSP90α as Predictive/Prognostic Biomarkers of Platinum-based Cancer Chemotherapy: An Exploratory Study
Authors: Sottile Mayra L. , Cuello-Carrión Fernando D. , Gómez Laura C. , Semino Silvana , Ibarra Jorge , García María B. , Gonzalez Lucía , Vargas-Roig Laura M. , Nadin Silvina B.
Published: May 2022

Platinum analogs are commonly used for cancer treatment. There is increasing interest in finding biomarkers which could predict and overcome resistance, because to date there is no reliable predictive/prognostic marker for these compounds. Here we studied the immunohistochemical expression of proteins involved in DNA damage response and repair (γH2AX, 53BP1, ERCC1, MLH1, and MSH2) in primary tumor tissues from patients treated with platinum-based chemotherapy. Levels and localization of Heat Shock Protein (HSP)27 and phospho-(Thr5/7)-HSP90α (p-HSP90α) were also determined. The implications in clinical response, disease-free survival and overall survival were analyzed. High γH2AX and 53BP1 expressions were associated with poor clinical response. Nuclear p-HSP90α, as well as nuclear absence and low cytoplasmic expression of HSP27 correlated with good response. Patients with high γH2AX and high cytoplasmic HSP27 expressions had shorter overall survival and disease-free survival. MLH1, MSH2, or ERCC1 were not associated with clinical response or survival. We report the potential utility of p-HSP90α, HSP27, γH2AX, and 53BP1 as predictive/prognostic markers for platinum-based chemotherapy. We present the first study that evaluates the predictive and prognostic value of p-HSP90α in primary tumors. Our research opens new possibilities for clinical oncology and shows the usefulness of immunohistochemistry for predicting chemotherapy response and prognosis in cancer.
Supporting a Learning System in Pediatric Emergency Pathways
Authors: Winters David Adam , Mehmi Ashley K. , Menzies-Wilson Richard , Folkard Samuel S. , Ryan Kate , Sevdalis Nick , Green James S.A.
Published: May 2022

Background

Scrotal pain is a common presentation to the emergency department requiring prompt investigation and management to identify testicular torsion and increase the opportunity for testicular salvage. Using national data obtained from the NHS Improvement, we aim to identify key suboptimal areas in the acute diagnosis and management of testicular torsion with a view to learning from these and improving outcomes.

Methods

A freedom of information request was made to all 134 hospital groups in England and Wales that manage testicular torsion. Serious incidents experienced by these hospitals were analyzed to see whether those with pediatric emergency departments fared better than those without. In addition, a qualitative thematic analysis of the NHS Improvement National Reporting and Learning System database over a 12-year period (2007–2019) was undertaken, to identify common themes associated with orchidectomies and “near-miss” events in the pediatric population.

Results

Three hundred four patient safety incidents were returned and divided into 62 orchidectomies and 242 near-miss events. The most common factor in the orchidectomy group was individual factors (83.9%). Misdiagnosis of symptomatic testicle was not significant when comparing ED to specialist surgeons (odds ratio = 1.46, P = 0.3842). Atypical presentation resulting in orchidectomy was significant when comparing ED with specialists (odds ratio = 6, P = 0.0355). Near-miss events, not leading to orchidectomy, are often due to a wider variety of factors. A Mann-Whitney U test showed that there was no statistical significance in incidents when comparing general ED units caring for all ages with pediatric EDs in terms of incidents (U = 807.5, z = −1.124, P = 0.261).

Conclusions

There is a need for education in ED about atypical presentation of testicular torsion and examination of scrotum in cases of lower abdominal pain. It is also vital that specialist teams are cognizant of the standard operating procedures relevant to scrotal pain and testicular within the organization and the wider clinical network. Finally, there should be a drive for annual collation of data in urology and ED units with regards to testicular torsion as patient safety incidents may be underreported.
Anaphyl-Crisis
Authors: Patek Paul M. , Owda Dalia , Menoch Margaret J.A.
Published: May 2022

Objectives

Anaphylaxis is a serious allergic reaction that has the potential to be life-threatening if not recognized and managed rapidly. Several regional studies have shown increased incidence of anaphylaxis over the past decade. The objectives of this study were to determine rates of pediatric anaphylaxis in southeast Michigan between January 1, 2010, and December 31, 2019, and to describe the epidemiology of pediatric patients presenting to emergency centers in southeast Michigan with anaphylaxis.

