A narrative review of the controversy on the risk of mycobacterial infections with immune checkpoint inhibitor use: does Goldilocks have the answer?

Background and Objective: Immune checkpoint inhibitors (ICIs) have revolutionized oncologic treatment. Whether ICIs increase susceptibility to or provide protection against mycobacterial infections remains controversial. The objective of this narrative review is to summarize the literature on the link between ICI use and mycobacterial infections-tuberculosis and non-tuberculous mycobacterial (NTM) infections-and to critically discuss evidence linking ICIs with mycobacterial infections, the possible confounders, and, if indeed the ICIs predispose to such infections, the potential mechanisms of how this may occur. Methods: We conducted a literature search on PubMed for relevant articles published from 2011 to current time [2024] utilizing specific keywords of "immune checkpoint inhibitors", "programmed cell death protein-1", "PD-1", "programmed death-ligand 1", "PD-L1", "cytotoxic T-lymphocyte-associated protein-4", or "CTLA-4" with that of "non-tuberculous mycobacterial lung disease", "tuberculosis", or "mycobacteria". The bibliographies of identified papers were perused for additional relevant articles. Key Content and Findings: Ex vivo studies using human cells indicate that ICIs would be salubrious for the host against mycobacteria. Yet, many case reports associate ICI use with mycobacterial infections, mostly tuberculosis. Potential confounders include immunosuppression from the cancer, concomitant use of immunosuppressive drugs, lung injury and distortion from chemotherapeutics or radiation, and reporting bias. Mice with genetic disruption of the programmed cell death protein-1 (PD-1) gene are paradoxically more susceptible to Mycobacterium tuberculosis (M. tuberculosis). In contrast, mice administered neutralizing antibody to T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) or knocked out for TIM3 gene have greater capacity to control an M. tuberculosis infection. We posit that hosts with greater baseline immunodeficiency are more likely to derive benefit from ICIs against mycobacterial infections than those with more intact immunity, where ICIs are more likely to be detrimental. Conclusions: Studies are needed to test the hypothesis that ICIs may either protect or predispose to mycobacterial infections, depending on the baseline host immune status. Prospective studies are required of patients on ICIs that control for potential confounders as anecdotal case reports are insufficient to provide a causal link. Murine studies with ICIs are also required to corroborate or refute studies of mice with genetic disruption of an immune checkpoint.

Staphylococcal biofilm: penetration and bioavailability of vancomycin with or without rifampin.

We measured antibiotic penetration and bioavailability in staphylococcus biofilms using simulated humanized concentrations of fluorescent vancomycin plus or minus rifampin. Vancomycin percent recovery across biofilm layers was:upper = 46%, middle = 40%, and lower = 33%. Vancomycin plus rifampin was not significantly different (P = 0.65). Addition of rifampin did not improve vancomycin penetration across biofilm layers.

Electrophysiological assessment of nutritional optic neuropathy: a case report.

PURPOSE: To report an unexpectedly asymmetric, progressive nutritional optic neuropathy associated with vitamin A deficient optic canal hyperostosis in a 15-year-old female with a long history of a restricted diet. METHODS: We performed comprehensive ophthalmic assessments in a fifteen-year-old female with a long history of restricted eating who presented with suspected nutritional optic neuropathy, predominantly affecting the right eye vision. RESULTS: A review of computerised tomography and magnetic resonance imaging revealed bilateral optic canal hyperostosis likely associated with vitamin A deficiency. Electrodiagnostic tests and optical coherence tomography provided structure-function evidence of bilateral retinal ganglion cell dysfunction and notably revealed severe loss of temporal fibres in the left eye which showed cecocentral scotoma but normal visual acuity. Although selective damage of the papillomacular bundle has been well-documented in nutritional and toxic optic neuropathies, compressive optic canal hyperostosis secondary to nutritional deficiency has been rarely reported. CONCLUSIONS: Nutritional deficiencies are increasing in high-income countries and may be linked to the rise of gastrointestinal disorders, strict vegan and vegetarian diets and avoidant restrictive food intake disorder (ARFID) associated with conditions such as depression and autism spectrum syndrome (ASD). Our findings highlight the value of electrodiagnostic testing alongside imaging in complex nutritional optic neuropathies to help monitor, guide treatment and preserve remaining sight in a child.

