Representations of clinical practice guidelines and health equity in healthcare literature: An integrative review.

AIM: This paper reports an integrative review of international health literature that discusses health equity in relation to clinical practice guidelines (CPGs). BACKGROUND: Healthcare professionals (HCPs), policy makers, and decision makers rely on sound empirical evidence to make fiscally responsible and appropriate decisions about the allocation of health resources and health service delivery. CPGs provide statements and recommendations that aim to standardize care with an implicit goal of achieving equity of care among diverse populations. Developers of CPGs must be careful not to exacerbate inequity when making recommendations. As such, it is important to determine how equity is discussed within the context of CPGs. DESIGN: This integrative review was conducted according to integrative review methods as outlined by Whittemore and Knafl (2005), and Toronto and Remington (2020). These authors outlined a systematic process for the identification of relevant literature across health disciplines to examine the state of knowledge pertaining to a phenomenon such as health equity. SEARCH METHODS: The computerized databases PubMed, CINAHL, Cochrane, Embase, Medline, and Web of Science were searched using a combination of keywords. Search parameters included international peer-reviewed published, full-text, English language articles, editorials, and reports over the last decade (January 2011 to February 2022). A reference search of included articles was conducted to identify any additional articles. Dissertations and theses were not included. SEARCH OUTCOME: A total of 139 peer-reviewed English language articles were identified. RESULTS: The findings of this review revealed five main ways in which health equity is in context of CPGs including if they target or exacerbate inequity among disadvantaged populations, equity and CPG development, implementation, and evaluation, and checklists and tools to assist developers and users of CPG to consider equity. Although critical appraisal tools exist to assist users of CPGs assess and to evaluate how well CPGs address issues of equity, the definition of equity and how CPG development panels should incorporate and articulate it remains unclear and haphazard. As such, recommendations intended to be implemented by HCPs to optimize health equity remains diverse and unclear. CONCLUSION: The way equity is discussed within the reviewed health literature has implications for their uptake by and utility for HCPs. The ability of HCPs to implement CPGs may be hindered without an appreciation and integration of equity considerations across the various phases of CPG conceptualization, development, implementation, and evaluation, and their relevance and appropriateness to diverse geographic and socioeconomic contexts with variable access to health human resources and services. This situation could be improved if equity were more clearly articulated within all aspects of the CPG process. CLINICAL RELEVANCE: Understanding how equity is discussed in the literature relative to CPGs has implications for their uptake by and utility for HCPs in their goal of providing equitable health care. Successful implementation of CPGs with consideration equity could be improved if equity were more clearly articulated within all aspects of the CPG process including conceptualization, development, implementation, and evaluation.

Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy.

BACKGROUND & AIMS: Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury. METHODS: Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed. RESULTS: Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33-229 days), with a majority receiving prednisolone for 60-120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications. CONCLUSIONS: Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention. LAY SUMMARY: Onasemnogene abeparvovec is a type of medicine called a "gene therapy," which is used to treat babies and young children who have a rare, serious inherited condition called "spinal muscular atrophy" (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly.

