Advances in development of new tuberculosis vaccines.

PURPOSE OF REVIEW: Tuberculosis (TB) remains a global public health emergency and caused 1.6 million deaths in 2021. The aim of this review is to provide recent updates on advances in TB vaccine development for prevention and adjunct therapy. RECENT FINDINGS: Targets use indications guiding late stage TB vaccine development have been established, namely: (i) Prevention of disease (PoD), (ii) Prevention of recurrent disease (PoR), (iii) Prevention of established infection in previously uninfected patients (PoI), and (iv) Adjunctive immunotherapy. Novel approaches include vaccines designed to induce immune responses beyond established CD4+, Th1-biased T cell immunity, novel animal models for use in challenge/protection studies, and controlled human infection models to generate vaccine efficacy data. SUMMARY: Recent efforts at developing effective TB vaccines for prevention and adjunct treatment utilising new targets and technologies have yielded 16 candidate vaccines demonstrating proof of concept for inducing potentially protective immune responses to TB which is currently under evaluation in different stages of clinical trials.

An anchor-tether 'hindered' HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model.

BACKGROUND: Neuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain. Whilst 2,6-substituted phenols, such as 2,6-di-tert-butylphenol (26DTB-P), selectively inhibit HCN1 gating and are antihyperalgesic, the development of therapeutically tolerable, HCN-selective antihyperalgesics based on their inverse agonist activity requires that such drugs spare the cardiac isoforms and do not cross the blood-brain barrier. METHODS: In silico molecular dynamics simulation, in vitro electrophysiology, and in vivo rat spared nerve injury methods were used to test whether 'hindered' variants of 26DTB-P (wherein a hydrophilic 'anchor' is attached in the para-position of 26DTB-P via an acyl chain 'tether') had the desired properties. RESULTS: Molecular dynamics simulation showed that membrane penetration of hindered 26DTB-Ps is controlled by a tethered diol anchor without elimination of head group rotational freedom. In vitro and in vivo analysis showed that BP4L-18:1:1, a variant wherein a diol anchor is attached to 26DTB-P via an 18-carbon tether, is an HCN1 inverse agonist and an orally available antihyperalgesic. With a CNS multiparameter optimisation score of 2.25, a >100-fold lower drug load in the brain vs blood, and an absence of adverse cardiovascular or CNS effects, BP4L-18:1:1 was shown to be poorly CNS penetrant and cardiac sparing. CONCLUSIONS: These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.

Nicotinamide Riboside Improves Enteric Neuropathy in Streptozocin-Induced Diabetic Rats Through Myenteric Plexus Neuroprotection.

BACKGROUND: Diabetes Mellitus causes a systemic oxidative stress due in part to the hyperglycemia and the reactive oxygen species generated. Up to 75% of diabetic patients present with an autonomic neuropathy affecting the Enteric Nervous System. Deficits in the human population are chronic dysmotilities with either increased (i.e., constipation) or decreased (i.e., diarrhea) total gastrointestinal transit times. These are recapitulated in the streptozocin-induced diabetic rat, which is a model of Type I Diabetes Mellitus. AIMS: Examine the effects that a precursor of nicotinamide adenosine dinucleotide (NAD), nicotinamide riboside (NR), had on the development of dysmotility in induced diabetic rats and if fecal microbiota transplant (FMT) could produce the same results. MATERIALS AND METHODS: Utilizing a 6-week treatment paradigm, NR was administered intraperitoneally every 48 h. Total gastrointestinal transit time was assessed weekly utilizing the carmine red method. Three weeks following hyperglycemic induction, FMT was performed between NR-treated animals and untreated animals. SIGNIFICANT RESULTS: There is improvement in overall gastrointestinal transit time with the use of NR. 16S microbiome sequencing demonstrated decreased alpha and beta diversity in induced diabetic rats without change in animals receiving FMT. Improvements in myenteric plexus ganglia density in small and large intestines in diabetic animals treated with NR were seen. CONCLUSIONS: NR treatment led to functional improvement in total gastrointestinal transit time in induced diabetic animals. This was associated with neuroprotection in the myenteric plexuses of both small and large intestines of induced diabetic rats. This represents an important first step in showing NR's benefit as a treatment for diabetic enteric neuropathy. Streptozocin-induced diabetic rats have improved transit times and increased myenteric plexus ganglia density when treated with intraperitoneal nicotinamide riboside.