Methods

We performed a retrospective chart review of all pediatric patients aged 0 to 17 years presenting to 2 large emergency centers from 2010 to 2019 with a diagnosis of anaphylaxis using International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. Epidemiological and visit data, including length of stay, use of intravenous medication, and emergency severity index, were extracted and analyzed. Pediatric anaphylaxis rates were calculated based on detected anaphylaxis cases divided by total pediatric emergency department visits to the 2 emergency centers. A Poisson regression model was used to predict rates of anaphylaxis per 100,000 emergency department visits.

Results

One thousand three hundred ninety-one pediatric visits for anaphylaxis were identified during a period between January 1, 2010, and December 31, 2019. There was a significant rate of increase in pediatric anaphylaxis cases over the 10-year study period at both suburban emergency centers, with an annual increase of 21% and 13%. There was no significant change in trends in demographic factors. Most anaphylaxis cases were young, White males with private insurance. Most children did not receive intravenous medications (77%). The median length of stay increased by 1.5 hours over the study period and 92% of patients were discharged home.

Conclusions

Pediatric emergency center visits and length of stay for anaphylaxis in southeast Michigan have markedly increased over the past 10 years.
Potential of Photon-Counting Detector CT for Radiation Dose Reduction for the Assessment of Interstitial Lung Disease in Patients With Systemic Sclerosis
Authors: Jungblut Lisa , Euler André , von Spiczak Jochen , Sartoretti Thomas , Mergen Victor , Englmaier Vanessa , Landsmann Anna , Mihai Carmen-Marina , Distler Oliver , Alkadhi Hatem , Frauenfelder Thomas , Martini Katharina
Published: May 2022

Objective

The aim of this study was to determine the potential of photon-counting detector computed tomography (PCD-CT) for radiation dose reduction compared with conventional energy-integrated detector CT (EID-CT) in the assessment of interstitial lung disease (ILD) in systemic sclerosis (SSc) patients.

Methods

In this retrospective study, SSc patients receiving a follow-up noncontrast chest examination on a PCD-CT were included between May 2021 and December 2021. Baseline scans were generated on a dual-source EID-CT by selecting the tube current-time product for each of the 2 x-ray tubes to obtain a 100% (D100), a 66% (D66), and a 33% dose image (D33) from the same data set. Slice thickness and kernel were adjusted between the 2 scans. Image noise was assessed by placing a fixed region of interest in the subcutaneous fat. Two independent readers rated subjective image quality (5-point Likert scale), presence, extent, diagnostic confidence, and accuracy of SSc-ILD. D100 interpreted by a radiologist with 22 years of experience served as reference standard. Interobserver agreement was calculated with Cohen κ, and mean variables were compared by a paired t test.

Results

Eighty patients (mean 56 ± 14; 64 women) were included. Although CTDIvol of PCD-CT was comparable to D33 (0.72 vs 0.76 mGy, P = 0.091), mean image noise of PCD-CT was comparable to D100 (131 ± 15 vs 113 ± 12, P > 0.05). Overall subjective image quality of PCD-CT was comparable to D100 (4.72 vs 4.71; P = 0.874). Diagnostic accuracy was higher in PCD-CT compared with D33/D66 (97.6% and 92.5%/96.3%, respectively) and comparable to D100 (98.1%).