Vaccination with Mincle agonist UM-1098 and mycobacterial antigens induces protective Th1 and Th17 responses.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the top infectious killers in the world. The only licensed vaccine against TB, Bacille Calmette-Guérin (BCG), provides variable protection against pulmonary TB, especially in adults. Hence, novel TB vaccine approaches are urgently needed. Both Th1 and Th17 responses are necessary for protection against TB, yet effective adjuvants and vaccine delivery systems for inducing robust Th1 and Th17 immunity are lacking. Herein we describe a synthetic Mincle agonist, UM-1098, and a silica nanoparticle delivery system that drives Th1/Th17 responses to Mtb antigens. Stimulation of human peripheral blood mononuclear cells (hPBMCs) with UM-1098 induced high levels of Th17 polarizing cytokines IL-6, IL-1ß, IL-23 as well as IL-12p70, IL-4 and TNF-α in vitro. PBMCs from both C57BL/6 and BALB/c mice responded with a similar cytokine pattern in vitro and in vivo. Importantly, intramuscular (I.M.) vaccination with UM-1098-adjuvanted TB antigen M72 resulted in significantly higher antigen-specific IFN-γ and IL-17A levels in C57BL/6 wt mice than Mincle KO mice. Vaccination of C57BL/6 wt mice with immunodominant Mtb antigens ESAT6/Ag85B or M72 resulted in predominantly Th1 and Th17 responses and induced antigen-specific serum antibodies. Notably, in a virulent Mtb challenge model, vaccination with UM-1098 adjuvanted ESAT6/Ag85B or M72 significantly reduced lung bacterial burden when compared with unvaccinated mice and protection occurred in the absence of pulmonary inflammation. These data demonstrate that the synthetic Mincle agonist UM-1098 induces strong Th1 and Th17 immunity after vaccination with Mtb antigens and provides protection against Mtb infection in mice.

Assessment of athletic health care facility surfaces for MRSA in the secondary school setting.

Methicillin-resistant Staphylococcus aureus (MRSA) was once largely a hospital-acquired infection, but increasingly, community-associated MRSA (CA-MRSA) is causing outbreaks among otherwise healthy people in athletic settings. Secondary school athletic trainers, student athletes, and the general student population may be at elevated risk of MRSA infection. To identify the prevalence of MRSA on surfaces in high school athletic training settings, 10 rural high school athletic training facilities and locker rooms were sampled for MRSA. Results showed 90% of facilities had two or more positive MRSA surfaces, while one school had no recoverable MRSA colonies. Of all surfaces tested (N=90), 46.7% produced a positive result. From this limited sample, it is evident that significant exposure opportunities to MRSA exist in athletic training clinics and adjacent facilities for both the patient and the clinician. Furthermore, the findings point to the need for community hygiene education about skin and soft tissue infections like MRSA.

Modulation of agonist binding to AMPA receptors by 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546): differential effects across brain regions and GluA1-4/transmembrane AMPA receptor regulatory protein combinations.

Ampakines are cognitive enhancers that potentiate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents and synaptic responses by slowing receptor deactivation. Their efficacy varies greatly between classes of neurons and brain regions, but the factor responsible for this effect remains unclear. Ampakines also increase agonist affinity in binding tests in ways that are related to their physiological action. We therefore examined 1) whether ampakine effects on agonist binding vary across brain regions and 2) whether they differ across receptor subunits expressed alone and together with transmembrane AMPA receptor regulatory proteins (TARPs), which associate with AMPA receptors in the brain. We found that the maximal increase in agonist binding (E(max)) caused by the prototypical ampakine 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) differs significantly between brain regions, with effects in hippocampus and cerebellum being nearly three times larger than that in thalamus, brainstem, and striatum, and cortex being intermediate. These differences can be explained at least in part by regional variations in receptor subunit and TARP expression because combinations prevalent in hippocampus (GluA2 with TARPs gamma3 and gamma8) exhibited E(max) values nearly twice those of combinations abundant in thalamus (GluA4 with gamma2 or gamma4). TARPs seem to be critical because GluA2 and GluA4 alone had comparable E(max) and also because hippocampal and thalamic receptors had similar E(max) after solubilization with Triton X-100, which probably removes associated proteins. Taken together, our data suggest that variations in physiological drug efficacy, such as the 3-fold difference previously seen in recordings from hippocampus versus thalamus, may be explained by region-specific expression of GluA1-4 as well as TARPs.

Physiological significance of high- and low-affinity agonist binding to neuronal and recombinant AMPA receptors.

