Drug platforms that enable the directed delivery of therapeutics to sites of diseases to maximize efficacy and limit off-target effects are needed. Here, we report the development of PROT3EcT, a ...suite of commensal Escherichia coli engineered to secrete proteins directly into their surroundings. These bacteria consist of three modular components: a modified bacterial protein secretion system, the associated regulatable transcriptional activator, and a secreted therapeutic payload. PROT3EcT secrete functional single-domain antibodies, nanobodies (Nbs), and stably colonize and maintain an active secretion system within the intestines of mice. Furthermore, a single prophylactic dose of a variant of PROT3EcT that secretes a tumor necrosis factor-alpha (TNF-α)-neutralizing Nb is sufficient to ablate pro-inflammatory TNF levels and prevent the development of injury and inflammation in a chemically induced model of colitis. This work lays the foundation for developing PROT3EcT as a platform for the treatment of gastrointestinal-based diseases.
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•Engineering of PROT3EcT, E. coli outfitted with a programmable protein secretion system•PROT3EcT secrete functional nanobodies into their surroundings•Pretreating with anti-TNF-α-secreting PROT3EcT limits colitis in a preclinical IBD model
Lynch, González-Prieto, et al. describe the development of PROT3EcT, a suite of E. coli outfitted with a modified bacterial secretion system that enables the secretion of therapeutic payloads into their surroundings. Pretreating with a TNF-α-neutralizing nanobody-secreting PROT3EcT prevents colitis in a preclinical IBD model, providing proof of concept for further platform development.
Hypothyroidism is a common disease that is more prevalent in female populations. The purpose of this paper is to discuss the evidence, risks, and benefits of screening asymptomatic women for ...hypothyroidism. There is lack of evidence to support clinical management of asymptomatic individuals with an elevated TSH and normal serum thyroxine levels. Patients with subclinical hypothyroidism, especially the elderly, are at risk of overtreatment. Given these considerations, the majority of US and UK professional organizations do not support universal screening. Many do offer caveats for special groups, including pregnant people, who may need screening if there are clinical symptoms or family history of autoimmune disease. In conclusion, targeted screening may be best recommended based on risk factors, symptoms, and clinical suspicion, rather than at a universal level. Keywords: asymptomatic, subclinical, overt, universal
Despite having a high risk of acquiring sexually transmitted infections, people who inject drugs (PWID) often do not receive recommended HPV screenings due to barriers to healthcare. Guideline-based ...cervical HPV screening and vaccination can prevent cervical cancer. Low-cost, low-barrier methods for cancer screening and prevention are important for vulnerable communities such as PWID.
We examined acceptability of HPV self-sampling at a syringe services program (SSP). Participants with a cervix (n = 49) participated in patient education followed by a survey to assess willingness to perform HPV self-sampling versus standard of care.
59% found self-sampling to be acceptable, citing privacy, ease, and quickness. Among those opting for HPV screening delivered by a provider (n = 16), participants cited concerns about adequate sampling (81%) and test accuracy (75%). Notably, only 18% of participants reported complete HPV vaccination.
Cervical HPV self-sampling was acceptable to PWID. SSP-based efforts to provide preventative health services could place tools for cancer screening into the hands of PWID, a need-to-reach community.
Objective
Late‐onset GM2 gangliosidosis (LOGG) subtypes late‐onset Tay‐Sachs (LOTS) and Sandhoff disease (LOSD) are ultra‐rare neurodegenerative lysosomal storage disorders presenting with weakness, ...ataxia, and neuropsychiatric symptoms. Previous studies considered LOTS and LOSD clinically indistinguishable; recent studies have challenged this. We performed a scoping review to ascertain whether imaging and clinical features may differentiate these diseases.
Methods
We examined MEDLINE/non‐MEDLINE databases up to May 2022. Articles reporting brain imaging findings in genetically/enzymatically confirmed LOGG, symptom onset at age ≥ 10 years (or evaluated at least once ≥18 years) were included, yielding 170 LOGG patients (LOTS = 127, LOSD = 43) across 68 papers. We compared LOTS versus LOSD and performed regression analyses. Results were corrected for multiple comparisons.