The effect of diabetes mellitus on outcomes of patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus: data from a prospective double-blind clinical trial comparing treatment with linezolid versus vancomycin.

BACKGROUND: The presence of diabetes mellitus increases the risk of several severe infections, but data on its effect on treatment outcomes in patients with nosocomial pneumonia (NP) caused by methicillin-resistant Staphylococcus aureus (MRSA) are limited. METHODS: We retrospectively analyzed data from a double-blind, randomized, multi-center, international clinical trial of culture-confirmed MRSA NP that compared treatment with linezolid to vancomycin. Specifically, we evaluated the clinical and microbiologic outcomes of patients with and without diabetes in the modified intent to treat population at end-of-treatment (EOT) and end-of-study (EOS, 7-30 days post-EOT). RESULTS: Among 448 enrolled patients 183 (40.8 %) had diabetes mellitus, 87 (47.5 %) of whom received linezolid and 96 (52.5 %) vancomycin. Baseline demographic and clinical characteristics were similar for the two treatment groups. Clinical success rates at EOS were 57.6 % with linezolid and 39.3 % with vancomycin, while microbiological success rates were 58.9 % with linezolid and 41.1 % with vancomycin. Among diabetic patients, rates of mortality and study drug-related adverse effects were similar between the treatment groups. Overall day 28 mortality rates were higher among diabetic patients compared to non-diabetic patients (23.5 vs 14.7 %, respectively: RD = 8.8 %, 95 % CI [1.4, 16.3]). CONCLUSIONS: Among diabetic patients with MRSA NP, treatment with linezolid, compared to vancomycin, was associated with higher clinical and microbiologic success rates, and comparable adverse event rates. TRIAL REGISTRATION: NCT00084266 .

Metabolic Profiling and Classification of Propolis Samples from Southern Brazil: An NMR-Based Platform Coupled with Machine Learning.

The chemical composition of propolis is affected by environmental factors and harvest season, making it difficult to standardize its extracts for medicinal usage. By detecting a typical chemical profile associated with propolis from a specific production region or season, certain types of propolis may be used to obtain a specific pharmacological activity. In this study, propolis from three agroecological regions (plain, plateau, and highlands) from southern Brazil, collected over the four seasons of 2010, were investigated through a novel NMR-based metabolomics data analysis workflow. Chemometrics and machine learning algorithms (PLS-DA and RF), including methods to estimate variable importance in classification, were used in this study. The machine learning and feature selection methods permitted construction of models for propolis sample classification with high accuracy (>75%, reaching ∼90% in the best case), better discriminating samples regarding their collection seasons comparatively to the harvest regions. PLS-DA and RF allowed the identification of biomarkers for sample discrimination, expanding the set of discriminating features and adding relevant information for the identification of the class-determining metabolites. The NMR-based metabolomics analytical platform, coupled to bioinformatic tools, allowed characterization and classification of Brazilian propolis samples regarding the metabolite signature of important compounds, i.e., chemical fingerprint, harvest seasons, and production regions.

Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review.

Gallstone (GS) disease is common and arises from a combination of genetic and environmental factors. Although genetic abnormalities specifically leading to cholesterol GSs are rare, there are clinically significant gene variants associated with cholesterol GSs. In contrast, most bilirubin GSs can be attributed to genetic defects. The pathogenesis of cholesterol and bilirubin GSs differs greatly. Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily, including ABCG8, ABCG5, ABCB4, and ABCB11, as well as genes from the apolipoprotein family such as ApoB100 and ApoE (especially the E3/E3 and E3/E4 variants), and members of the MUC family. Conversely, bilirubin GSs are associated with genetic variants in highly expressed hepatic genes, notably UGT1A1, ABCC2 (MRP2), ABCC3 (MRP3), CFTR, and MUC, alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis. While genetic cases constitute a small portion of GS disease, recognizing genetic predisposition is essential for proper diagnosis, treatment, and genetic counseling.

Perspectives on development and advancement of new tuberculosis vaccines.