Radioligand binding studies have shown that AMPA receptors exist in two variants that differ about twenty-fold in their binding affinities, with brain receptors being mainly of the low-affinity type and recombinantly expressed receptors having almost exclusively high affinity. However, the physiological correlate of high- and low-affinity binding is not yet known. In this study we examined if physiological experiments similarly reveal evidence for two distinct receptor variants. We therefore measured equilibrium desensitization by glutamate and determined IC(50) values for neuronal receptors and for the homomeric receptors GluR1-4 expressed in HEK293 cells. Contrary to the prediction that these IC(50) values exhibit large differences commensurate with those of high- and low-affinity binding, values for homomeric receptors (1-18 microM) were on an average not different from those of neuronal receptors (3-10 microM). Moreover, simulations with kinetic receptor models suggest that the IC(50) values for neuronal and recombinant receptors correspond to the binding affinity of the low-affinity receptor variant. These findings indicate that the high-affinity binding measured in heterologous expression systems represents an immature receptor variant that does not contribute to the currents recorded from these cells, and that the functional low-affinity receptors are present in such small number that they are effectively masked in binding assays by the high-affinity receptors. Thus, in order to compare experimentally determined saturation binding profiles with those predicted by kinetic receptor models and with dose-response curves from physiological studies, it will be imperative to develop methods for isolating first the low-affinity receptors.

Factors affecting guanine nucleotide binding to rat AMPA receptors.

Glutamate receptors are competitively inhibited by guanine nucleotides. Insight into the physiological function of this inhibition would be greatly advanced if nucleotide binding could be eliminated through mutations without altering other aspects of receptor function, or if compounds were discovered that selectively prevent nucleotide binding. It was previously reported that a lysine in the chick kainate binding protein (cKBP) is specifically involved in guanine nucleotide binding. In the present study we mutated the equivalent lysine in the rat AMPA receptor subunit GluR1 flip to alanine (K445A) and assessed changes in nucleotide affinity from the displacement of [(3)H]fluorowillardiine. As in the cKBP, the affinity for nucleotides was greatly reduced while the binding affinity for agonists remained unchanged. The reduction in affinity was largest for GTP (factor of 5.8) and GDP (4.4) and minor for GMP and guanosine. This suggests that K445 is involved in stabilizing the second phosphate of the nucleotide. Given that bulkier analogs like GDP-fucose are also accommodated at this site, it seems likely that nucleotides bind in such a way that their phosphates project out of the cleft. In excised-patch recordings using short pulses of glutamate, the K445A mutation increased the EC(50) for the peak response 1.8-fold and accelerated desensitization and deactivation. This indicates that the effects of this mutation are not as specific as previously suggested. Efforts to selectively eliminate inhibition by nucleotides may therefore depend on mapping out further the docking site. In a first attempt using point mutations we ruled out several amino acids around the cleft as being involved in nucleotide binding. Also, the AMPA receptor modulator PPNDS which competitively inhibits nucleotide binding to purinergic receptors did not affect nucleotide inhibition, suggesting that there are major differences in the topography between purinergic and glutamate receptors. Thus new approaches, including crystallography, may be called for to identify residues uniquely involved in nucleotide binding.

Macrophage-mediated lymphangiogenesis: the emerging role of macrophages as lymphatic endothelial progenitors.

It is widely accepted that macrophages and other inflammatory cells support tumor progression and metastasis. During early stages of neoplastic development, tumor-infiltrating macrophages (TAMs) mount an immune response against transformed cells. Frequently, however, cancer cells escape the immune surveillance, an event that is accompanied by macrophage transition from an anti-tumor to a pro-tumorigenic type. The latter is characterized by high expression of factors that activate endothelial cells, suppress immune response, degrade extracellular matrix, and promote tumor growth. Cumulatively, these products of TAMs promote tumor expansion and growth of both blood and lymphatic vessels that facilitate metastatic spread. Breast cancers and other epithelial malignancies induce the formation of new lymphatic vessels (i.e., lymphangiogenesis) that leads to lymphatic and subsequently, to distant metastasis. Both experimental and clinical studies have shown that TAMs significantly promote tumor lymphangiogenesis through paracrine and cell autonomous modes. The paracrine effect consists of the expression of a variety of pro-lymphangiogenic factors that activate the preexisting lymphatic vessels. The evidence for cell-autonomous contribution is based on the observed tumor mobilization of macrophage-derived lymphatic endothelial cell progenitors (M-LECP) that integrate into lymphatic vessels prior to sprouting. This review will summarize the current knowledge of macrophage-dependent growth of new lymphatic vessels with specific emphasis on an emerging role of macrophages as lymphatic endothelial cell progenitors (M-LECP).