Correlation of long-term care facility vaccination practices between seasons and resident types.

BACKGROUND: Influenza vaccination varies widely across long-term care facilities (LTCFs) due to staff behaviors, LTCF practices, and patient factors. It is unclear how seasonal LTCF vaccination varies between cohabitating but distinct short-stay and long-stay residents. Thus, we assessed the correlation of LTCF vaccination between these populations and across seasons. METHODS: The study design is a national retrospective cohort using Medicare and Minimum Data Set (MDS) data. Participants include U.S. LTCFs. Short-stay and long-stay Medicare-enrolled residents age ≥ 65 in U.S. LTCFs from a source population of residents during October 1st-March 31st in 2013-2014 (3,042,881 residents; 15,683 LTCFs) and 2014-2015 (3,143,174, residents; 15,667 LTCFs). MDS-assessed influenza vaccination was the outcome. Pearson correlation coefficients were estimated to assess seasonal correlations between short-stay and long-stay resident vaccination within LTCFs. RESULTS: The median proportion of short-stay residents vaccinated across LTCFs was 70.4% (IQR, 50.0-82.7%) in 2013-2014 and 69.6% (IQR, 50.0-81.6%) in 2014-2015. The median proportion of long-stay residents vaccinated across LTCFs was 85.5% (IQR, 78.0-90.9%) in 2013-2014 and 84.6% (IQR, 76.6-90.3%) in 2014-2015. Within LTCFs, there was a moderate correlation between short-stay and long-stay vaccination in 2013-2014 (r = 0.50, 95%CI: 0.49-0.51) and 2014-2015 (r = 0.53, 95%CI: 0.51-0.54). Across seasons, there was a moderate correlation for LTCFs with short-stay residents (r = 0.54, 95%CI: 0.53-0.55) and a strong correlation for those with long-stay residents (r = 0.68, 95%CI: 0.67-0.69). CONCLUSIONS: In LTCFs with inconsistent influenza vaccination across seasons or between populations, targeted vaccination protocols for all residents, regardless of stay type, may improve successful vaccination in this vulnerable patient population.

Chronic obstructive pulmonary disease and obstructive sleep apnoea overlap: co-existence, co-morbidity, or causality?

PURPOSE OF REVIEW: The chronic obstructive pulmonary disease and obstructive sleep apnoea overlap syndrome is associated with higher morbidity and mortality rates than either disease alone. There is evidence of a bidirectional relationship between the two conditions, with the overlap syndrome encompassing a spectrum of clinical phenotypes. RECENT FINDINGS: This review examines the evidence for the various factors that determine the overlap syndrome, the impact overlap syndrome has on co-morbidities, and implications for diagnosis and treatment. SUMMARY: The accurate diagnosis of the overlap syndrome is critical given its implications for treatment optimisation and reduction in healthcare utilisation and costs.

National trends in hospital, long-term care and outpatient Acinetobacter baumannii resistance rates.

