Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations.

Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models.

Surgical Treatment of Single-Level Lumbar Stenosis Is Associated with Lower 2-Year Mortality and Total Cost Compared with Nonsurgical Treatment: A Risk-Adjusted, Paired Analysis.

Background: Spine surgery has demonstrated cost-effectiveness in reducing pain and restoring function, but the impact of spine surgery relative to nonsurgical care on longer-term outcomes has been less well described. Our objective was to compare single-level surgical treatment for lumbar stenosis, with or without spondylolisthesis, and nonsurgical treatment with respect to patient mortality, resource utilization, and health-care payments over the first 2 years following initial treatment.

Methods: A retrospective review of the Medicare National Database Fee for Service Files from 2011 to 2017 was performed.

Extended-age Out-of-sample Validation of Risk Stratification Index 3.0 Models Using Commercial All-payer Claims.

Background: The authors previously reported a broad suite of individualized Risk Stratification Index 3.0 (Health Data Analytics Institute, Inc., USA) models for various meaningful outcomes in patients admitted to a hospital for medical or surgical reasons.

Risk Stratification Index 3.0, a Broad Set of Models for Predicting Adverse Events during and after Hospital Admission.

Background: Risk stratification helps guide appropriate clinical care. Our goal was to develop and validate a broad suite of predictive tools based on International Classification of Diseases, Tenth Revision, diagnostic and procedural codes for predicting adverse events and care utilization outcomes for hospitalized patients.

Methods: Endpoints included unplanned hospital admissions, discharge status, excess length of stay, in-hospital and 90-day mortality, acute kidney injury, sepsis, pneumonia, respiratory failure, and a composite of major cardiac complications.

Changes in Optic Nerve Head and Retinal Morphology During Spaceflight and Acute Fluid Shift Reversal.

Importance: Countermeasures that reverse the headward fluid shift experienced in weightlessness have the potential to mitigate spaceflight-associated neuro-ocular syndrome. This study investigated whether use of the countermeasure lower-body negative pressure during spaceflight was associated with changes in ocular structure.

Objective: To determine whether changes to the optic nerve head and retina during spaceflight can be mitigated by brief in-flight application of 25-mm Hg lower-body negative pressure.

Covid-19 and excess mortality in medicare beneficiaries.

We estimated excess mortality in Medicare recipients in the United States with probable and confirmed Covid-19 infections in the general community and amongst residents of long-term care (LTC) facilities. We considered 28,389,098 Medicare and dual-eligible recipients from one year before February 29, 2020 through September 30, 2020, with mortality followed through November 30th, 2020. Probable and confirmed Covid-19 diagnoses, presumably mostly symptomatic, were determined from ICD-10 codes.

Optic disc edema and chorioretinal folds develop during strict 6° head-down tilt bed rest with or without artificial gravity.

Spaceflight associated neuro-ocular syndrome (SANS) is hypothesized to develop as a consequence of the chronic headward fluid shift that occurs in sustained weightlessness. We exposed healthy subjects (n = 24) to strict 6° head-down tilt bed rest (HDTBR), an analog of weightlessness that generates a sustained headward fluid shift, and we monitored for ocular changes similar to findings that develop in SANS. Two-thirds of the subjects received a daily 30-min exposure to artificial gravity (AG, 1 g at center of mass, ~0.

Intraocular pressure and choroidal thickness respond differently to lower body negative pressure during spaceflight.

Spaceflight-associated neuro-ocular syndrome (SANS) develops during long-duration (>1 mo) spaceflight presumably because of chronic exposure to a headward fluid shift that occurs in weightlessness. We aimed to determine whether reversing this headward fluid shift with acute application of lower body negative pressure (LBNP) can influence outcome measures at the eye. Intraocular pressure (IOP) and subfoveal choroidal thickness were therefore evaluated by tonometry and optical coherence tomography (OCT), respectively, in 14 International Space Station crewmembers before flight in the seated, supine, and 15° head-down tilt (HDT) postures and during spaceflight, without and with application of 25 mmHg LBNP.

Association Between First-Line Immune Checkpoint Inhibition and Survival for Medicare-Insured Patients With Advanced Non-Small Cell Lung Cancer.

Importance: Immunotherapy is now a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC), but its uptake and effectiveness among older patients outside clinical trials remain poorly understood.

Objective: To understand treatment patterns and evaluate the overall survival associated with checkpoint inhibitor immunotherapy, cytotoxic chemotherapy, and combined chemoimmunotherapy for older patients who have advanced NSCLC and Medicare coverage.

Design, Setting, And Participants: This retrospective cohort study included Medicare-insured patients in the US aged 66 to 89 years who initiated first palliative-intent systemic therapy for lung cancer between January 1, 2016, and December 31, 2018.

Mechanical countermeasures to headward fluid shifts.

Head-to-foot gravitationally induced hydrostatic pressure gradients in the upright posture on Earth are absent in weightlessness. This results in a relative headward fluid shift in the vascular and cerebrospinal fluid compartments and may underlie multiple physiological consequences of spaceflight, including the spaceflight-associated neuro-ocular syndrome. Here, we tested three mechanical countermeasures [lower body negative pressure (LBNP), venoconstrictive thigh cuffs (VTC), and impedance threshold device (ITD) resistive inspiratory breathing] individually and in combination to reduce a posture-induced headward fluid shift as a ground-based spaceflight analog.

Mutant Nmnat1 leads to a retina-specific decrease of NAD+ accompanied by increased poly(ADP-ribose) in a mouse model of NMNAT1-associated retinal degeneration.