Heterogeneous integration of InGaAs nanowires on the rear surface of Si solar cells for efficiency enhancement.

We demonstrate energy-conversion-efficiency (η) enhancement of silicon (Si) solar cells by the heterogeneous integration of an In(x)Ga(1-x)As nanowire (NW) array on the rear surface. The NWs are grown via a catalyst-free, self-assembled method on Si(111) substrates using metalorganic chemical vapor deposition (MOCVD). Heavily p-doped In(x)Ga(1-x)As (x ≈ 0.7) NW arrays are utilized as not only back-reflectors but also low bandgap rear-point-contacts of the Si solar cells. External quantum efficiency of the hybrid In(x)Ga(1-x)As NW-Si solar cell is increased over the entire solar response wavelength range; and η is enhanced by 36% in comparison to Si solar cells processed under the same condition without the NWs.

Fenbendazole treatment and litter size in rats.

Fenbendazole is commonly used in laboratory animal medicine as an anthelmintic for elimination of pinworms. It is generally regarded as a safe drug with minimal side effects. In our facility, 2 breeding colonies of rats were treated with fenbendazole to eliminate pinworms. Analysis of the breeding records revealed that feeding Sprague-Dawley rats a diet containing fenbendazole on a continuous basis for 7 consecutive weeks was associated with a significant reduction in litter size. Although the mechanism underlying this effect is unknown, the finding prompts caution when using fenbendazole to treat valuable breeding colonies or strains that are poor breeders.

Divergent effects of the purinoceptor antagonists suramin and pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Suramin is a large naphthyl-polysulfonate compound that inhibits an array of receptors and enzymes, and it has also been reported to block currents mediated by glutamate receptors. This study shows that suramin and several structurally related compounds [8,8'-[carbonylbis(imino-3,1-phenylenecarbonylamino)]bis-(1,3,5-naphthalenetrisulfonic acid), 6Na (NF023), 8,8'-(carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino))bis-1,3,5-naphthalenetrisulfonic acid, Na (NF279), and 4,4',4'',4'''-[carbonyl-bis[imino-5,1,3-benzenetriyl-bis-(carbonylimino)]]tetrakis-benzene-1,3-disulfonic acid, 8Na (NF449)] reduce binding of [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and [3H]fluorowillardiine to rat brain membranes and homomeric GluR1-4 receptors, with IC50 values in the range of 5 to 180 microM. Inhibition often was less than complete at saturating drug concentrations and thus seems to be noncompetitive in nature. Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) is a potent antagonist of purinoceptors that shares some structural elements with suramin yet is smaller than the latter. PPNDS also had potent effects on AMPA receptors (EC50 value of 4 microM) but of a kind not seen with the other compounds in that it increased binding affinity for radioagonists severalfold. In addition, PPNDS slowed association and dissociation rates more than 10 times. In physiological experiments with GluR2 receptors, PPNDS at 50 microM reduced the peak current by 30 to 50% but had only small effects on other waveform aspects such desensitization and steady-state currents. This pattern of effects differentiates PPNDS from other compounds such as thiocyanate and up-modulators, which increase agonist binding by enhancing desensitization or slowing deactivation, respectively. Receptor model simulations indicate that most effects can be accounted for by assuming that PPNDS slows agonist binding/unbinding and stabilizes the bound-closed state of the receptor. By extension, suramin is proposed to stabilize the unbound state and thereby to reduce affinity for agonists. These drugs thus act through a novel type of noncompetitive antagonism.