Longitudinal evaluation of neurologic-post acute sequelae SARS-CoV-2 infection symptoms.

OBJECTIVE: To assess the initial features and evolution of neurologic Postacute Sequelae of SARS-CoV-2 infection (neuro-PASC) in patients with and without prior neurologic disease. METHODS: Participants with neurologic symptoms following acute SARS-CoV-2 infection were recruited from October 9, 2020 to October 11, 2021. Clinical data included a SARS-CoV-2 infection history, neurologic review of systems, neurologic exam, Montreal cognitive assessment (MoCA), and symptom-based self-reported surveys at baseline (conducted after acute infection) and 6-month follow-up assessments. RESULTS: Fifty-six participants (69% female, mean age 50 years, 29% with prior neurologic disease such as multiple sclerosis) were enrolled, of which 27 had completed the 6-month follow-up visit in this ongoing study. SARS-CoV-2 infection severity was largely described as mild (39.3%) or moderate (42.9%). At baseline, following acute infection, the most common neurologic symptoms were fatigue (89.3%) and headaches (80.4%). At the 6-month follow-up, memory impairment (68.8%) and decreased concentration (61.5%) were the most prevalent, though on average all symptoms showed a reduction in reported severity score at the follow-up. Complete symptom resolution was reported in 33.3% of participants by 6 months. From baseline to 6 months, average MoCA scores improved overall though 26.3% of participants' scores decreased. A syndrome consisting of tremor, ataxia, and cognitive dysfunction (PASC-TAC) was observed in 7.1% of patients. INTERPRETATION: Early in the neuro-PASC syndrome, fatigue and headache are the most commonly reported symptoms. At 6 months, memory impairment and decreased concentration were most prominent. Only one-third of participants had completed resolution of neuro-PASC at 6 months, although persistent symptoms trended toward improvement at follow-up.

Immunological Findings and Clinical Outcomes of Infants With Positive Newborn Screening for Severe Combined Immunodeficiency From a Tertiary Care Center in the U.S.

The implementation of severe combined immunodeficiency (SCID) newborn screening has played a pivotal role in identifying these patients early in life as well as detecting various milder forms of T cell lymphopenia (TCL). In this study we reviewed the diagnostic and clinical outcomes, and interesting immunology findings of term infants referred to a tertiary care center with abnormal newborn SCID screens over a 6-year period. Key findings included a 33% incidence of non-SCID TCL including infants with novel variants in FOXN1, TBX1, MYSM1, POLD1, and CD3E; 57% positivity rate of newborn SCID screening among infants with DiGeorge syndrome; and earlier diagnosis and improved transplant outcomes for SCID in infants diagnosed after compared to before implementation of routine screening. Our study is unique in terms of the extensive laboratory workup of abnormal SCID screens including lymphocyte subsets, measurement of thymic output (TREC and CD4TE), and lymphocyte proliferation to mitogens in nearly all infants. These data allowed us to observe a stronger positive correlation of the absolute CD3 count with CD4RTE than with TREC copies, and a weak positive correlation between CD4RTE and TREC copies. Finally, we did not observe a correlation between risk of TCL and history of prenatal or perinatal complications or low birth weight. Our study demonstrated SCID newborn screening improves disease outcomes, particularly in typical SCID, and allows early detection and discovery of novel variants of certain TCL-associated genetic conditions.

Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Prevalence and Characteristics of Physiological Gaze-Evoked and Rebound Nystagmus: Implications for Testing Their Pathological Counterparts.

Objective: Cerebellar diseases frequently affect the ocular motor neural velocity-to-position integrator by increasing its leakiness and thereby causing gaze-evoked nystagmus (GEN) and rebound nystagmus (RN). Minor leakiness is physiological and occasionally causes GEN in healthy humans. We aimed to evaluate the characteristics of GEN/RN in healthy subjects for better differentiation between physiological and pathological GEN/RN. Methods: Using video-oculography, eye position was measured in 14 healthy humans at straight ahead eye position before and after, and during 30 s of ocular fixation at 4 horizontal eccentric targets between 30° and 45°. We determined the eye drift velocity and the prevalence of nystagmus before/during/after eccentric fixation. Results: Eye drift velocities during (range: 0.62 ± 0.53°/s to 1.78 ± 0.69°/s) and after eccentric gaze (range: 0.28 ± 0.52°/s to 1.48 ± 1.02°/s) increased with the amount of gaze eccentricity (30°-45°). During continuous eccentric gaze, eye drift velocities decreased by 0.41 ± 0.18°/s at 30°, and 0.84 ± 0.38°/s at 45° gaze eccentricity. GEN was elicited in 71% of subjects at 30° gaze eccentricity. Twenty-one percent showed RN thereafter. This prevalence increased to 100% (GEN)/72% (RN) at 45° gaze eccentricity. RN found after 30° gaze eccentricity was of low velocity (0.82 ± 0.21°/s) and occurred after minor drift velocity decrease during prior eccentric gaze (0.43 ± 0.15°/s). Conclusion: GEN and RN should be tested using horizontal gaze eccentricities of <30°, since most healthy subjects physiologically show GEN and RN at higher eccentricities. In case of an uncertain result, both the reduction of eye drift velocity during eccentric gaze and the velocity of RN can be analyzed to distinguish physiological from pathological nystagmus.