Conclusions

With PCD-CT, a radiation dose reduction of 66% compared with EID-CT is feasible, without penalty in image quality and diagnostic performance for the evaluation of ILD.
Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm
Authors: Künstner Axel , Schwarting Julian , Witte Hanno M. , Bernard Veronica , Stölting Stephanie , Kusch Kathrin , Nagarathinam Kumar , von Bubnoff Nikolas , Murga Penas Eva M. , Merz Hartmut , Busch Hauke , Feller Alfred C. , Gebauer Niklas
Published: May 2022

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignancy assumed to originate from plasmacytoid dendritic cells (pDCs), which mostly affects the skin, bone marrow, lymph nodes and sequentially other organ systems. RNA-, targeted- and exome sequencing studies have identified molecular characteristics, associated with BPDCN-pathogenesis, yet an integrative molecular assessment of BPDCN remains pending. Here, we combined paired WES/RNA-Seq with genome-wide copy-number analysis to characterize 47 BPDCN patients for mutational drivers, cytogenetic aberrations and gene-expression profiles. We identified alterations in epigenetic regulators (TET2, EP300, DNMT3A, SF3B1, EZH2) and a mutational disruption of RTK-RAS signaling (NF1, NRAS, EGFR) as drivers of BPDCN alongside deletions of tumor suppressors (CDKN2A, RB1, TP53), amplifications of oncogenes (IDH2, MET, EZH2) and recurrent fusions (MYB, ALK). The mutational landscape further provides evidence for frequent induction of PDGF signaling and extracellular matrix interactions as well as a gender specificity and a subset of MSIhigh patients. Many genes affected in BPDCN are shared with chronic myelomonocytic leukemia (CMML), emphasizing a close relationship between these entities and to a lesser extent with acute myeloid leukemia (AML). Ontological assessment of RNA-Seq data revealed two BPDCN subtypes, a typical pDC-derived subtype (C1) and a (common) cDC-enriched subtype (C2), which were then shown to exhibit distinct mutational (EP300, ARID2, NF1 mutations in typical pDC vs. DNMT3A, SRSF2 mutations in the cDC-enriched subtype) and clinical features.

In summary, our hitherto most comprehensive characterization of BPDCN reveals molecular hallmarks alongside actionable vulnerabilities and highlights two novel subtypes that are molecularly and clinically distinct.

Key Points

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Paired WES/RNA-Seq and copy number analysis of a large BPDCN cohort reveals two molecularly and clinically distinct subtypes.

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Multi-omics identify recurrent therapeutic targets and vulnerabilities including MSIhigh and mutations within epigenetic regulation of gene expression and RTK-RAS signaling.
Governance is key to controlling SARS-CoV-2’s vaccine resistance
Authors: Okamoto Kenichi W. , Chaves Luis F. , Wallace Rodrick , Wallace Robert G.
Published: May 2022

Little attention has been paid to governance’s impacts on the evolution of SARS-CoV-2, the virus that causes COVID-19. To evaluate such impacts on the evolution of vaccine resistance, we analyzed a stochastic compartmental model to quantify the risk a mutant strain capable of evading immunity emerges post-vaccine rollout. We calibrated the model with publicly available data for four territories in the Western Hemisphere qualitatively differing in pandemic interventions. The model shows an immune-evading strain to be readily selected over all infectivities in Texas. In Panama, only a high level of transmission permits immune evasion to evolve. No invasion appears likely in Costa Rica and Uruguay. Programs combining pharmaceutical and nonpharmaceutical interventions are best positioned to remove the epidemiological space SARS-CoV-2 needs to evolve vaccine resistance.

One Sentence Summary

Modes of governance and production help set the evolutionary trajectories of vaccine resistance in SARS-CoV-2 before vaccine campaigns begin.
FPocketWeb: Protein pocket hunting in a web browser
Authors: Kochnev Yuri , Durrant Jacob D.
Published: May 2022

Motivation

Detecting macromolecular (e.g., protein) cavities where small molecules bind is an early step in computer-aided drug discovery. Multiple pocket-detection algorithms have been developed over the past several decades. Among them, fpocket, created by Schmidtke and Le Guilloux, is particularly popular. Like many programs used in computational-biology research, fpocket requires users to download and install an executable file. That file must also be run via a command-line interface, further complicating use. An existing fpocket server application effectively addresses these challenges, but it requires users to upload their possibly proprietary structures to a third-party server.

Results

The FPocketWeb web app builds on this prior work. It runs the fpocket3 executable entirely in a web browser without requiring installation. The pocket-finding calculations occur on the user’s computer rather than on a remote server.

Availability

A working version of the open-source FPocketWeb app can be accessed free of charge from http://durrantlab.com/fpocketweb.