Effect of Anisotropic Brain Conductivity on Patient-Specific Volume of Tissue Activation in Deep Brain Stimulation for Parkinson Disease.

OBJECTIVE: Deep brain stimulation (DBS) modeling can improve surgical targeting by quantifying the spatial extent of stimulation relative to subcortical structures of interest. A certain degree of model complexity is required to obtain accurate predictions, particularly complexity regarding electrical properties of the tissue around DBS electrodes. In this study, the effect of anisotropy on the volume of tissue activation (VTA) was evaluated in an individualized manner. METHODS: Tissue activation models incorporating patient-specific tissue conductivity were built for 40 Parkinson disease patients who had received bilateral subthalamic nucleus (STN) DBS. To assess the impact of local changes in tissue anisotropy, one VTA was computed at each electrode contact using identical stimulation parameters. For comparison, VTAs were also computed assuming isotropic tissue conductivity. Stimulation location was considered by classifying the anisotropic VTAs relative to the STN. VTAs were characterized based on volume, spread in three directions, sphericity, and Dice coefficient. RESULTS: Incorporating anisotropy generated significantly larger and less spherical VTAs overall. However, its effect on VTA size and shape was variable and more nuanced at the individual patient and implantation levels. Dorsal VTAs had significantly higher sphericity than ventral VTAs, suggesting more isotropic behavior. Contrastingly, lateral and posterior VTAs had significantly larger and smaller lateral-medial spreads, respectively. Volume and spread correlated negatively with sphericity. CONCLUSION: The influence of anisotropy on VTA predictions is important to consider, and varies across patients and stimulation location. SIGNIFICANCE: This study highlights the importance of considering individualized factors in DBS modeling to accurately characterize the VTA.

Intrinsic auricular muscle zone stimulation for Parkinson disease: The EARSTIM-PD Phase II multi-center pilot study results.

BACKGROUND: Studies have suggested that intrinsic auricular muscle zones (IAMZ) stimulation alleviates motor features of Parkinson disease (PD). METHODS: A randomized, blinded, active sham-controlled pilot trial was conducted to evaluate the safety and dose-response-time curve of Earstim using a 3-treatment, 3-period crossover design in PD patients experiencing OFF time on levodopa. Treatments were: short (20-min) IAMZ stimulation; long (60-min) IAMZ stimulation; and 20-min active sham stimulation of non-muscular areas. Assessment time points were: prior to treatment, and 20, 40, 60, 90, and 120 min after treatment onset. Primary safety endpoints were adverse events frequency and severity. Primary efficacy endpoint was the change in MDS-UPDRS motor score at 20 min after treatment onset in the IAMZ treatment groups versus sham. RESULTS: Forty-six individuals consented; 38 were randomized (average age 64 years, 65 % male, mean 8.2 years from diagnosis). No serious adverse events or significant device-related events occurred. At 20 min after treatment onset, motor improvements did not differ between IAMZ treatments versus sham. However, at 60 min after treatment onset, motor improvement peaked on IAMZ treatments compared to sham (difference: 3.1 [-5.9 to 0.3], p = 0.03). While the difference in 120-min AUC change between IAMZ treatments versus sham was not significant, the short-stimulation IAMZ treatment showed the largest aggregate motor score improvement (AUC = -456 points, 95 % CI -691 to -221) compared to sham. CONCLUSION: Earstim was well-tolerated. The greatest motor improvement occurred at 60 min after stimulation onset in the short-stimulation IAMZ treatment, and supports its further study to alleviate OFF periods.

Impact of subthalamic nucleus stimulation on urinary dysfunction and constipation in Parkinson's disease.

OBJECTIVE: The effect of subthalamic nucleus (STN) deep brain stimulation (DBS) on urinary dysfunction and constipation in Parkinson's disease (PD) is variable. This study aimed to identify potential surgical and nonsurgical variables predictive of these outcomes. METHODS: The authors used the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I to assess urinary dysfunction (item 10) and constipation (item 11) preoperatively and at 6-12 months postoperatively. A multiple linear regression model was used to investigate the impact of global cerebral atrophy (GCA) and active electrode contact location on the urinary dysfunction and constipation follow-up scores, controlling for age, disease duration, baseline score, motor improvement, and levodopa-equivalent dose changes. An electric field model was applied to localize the maximal-effect sites for constipation and urinary dysfunction compared with those for motor improvement. RESULTS: Among 74 patients, 23 improved, 28 deteriorated, and 23 remained unchanged for urinary dysfunction; 25 improved, 15 deteriorated, and 34 remained unchanged for constipation. GCA score and age significantly predicted urinary dysfunction follow-up score (R2 = 0.36, p < 0.001). Increased GCA and age were independently associated with worsening urinary symptoms. Disease duration, baseline constipation score, and anterior active electrode contacts in both hemispheres were significant predictors of constipation follow-up score (R2 = 0.31, p < 0.001). Higher baseline constipation score and disease duration were associated with worsening constipation; anterior active contact location was associated with improvement in constipation. CONCLUSIONS: Anterior active contact location was associated with improvement in constipation in PD patients after STN DBS. PD patients with greater GCA scores before surgery were more likely to experience urinary deterioration after DBS.