Introduction. Acinetobacter baumannii is a top-priority pathogen of the World Health Organization (WHO) and the Centers for Disease Control (CDC) due to antibiotic resistance.Gap Statement. Trends in A. baumannii resistance rates that include community isolates are unknown.Aim. Identify trends in A. baumannii resistance rates across the Veterans Affairs (VA) Healthcare System, including isolates from patients treated in hospitals, long-term care facilities and outpatient clinics nationally.Methodology. We included A. baumannii clinical cultures collected from VA patients from 2010 to 2018. Cultures were categorized by location: VA medical centers (VAMCs), long-term care (LTC) units [community living centers (CLCs)], or outpatient. We assessed carbapenem resistance, multidrug resistance (MDR) and extensive drug resistance (XDR). Time trends were assessed with Joinpoint regression.Results. We identified 19 376 A. baumannii cultures (53% VAMCs, 4% CLCs, 43% outpatient). Respiratory cultures were the most common source of carbapenem-resistant (43 %), multidrug-resistant (49 %) and extensively drug-resistant (21 %) isolates. Over the study period, the number of A. baumannii cultures decreased significantly in VAMCs (11.9% per year). In 2018, carbapenem resistance was seen in 28% of VAMC isolates and 36% of CLC isolates, but only 6% of outpatient isolates, while MDR was found in 31% of VAMC isolates and 36% of CLC isolates, but only 8 % of outpatient isolates. Carbapenem-resistant, multidrug-resistant and extensively drug-resistant A. baumannii isolates decreased significantly in VAMCs and outpatient clinics over time (VAMCs: by 4.9, 7.2 and 6.9%; outpatient: by 11.3, 10.5 and 10.2% per year). Resistant phenotypes remained stable in CLCs.Conclusion. In the VA nationally, the prevalence of A. baumannii is decreasing, as is resistance. Carbapenem-resistant and multidrug-resistant A. baumannii remain common in VAMCs and CLCs. The focus of infection control and antimicrobial stewardship efforts to prevent transmission of resistant A. baumannii should be in hospital and LTC settings.

Visual electrophysiology in the assessment of toxicity and deficiency states affecting the visual system.

Visual disturbance or visual failure due to toxicity of an ingested substance or a severe nutritional deficiency can present significant challenges for diagnosis and management, for instance, where an adverse reaction to a prescribed medicine is suspected. Objective assessment of visual function is important, particularly where structural changes in the retina or optic nerve have not yet occurred, as there may be a window of opportunity to mitigate or reverse visual loss. This paper reviews a number of clinical presentations where visual electrophysiological assessment has an important role in early diagnosis or management alongside clinical assessment and ocular imaging modalities. We highlight the importance of vitamin A deficiency as an easily detected marker for severe combined micronutrient deficiency.

Metformin is Associated with Decreased 30-Day Mortality Among Nursing Home Residents Infected with SARS-CoV2.

OBJECTIVES: The COVID-19 pandemic presents an urgent need to investigate whether existing drugs can enhance or even worsen prognosis; metformin, a known mammalian target of rapamycin (m-TOR) inhibitor, has been identified as a potential agent. We sought to evaluate mortality benefit among older persons infected with SARS-CoV-2 who were taking metformin as compared to those who were not. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: 775 nursing home residents infected with SARS-CoV-2 who resided in one of the 134 Community Living Centers (CLCs) of the Veterans Health Administration (VHA) during March 1, 2020, to May 13, 2020, were included. METHODS: Using a window of 14 days prior to SARS-CoV-2 testing, bar-coded medication administration records were examined for dispensing of medications for diabetes. The COVID-19-infected residents were divided into 4 groups: (1) residents administered metformin alone or in combination with other medications, (2) residents who used long-acting or daily insulin, (3) residents administered other diabetes medications, and (4) residents not administered diabetes medication, including individuals without diabetes and patients with untreated diabetes. Proportional hazard models adjusted for demographics, hemoglobin A1c, body mass index, and renal function. RESULTS: Relative to those not receiving diabetes medications, residents taking metformin were at significantly reduced hazard of death [adjusted hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.28, 0.84] over the subsequent 30 days from COVID-19 diagnosis. There was no association with insulin (adjusted HR 0.99, 95% CI 0.60, 1.64) or other diabetes medications (adjusted HR 0.71, 95% CI 0.38, 1.32). CONCLUSIONS AND IMPLICATIONS: Our data suggest a reduction in 30-day mortality following SARS-CoV-2 infection in residents who were on metformin-containing diabetes regimens. These findings suggest a relative survival benefit in nursing home residents on metformin, potentially through its mTOR inhibition effects. A prospective study should investigate the therapeutic benefits of metformin among persons with COVID-19.

Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes.

The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.

In vivo toxicology of excipients commonly employed in drug discovery in rats.