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is required for nuclear nicotinamide adenine mononucleotide (NAD+) biosynthesis in all nucleated cells, and despite its functional ubiquity, mutations in this gene lead to an isolated retinal degeneration. The mechanisms underlying how mutant NMNAT1 causes disease are not well understood, nor is the reason why the pathology is confined to the retina. Using a mouse model of NMNAT1-associated retinal degeneration that harbors the p.

Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of -Associated Retinal Degeneration.

No treatment is available for nicotinamide mononucleotide adenylyltransferase 1 ()-associated retinal degeneration, an inherited disease that leads to severe vision loss early in life. Although the causative gene, , plays an essential role in nuclear nicotinamide adenine dinucleotide (NAD) metabolism in tissues throughout the body, -associated disease is isolated to the retina. Since this condition is recessive, supplementing the retina with a normal copy of should protect vulnerable cells from disease progression.

Parthanatos as a Cell Death Pathway Underlying Retinal Disease.

Parthanatos is a programmed cell death pathway mediated by the effects of pathogenically high levels of poly(ADP-ribose) polymerase 1 (PARP1) activity. This process underlies a broad range of diseases affecting many tissues and organs across the body, including the retina. This chapter reviews mechanisms that are currently understood to drive parthanatos in the context of retinal diseases associated with this form of cell death.

Ift172 conditional knock-out mice exhibit rapid retinal degeneration and protein trafficking defects.

Intraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outersegments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies.

Allele-Specific CRISPR-Cas9 Genome Editing of the Single-Base P23H Mutation for Rhodopsin-Associated Dominant Retinitis Pigmentosa.

Treatment strategies for dominantly inherited disorders typically involve silencing or ablating the pathogenic allele. CRISPR-Cas nucleases have shown promise in allele-specific knockout approaches when the dominant allele creates unique protospacer adjacent motifs that can lead to allele-restricted targeting. Here, we present a spacer-mediated allele-specific knockout approach that utilizes both SpCas9 variants and truncated single-guide RNAs to achieve efficient discrimination of a single-nucleotide mutation in rhodopsin ()-P23H mice, a model of dominant retinitis pigmentosa.

Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with / Opsin Interchange Mutations.

Purpose: Human long () and middle () wavelength cone opsin genes are highly variable due to intermixing. Two / cone opsin interchange mutants, designated and , are associated with clinical diagnoses, including red-green color vision deficiency, blue cone monochromacy, cone degeneration, myopia, and Bornholm Eye Disease. Because the protein and splicing codes are carried by the same nucleotides, intermixing and genes can cause disease by affecting protein structure and splicing.

Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease.

The nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) enzyme is essential for regenerating the nuclear pool of NAD(+) in all nucleated cells in the body, and mounting evidence also suggests that it has a separate role in neuroprotection. Recently, mutations in the NMNAT1 gene were associated with Leber congenital amaurosis, a severe retinal degenerative disease that causes blindness during infancy. Availability of a reliable mammalian model of NMNAT1-Leber congenital amaurosis would assist in determining the mechanisms through which disruptions in NMNAT1 lead to retinal cell degeneration and would provide a resource for testing treatment options.

S-opsin knockout mice with the endogenous M-opsin gene replaced by an L-opsin variant.

Specific variants of human long-wavelength (L) and middle-wavelength (M) cone opsin genes have recently been associated with a variety of vision disorders caused by cone malfunction, including red-green color vision deficiency, blue cone monochromacy, myopia, and cone dystrophy. Strikingly, unlike disease-causing mutations in rhodopsin, most of the cone opsin alleles that are associated with vision disorders do not have deleterious point mutations. Instead, specific combinations of normal polymorphisms that arose by genetic recombination between the genes encoding L and M opsins appear to cause disease.

Cone-isolating ON-OFF electroretinogram for studying chromatic pathways in the retina.

The electroretinogram (ERG) provides information about outer retina function in both clinical and research applications. ERG components elicited by light increments and decrements can be separated using a long-flash paradigm in which periods of light ON and OFF are alternated. Here, the ON-OFF ERG is combined with a silent substitution technique to elicit responses from individual cone photoreceptor classes by modulating the intensities of three color lights between the two periods.

Quantitative electroencephalogram biomarkers for predicting likelihood and speed of achieving sustained remission in major depression: a report from the biomarkers for rapid identification of treatment effectiveness in major depression (BRITE-MD) trial.

Objective: Clinical trials in major depressive disorder (MDD) commonly assess remission at a single endpoint. Complementary, clinically relevant metrics include the likelihood and speed of achieving sustained remission. A neurophysiologic measure, the Antidepressant Treatment Response (ATR) index, previously predicted 8-week outcomes of pharmacotherapy.

Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.

Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period.

Hospital stay and mortality are increased in patients having a "triple low" of low blood pressure, low bispectral index, and low minimum alveolar concentration of volatile anesthesia.

Background: Low mean arterial pressure (MAP) and deep hypnosis have been associated with complications and mortality. The normal response to high minimum alveolar concentration (MAC) fraction of anesthetics is hypotension and low Bispectral Index (BIS) scores. Low MAP and/or BIS at lower MAC fractions may represent anesthetic sensitivity.

The antidepressant treatment response index and treatment outcomes in a placebo-controlled trial of fluoxetine.

Recent research aims at developing a biomarker to predict antidepressant treatment outcomes in major depressive disorder. The Antidepressant Treatment Response (ATR) index has been correlated with response to antidepressant medication (, ) but has not been assessed in a placebo-controlled trial. EEGs recorded at pretreatment baseline and after 1 week of randomized treatment were used to calculate ATR index for 23 subjects with major depressive disorder who were treated for 8 weeks with fluoxetine (FLX) 20 mg (n = 12) or placebo (n = 11).