Tuberculosis (TB) remains a leading cause of death worldwide and is estimated to have caused 1.3 million deaths worldwide in 2022. Approximately one quarter of the world's population are infected with Mycobacterium tuberculosis, of whom up to 10% will progress to developing active TB disease. Achieving the World Health Organization End TB Strategy targets of a 95% reduction in TB mortality and a 90% reduction in TB incidence worldwide by 2035 remains a daunting task. The continuing spread of multidrug-resistant TB adds another obstacle to achieving global TB control. Larger funding pledges coupled with technological advances have recently enabled the enhancement of TB vaccine development efforts. These are yielding a pipeline of over 17 products currently in different stages of clinical trials. Emerging promising phase I and II trial results and advancement to phase III trials have necessitated "vaccine preparedness" in parallel so that a smooth transition from any positive clinical trial result to phase IV evaluation and implementation into policy and practice can follow. Promotion of a human rights-based approach, which recognizes and upholds the fundamental rights of all affected by the disease, is essential to ensure universal access to quality TB vaccines, regardless of their background or personal circumstances.

The ACL in the arthritic knee: how often is it present and can preoperative tests predict its presence?

BACKGROUND: TKA with retention of the anterior cruciate ligament (ACL) may improve kinematics and function. However, conflicting reports exist concerning the prevalence of intact ACLs at the time of TKA. QUESTIONS/PURPOSES: Therefore, we asked: (1) what was the ACL status at TKA; (2) what was the sensitivity and specificity of the Lachman test; (3) did MRI ACL integrity correlate with intraoperative observation; (4) did MRI tibial wear patterns correlate with ACL integrity; and (5) did ACL status depend on age or sex? METHODS: We evaluated 200 patients for ACL integrity at the time of TKA. All patients underwent a Lachman test under anesthesia. Intraoperatively, the ACL was characterized as intact, frayed, disrupted, or absent. In 100 patients, MRIs were performed, from which the ACL was graded as intact, indeterminate, or disrupted, and the AP location of tibial wear was categorized. RESULTS: The ACL was intact in 155 patients (78%). The Lachman test alone had poor diagnostic ability. The MRI predicted a tear, but we observed two ACLs with indeterminate status that were disrupted. All knees with anterior wear on the medial tibial condyle had an intact ACL (n = 45), and all knees with posterior wear on the medial tibial condyle had a disrupted ACL (n = 8). CONCLUSIONS: Although the Lachman test alone had poor sensitivity, when combined with MRI they together provide a sensitivity of 93.3% and specificity of 99%, which we believe makes these reasonable tests for assessing ACL status in the arthritic knee.

Critical review of minimally invasive approaches in knee arthroplasty.

Despite high survivorship for total knee arthroplasty, many reports have described low patient-satisfaction rates. Standard parapatellar approaches have been linked with decreased quadriceps muscle strength, which may in turn lead to prolonged rehabilitation and altered kinematics. Although technically demanding, minimally invasive techniques offer the potential for shorter recovery times and improved strength. Our purpose was to compare perioperative factors, the clinical and radiographic outcomes, complications, and survivorship of several minimally invasive approaches to each other and to the conventional medial parapatellar approach. A total of 23 level I or II studies were reviewed. There were no statistically significant differences in perioperative factors, clinical or radiographic outcomes, survivorship, or complication rates between patients the various minimally invasive approaches to a standard approach. The only significant difference observed was in recovery of quadriceps muscle function (shorter in patients who had a minimally invasive approach). The minimally invasive lateral approach had more complications than the other minimally invasive approaches. The mini-midvastus approach had the best clinical outcomes at 1 and 3 months when compared with other minimally invasive approaches and standard approaches. The mini-subvastus approach had the lowest rate of complications, overall. Further multicenter randomized trials are needed to determine the minimally invasive approach that best improves outcomes while minimizing complications.

COVID-19 risk perception, cognitive dissonance, and vaccine hesitancy.

The COVID-19 pandemic has shown that despite having high risk for severe disease, some individuals had low-risk perception and consequently they refused vaccination. This was more common among individuals with distrust in the government and the scientific organizations. Cognitive dissonance occurs when a person participates in an action that goes against one's beliefs. In order to reduce the dissonance, the individual often avoids the action. Recently, dissonance-based interventions have been shown to be effective in changing various health, environmental, and social behaviors. The impact of these interventions may persist for several years. Cognitive dissonance may be another mechanism for vaccine refusal among people with mistrust in the system. There is a need to investigate the role of cognitive dissonance in vaccine refusal and the effectiveness of dissonance-based interventions to reduce vaccine hesitancy among individuals with high risk for severe disease and low vaccination rates.

Probucol is anti-hyperalgesic in a mouse peripheral nerve injury model of neuropathic pain.