INTRODUCTION: Toxicology and pharmacology studies conducted in the early stages of drug discovery often require formulation strategies involving the use of excipients with limited knowledge regarding their preclinical safety liabilities. The use of excipients is vital to efforts to solubilize and deliver small molecules in drug discovery. Whilst excipients can have a significant impact on pharmacology and toxicology studies by enabling solubility to maximize systemic exposure, they also have the potential to obscure clinical pathology endpoints. In this article, we report on the in vivo safety in rats for 18 excipients commonly employed in formulations for preclinical pharmacology and toxicology studies. METHODS: The test articles were administered once daily for five days, by oral gavage to male Sprague Dawley rats, and the animals monitored for visible clinical signs. At the end of the study, routine necropsy and clinical pathology endpoints were investigated. RESULTS: None of the excipients tested were acutely toxic. However, there were effects on parameters commonly evaluated as indicators of health and/or toxicological response in regulated preclinical safety studies. DISCUSSION: While the excipients tested were generally well tolerated, several were found to affect common clinical pathology endpoints in a manner that might confound or conceivably mask the interpretation of compound mediated adverse/pharmacological effects.

Early toxicology signal generation in the mouse.

The rat has been the preferred rodent toxicology species since before regulatory requirements have been in place, and there exists in the pharmaceutical industry and the regulatory agencies a significant amount of historical data for the rat. The resulting experience base with the rat makes the possibility of replacing it with the mouse for regulated toxicology studies untenable for all but the most extreme circumstances. However, toxicologists are very familiar with the mouse as a model for chronic carcinogenicity studies, and there exist multiple preclinical mouse models of disease. The authors evaluated the use of the mouse for early in vivo toxicology signal generation and prioritization of small molecule lead compounds prior to nomination of a development candidate. In five-day oral gavage studies with three test agents in the mouse, the authors were able to identify the same dose-limiting toxicities as those identified in the rat, including examples of compound-mediated hemolysis as well as microscopic lesions in the alimentary canal, kidney, and pancreas. Performing early signal generation studies in the mouse allows for earlier assessment of the safety liabilities of small molecules, requires significantly less compound, and allows evaluation of more compounds earlier in the project's life cycle.

Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders.

During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

Interpretation of laser desorption mass spectra of unexpected inorganic species found in a cosmetic sample of forensic interest: fingernail polish.

When analytes containing color are irradiated with a pulsed UV laser in the ion source of a mass spectrometer, molecules such as dyes or pigments absorb energy, resulting in their desorption and ionization. This method, laser desorption mass spectrometry (LDMS), has been used successfully to analyze colorants of forensic interest in a wide variety of materials. Here, we present and interpret the most complex of such spectra obtained to date from a sample of fingernail polish. Interpretation of the spectrum provides a unique opportunity to characterize the laser desorption mass spectra of some unexpected inorganic materials found in cosmetics, such as "broken glass", cyanide compounds, and heavy metals. Also, the possibility of a useful forensic database of LDMS spectra of fingernail polishes is considered.

Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract.

5-Hydroxytryptamine (serotonin) (5-HT) is a neurotransmitter with both central and peripheral functions, including the modulation of mood, appetite, hemodynamics, gastrointestinal (GI) sensation, secretion, and motility. Its synthesis is initiated by the enzyme tryptophan hydroxylase (TPH). Two isoforms of TPH have been discovered: TPH1, primarily expressed in the enterochromaffin cells of the gastrointestinal tract, and TPH2, expressed exclusively in neuronal cells. Mice lacking Tph1 contain little to no 5-HT in the blood and GI tract while maintaining normal levels in the brain. Because GI 5-HT is known to play important roles in normal and pathophysiology, we set out to discover and characterize novel compounds that selectively inhibit biosynthesis of GI 5-HT. Here, we describe two of a series of these inhibitors that are potent for TPH activity both in biochemical and cell-based assays. This class of compounds has unique properties with respect to pharmacokinetic and pharmacodynamic effects on GI serotonin production. Similar to the Tph1 knockout results, these TPH inhibitors have the ability to selectively reduce 5-HT levels in the murine GI tract without affecting brain 5-HT levels. In addition, administration of these compounds in a ferret model of chemotherapy-induced emesis caused modest reductions of intestinal serotonin levels and a decreased emetic response. These findings suggest that GI-specific TPH inhibitors may provide novel treatments for various gastrointestinal disorders associated with dysregulation of the GI serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.