Results
Age of onset was lower in LOTS versus LOSD (17.9 ± 8.2 vs. 23.9 ± 14.4 years, p = 0.017), although disease duration was similar (p = 0.34). LOTS more commonly had psychosis/bipolar symptoms (35.0% vs. 9.30%, p = 0.011) but less frequent swallowing problems (4.10% vs. 18.60%, p = 0.041). Cerebellar atrophy was more common in LOTS (89.0%) versus LOSD (60.5%), p < 0.0001, with more severe atrophy in LOTS (p = 0.0005). Brainstem atrophy was documented only in LOTS (14.2%). Independent predictors of LOTS versus LOSD (odds ratio 95% confidence interval) included the presence of psychosis/bipolar symptoms (4.95 1.59–19.52, p = 0.011), no swallowing symptoms (0.16 0.036–0.64, p = 0.011), and cerebellar atrophy (5.81 2.10–17.08, p = 0.0009). Lower age of onset (0.96 0.93–1.00, p = 0.075) and tremor (2.50 0.94–7.43, p = 0.078) were marginally statistically significant but felt relevant to include in the model.
Interpretation
These data suggest significant differences in symptomatology, disease course, and imaging findings between LOTS and LOSD.
Background:
Gait and balance difficulties are among the most common clinical manifestations in adults with X-linked adrenoleukodystrophy, but little is known about the contributions of sensory loss, ...motor dysfunction, and postural control to gait dysfunction and fall risk.
Objective:
To quantify gait and balance deficits in both males and females with adrenoleukodystrophy and evaluate how environmental perturbations (moving surfaces and visual surrounds) affect balance and fall risk.
Methods:
We assessed sensory and motor contributions to gait and postural instability in 44 adult patients with adrenoleukodystrophy and 17 healthy controls using three different functional gait assessments (25 Foot Walk test, Timed Up and Go, and 6 Minute Walk test) and computerized dynamic posturography.
Results:
The median Expanded Disability Status Scale score for the patient cohort was 3.0 (range 0.0–6.5). Both males and females with adrenoleukodystrophy showed impairments on all three functional gait assessments relative to controls (
P
< 0.001). Performance on walking tests and Expanded Disability Status Scale scores correlated with incidence of falls on computerized dynamic posturography, with the 25 Foot Walk being a moderately reliable predictor of fall risk (area under the ROC curve = 0.7675,
P
= 0.0038).
Conclusion:
We demonstrate that gait difficulties and postural control deficits occur in patients with adrenoleukodystrophy, albeit at an older age in females. Postural deficits were aggravated by eyes closed and dynamic conditions that rely on vestibular input, revealing challenges to the interplay of motor, sensory and vestibular circuitry in adrenoleukodystrophy.
The objectives of this study were to (1) investigate the association between human blood type and COVID-19 in both inpatient and longitudinal populations and (2) identify the association between ...blood type and severity of COVID-19 via presence of cellular biomarkers of severe infection in hospitalized individuals at our institution in South Florida. This study consisted of (1) a single-center retrospective analysis of 669 out of 2741 COVID-19-positive, screened patients seen from 1 January 2020 until 31 March 2021 at the University of Miami Emergency Department (ED) who tested positive for COVID-19 and had a documented ABO blood type and (2) a longitudinal SARS-CoV-2 immunity study (“CITY”) at the University of Miami Miller School of Medicine, consisting of 185 survey participants. In an inpatient setting, blood type appeared to be associated with COVID-19 severity and mortality. Blood type O sustained less risk of COVID-19 mortality, and blood type O- demonstrated less risk of developing COVID-19 pneumonia. Inpatients with O- blood type exhibited less biomarkers of severe infection than did other blood types. In a longitudinal setting, there was no association found between blood type and SARS-CoV-2 infection.
Urinary incontinence is common after spinal cord injury (SCI) due to loss of supraspinal coordination and unabated reflexes in both autonomic and somatic nervous systems; if unchecked, these ...disturbances can become life-threatening. This manuscript will review normal anatomy and physiology of the urinary system and discuss pathophysiology secondary to SCI. This includes a discussion of autonomic dysreflexia, as well as its diagnosis and management. The kidneys and the ureters, representing the upper urinary tract system, can be at risk related to dyssynergy between the urethral sphincters and high pressures that lead to potential vesicoureteral reflux, urinary tract infections, and calculi associated with neurogenic lower urinary tract dysfunction (NLUTD). Recent guidelines for diagnosis, evaluation, treatment and follow up of the neurogenic bladder will be reviewed and options provided for risk stratification and management. Mechanical, pharmacological, neurolysis and surgical management will be discussed.
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