2,6-di-tert-butylphenol (2,6-DTBP) ameliorates mechanical allodynia and thermal hyperalgesia produced by partial sciatic nerve ligation in mice, and selectively inhibits HCN1 channel gating. We hypothesized that the clinically utilized non-anesthetic dimerized congener of 2,6-DTBP, probucol (2,6-di-tert-butyl-4-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)sulfanylpropan-2-ylsulfanyl]phenol), would relieve the neuropathic phenotype that results from peripheral nerve damage, and that the anti-hyperalgesic efficacy in vivo would correlate with HCN1 channel inhibition in vitro. A single oral dose of probucol (800 mg/kg) relieved mechanical allodynia and thermal hyperalgesia in a mouse spared-nerve injury neuropathic pain model. While the low aqueous solubility of probucol precluded assessment of its possible interaction with HCN1 channels, our results, in conjunction with recent data demonstrating that probucol reduces lipopolysaccharide-induced mechanical allodynia and thermal hyperalgesia, support the testing/development of probucol as a non-opioid, oral antihyperalgesic albeit one of unknown mechanistic action.

Use of cementless, tapered femoral stems in patients who have a mean age of 20 years.

Young patients who undergo total hip arthroplasty are a unique group who has been challenging to successfully treat; however, newer prosthetic materials and designs have the potential to increase implant longevity. Fifty-three hips (40 patients who had a mean age of 20 years) underwent a total hip arthroplasty using a cementless, proximally hydroxyapatite-coated, tapered, femoral stem and a cementless acetabular cup. There was a 96% overall survivorship at approximately 5 years of mean follow-up (range, 2-7 years) with no femoral side failures. Younger patients undergoing total hip arthroplasty with newer component designs and materials may have similar excellent outcomes to older patients.

New technologies in knee arthroplasty.

Advances in surgical technique and implant design have increased the treatment options available to joint reconstruction surgeons. New technologies for component alignment such as custom cutting blocks and disposable cutting blocks hold the potential for more anatomic component positioning and less instrument turnover which may decrease infection rates. Improved component alignment may also be obtained with the use of computer-assisted surgery. Utilization of bone-sparing designs such as patellofemoral, unicompartmental, and bicompartmental knee arthroplasty allow for the surgeon to customize treatment based on patient symptoms by addressing each compartment individually. Gender-specific designs may be useful in the setting of populations which deviate from standard dimensions that are available in traditional unisex designs. New higher-conforming bearing designs such as rotating platform bearings allow for more natural knee kinematics, while also limiting polyethylene wear by decreasing contact stress. Newer interfaces for cementless fixation utilizing porous coated surfaces allows for biologic component fixation which has the potential to increase interface durability and implant survivorship. These new materials, designs, and techniques are challenging the traditional "gold standard" cemented total knee arthroplasty and have the potential for developing a more durable and naturally feeling prosthetic knee. Further study is required to identify which patients are most appropriate for each new technology.

Do we need gender-specific total joint arthroplasty?

BACKGROUND: Gender-specific differences in knee and hip anatomy have been well documented. Although it has been accepted these differences exist, there is controversy regarding if and how these differences should be addressed with gender-specific implant designs. QUESTIONS/PURPOSES: (1) What are the anatomic and morphologic differences, if any, in the knee and hip between men and women? (2) Do gender-specific TKA designs provide better clinical functioning, survivorship, and improved fit in women? (3) How have anatomic differences in the hip been addressed, if at all, by THA? METHODS: We conducted a systematic review of the MEDLINE database to identify all articles reviewing basic science and clinical outcomes of gender-specific total knee and total hip implants. From these, we reviewed 253 studies. RESULTS: The anatomic studies elucidated multiple differences in the anatomy of knees and hips between men and women. All reviewed studies report similar clinical function and satisfaction scores between men and women for gender-specific TKA and no improvement in these scores when comparing gender-specific TKA to unisex TKA. Current modularity in THA appears to accommodate any anatomic differences in the hip. CONCLUSIONS: Based on the available literature, there is no difference in the outcome of patients with a gender-specific knee arthroplasty versus a unisex arthroplasty. It does not appear gender-specific THAs would provide any benefit over current systems.

Results of MIS TKA at mean nine year follow-up.