Solving a Hamiltonian Path Problem with a bacterial computer.

BACKGROUND: The Hamiltonian Path Problem asks whether there is a route in a directed graph from a beginning node to an ending node, visiting each node exactly once. The Hamiltonian Path Problem is NP complete, achieving surprising computational complexity with modest increases in size. This challenge has inspired researchers to broaden the definition of a computer. DNA computers have been developed that solve NP complete problems. Bacterial computers can be programmed by constructing genetic circuits to execute an algorithm that is responsive to the environment and whose result can be observed. Each bacterium can examine a solution to a mathematical problem and billions of them can explore billions of possible solutions. Bacterial computers can be automated, made responsive to selection, and reproduce themselves so that more processing capacity is applied to problems over time. RESULTS: We programmed bacteria with a genetic circuit that enables them to evaluate all possible paths in a directed graph in order to find a Hamiltonian path. We encoded a three node directed graph as DNA segments that were autonomously shuffled randomly inside bacteria by a Hin/hixC recombination system we previously adapted from Salmonella typhimurium for use in Escherichia coli. We represented nodes in the graph as linked halves of two different genes encoding red or green fluorescent proteins. Bacterial populations displayed phenotypes that reflected random ordering of edges in the graph. Individual bacterial clones that found a Hamiltonian path reported their success by fluorescing both red and green, resulting in yellow colonies. We used DNA sequencing to verify that the yellow phenotype resulted from genotypes that represented Hamiltonian path solutions, demonstrating that our bacterial computer functioned as expected. CONCLUSION: We successfully designed, constructed, and tested a bacterial computer capable of finding a Hamiltonian path in a three node directed graph. This proof-of-concept experiment demonstrates that bacterial computing is a new way to address NP-complete problems using the inherent advantages of genetic systems. The results of our experiments also validate synthetic biology as a valuable approach to biological engineering. We designed and constructed basic parts, devices, and systems using synthetic biology principles of standardization and abstraction.

Serious infection from Staphylococcus aureus in 2 HIV-infected patients receiving fusion inhibitor therapy.

Fusion inhibitors are novel antiretroviral agents, administered as subcutaneous injections, approved for use in treatment-experienced HIV-infected patients. HIV-infected patients are at increased risk for Staphylococcus aureus colonization, specifically with methicillin-resistant S aureus (MRSA), and subsequent systemic infection. We present the cases of 2 patients without a history of MRSA infection in whom a series of severe S aureus infections developed after fusion inhibitor therapy.

Biomechanical comparison of transosseous and capsular repair of peripheral triangular fibrocartilage tears.

PURPOSE: The purpose of this study was to biomechanically compare the repair strength of peripheral triangular fibrocartilage complex (TFCC) repairs to the distal ulna using transosseous sutures (group I) versus TFCC repairs to the extensor carpi ulnaris tendon subsheath and surrounding dorsal capsule (group II). TYPE OF STUDY: Cadaveric biomechanical study. METHODS: Six matched pairs of fresh-frozen cadaveric upper extremities were procured. Each underwent the creation and repair of a peripheral, ulnar-sided detachment of the TFCC. Following stabilization of the humerus and radius, the maximum translations of the ulna in the dorsal and palmar directions were measured in response to an 8-lb traction load before disrupting the TFCC, after disrupting the TFCC, and after repairing the TFCC. RESULTS: There was a significant increase in the total translation of the ulna following disruption of the TFCC (P <.001) in both groups. The mean and standard deviation of the percent total translation eliminated following TFCC repair for group I specimens (transosseous suture) were 33.8% and 11.6%, respectively. The mean and standard deviation of the percent total translation eliminated following TFCC repair for group II specimens (capsular implantation) were 59.3% and 29.7%, respectively. The observed difference between the repair groups is not significant (P =.157). CONCLUSIONS: While disruption of the TFCC does significantly increase distal radioulnar joint (DRUJ) instability and repair of the TFCC does significantly restore DRUJ stability, the results of this study do not show a significant biomechanical difference between the 2 TFCC repair techniques in a cadaveric model.