The first 103 consecutive minimally invasive total knee arthroplasties performed by a single surgeon were assessed to determine the clinical and radiographic outcomes at a mean of 9-year follow-up (range, 8 to 10 years). Patients who died before final follow-up were 10 (13 knees), leaving 90 knees in 69 patients for final review. Outcome was evaluated using Knee Society pain and functional scores. Survival with revision as an end point was 97.1%. Knee Society scores and range of motion improved significantly to a mean of 96 and 92 points and a mean of 115 degrees, respectively. There were five patients who required surgical intervention for unexplained pain with findings of retained cement and adhesions. Radiographic analysis did not reveal any progressive radiolucencies. These results suggest that excellent long-term outcomes can be achieved with minimally invasive total knee arthroplasty.

Unicompartmental and total knee arthroplasty in the same patient.

This prospective randomized study compared the clinical and radiographic outcomes of unicompartmental knee arthroplasty versus total knee arthroplasty. The group consisted of 34 patients (19 males and 15 females), who had a mean age of 73 years (range, 49 to 86 years), and who fit the criteria for bilateral unicompartmental knee arthroplasty. Each patient received a unicompartmental prosthesis in one knee and a total knee arthroplasty in the other during a single anesthetic session. At a mean follow-up of 5 years (range, 24 to 89 months), the Knee Society pain and function scores were similar for both groups. There were no radiographic failures. Survivorship of the unicompartmental group was 85% compared with 100% in the total knee group (p = 0.05). All of the prostheses that failed had an all-polyethylene tibial component. These results suggest that unicompartmental knee arthroplasty may not offer similar survivorship when compared with total knee arthroplasty.

A Comparison Study of Two Cruciate-Retaining Total Knee Designs: A Preliminary Report.

Cruciate-retaining total knee arthroplasties have had high success rates. The purpose of this study was to compare a newer cruciate-retaining design to a previously used implant to determine if there were any changes in clinical or functional outcome. A total of 461 patients (553 knees) were identified who had total knee arthroplasty with this newer design. At latest 2-year follow-up, the mean range of motion was 121 degrees (range 105 to 140 degrees), the mean Knee Society pain score was 91 points (range, 57 to 100 points) and the functional score was 76 points (45 to 100 points). The comparison group of 211 patients (225 knees) had a mean range of motion of 119 degrees at 2 years (range, 90 to 142 degrees) with Knee Society pain and functional scores of 95 and 85 points, respectively (ranges 57 to 100, and 0 to 100, respectively). The use of the newer cruciate-retaining total knee arthroplasty showed comparable results to the previously used design at short-term follow-up. The cruciate-retaining design used in this study had no early failures, though further study is needed to make assessments regarding longer-term functional results and outcomes.

Failure to Upregulate the RNA Binding Protein ZBP After Injury Leads to Impaired Regeneration in a Rodent Model of Diabetic Peripheral Neuropathy.

Most diabetes patients eventually suffer from peripheral nerve degeneration. Unfortunately, there is no treatment for the condition and its mechanisms are not well understood. There is, however, an emerging consensus that the inability of peripheral nerves to regenerate normally after injury contributes to the pathophysiology. We have previously shown that regeneration of peripheral axons requires local axonal translation of a pool of axonal mRNAs and that the levels and members of this axonal mRNA pool are altered in response to injury. Here, we show that following sciatic nerve injury in a streptozotocin rodent model of type I diabetes, this mobilization of RNAs into the injured axons is attenuated and correlates with decreased axonal regeneration. This failure of axonal RNA localization results from decreased levels of the RNA binding protein ZBP1. Over-expression of ZBP1 rescues the in vitro growth defect in injured dorsal root ganglion neurons from diabetic rodents. These results provide evidence that decreased neuronal responsiveness to injury in diabetes is due to a decreased ability to alter the pool of axonal mRNAs available for local translation, and may open new therapeutic opportunities for diabetic peripheral neuropathy.

Addressing and Inspiring Vaccine Confidence in Black, Indigenous, and People of Color During the Coronavirus Disease 2019 Pandemic.

During the coronavirus disease 2019 (COVID-19) pandemic, we have witnessed profound health inequities suffered by Black, Indigenous, and People of Color (BIPOC). These manifested as differential access to testing early in the pandemic, rates of severe disease and death 2-3 times higher than white Americans, and, now, significantly lower vaccine uptake compared with their share of the population affected by COVID-19. This article explores the impact of these COVID-19 inequities (and the underlying cause, structural racism) on vaccine acceptance in BIPOC populations, ways to establish trustworthiness of healthcare institutions, increase vaccine access for BIPOC communities, and inspire confidence in COVID-19 vaccines.