Look-alike medications in the perioperative setting: scoping review of medication incidents and risk reduction interventions.

BACKGROUND: Look-alike medications, where ampoules or vials of intravenous medications look similar, may increase the risk of medication errors in the perioperative setting. AIM: This scoping review aimed to identify and explore the issues related to look-alike medication incidents in the perioperative setting and the reported risk reduction interventions. METHOD: Eight databases were searched including: CINAHL Complete, Embase, OVID Emcare, Pubmed, Scopus, Informit, Cochrane and Prospero and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR). Key search terms included anaesthesia, adverse drug event, drug error or medication error, look alike sound alike, operating theatres and pharmacy. Title and abstracts were screened independently and findings were extracted using validated tools in collaboration and consensus with co-authors. RESULTS: A total of 2567 records were identified to 4th July 2022; however only 18 publications met the inclusion criteria. Publication types consisted of case reports, letters to the editor, multimodal quality improvement activities or survey/audits, a controlled simulation study and one randomised clinical trial. Risk reduction intervention themes identified included regulation, procurement, standardisation of storage, labelling, environmental factors, teamwork factors and the safe administration. CONCLUSION: This review highlighted challenges with look-alike medications in the perioperative setting and identified interventions for risk reduction. Key interventions did not involve technology-based solutions and further research is required to assess their effectiveness in preventing patient harm.

The Black Men's Health Forum: Improving Health Knowledge and Willingness to Participate in Research.

The Black Men's Health Forum, a 6-week online health education intervention for African American men and accountability partners of African American men, was conducted to increase awareness of health issues that disproportionately affect African American men. In this article, we describe the intervention and report on the immediate benefits of the intervention, including changes in health knowledge and perception of research participation. Participants completed a pre-evaluation prior to participating in the forum and a post-evaluation after each session to capture data on sociodemographic information, medical history, health knowledge, and health behaviors. A total of 60 participants (30 African American men and 30 accountability partners) completed the forum. African American men had a mean age of 61.1 years while accountability partners had a mean age of 57.6 years. Overall health knowledge increased by 6.9 points for African American men and 2.8 points for accountability partners. Before the forum began, nine African American men reported ever participating in a research study. The proportion of African American men who reported that they would definitely participate in research in the next 12 months after participating in the forum increased by 40%. Through culturally tailored programming, the Black Men's Health Forum increased access to health information as well as African American male medical professionals and health researchers for African American men in the community. Exposure to health information resulted in significant increases in health knowledge and willingness to participate in health research among African American men.

Biological evaluation of indolactams for in vitro bryostatin 1-like activity.

Small molecule activators of protein kinase C (PKC) have traditionally been classified as either tumor promoters or suppressors. Although bryostatin 1 has well established anti-cancer activity, most natural products that target the PKC regulator domain exhibit tumor promotion properties. In this study, we examine a focused library of indolactam analogues in cell-based assays to establish the structural features of the scaffold that enhance bryostatin 1-like activity. These systematic biological assessments identified specific indole substitution patterns that impart diminished tumor promotion behavior in vitro for indolactam analogues, while still maintaining nanomolar potency for PKC.

Dorsal subthalamic deep brain stimulation improves pain in Parkinson's disease.

Introduction: Inconsistent effects of subthalamic deep brain stimulation (STN DBS) on pain, a common non-motor symptom of Parkinson's disease (PD), may be due to variations in active contact location relative to some pain-reducing locus of stimulation. This study models and compares the loci of maximal effect for pain reduction and motor improvement in STN DBS. Methods: We measured Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) Part I pain score (item-9), and MDS-UPDRS Part III motor score, preoperatively and 6-12 months after STN DBS. An ordinary least-squares regression model was used to examine active contact location as a predictor of follow-up pain score while controlling for baseline pain, age, dopaminergic medication, and motor improvement. An atlas-independent isotropic electric field model was applied to distinguish sites of maximally effective stimulation for pain and motor improvement. Results: In 74 PD patients, mean pain score significantly improved after STN DBS (p = 0.01). In a regression model, more dorsal active contact location was the only significant predictor of pain improvement (R2 = 0.17, p = 0.03). The stimulation locus for maximal pain improvement was lateral, anterior, and dorsal to that for maximal motor improvement. Conclusion: STN stimulation, dorsal to the site of optimal motor improvement, improves pain. This region contains the zona incerta, which is known to modulate pain in humans, and may explain this observation.

Predictors of Cognitive Change in Parkinson Disease: A 2-year Follow-up Study.

BACKGROUND: Mild cognitive impairment is common in Parkinson disease (PD-MCI). However, instability in this clinical diagnosis and variability in rates of progression to dementia raises questions regarding its utility for longitudinal tracking and prediction of cognitive change in PD. We examined baseline neuropsychological test and cognitive diagnosis predictors of cognitive change in PD. METHODS: Persons with PD, without dementia PD (N=138) underwent comprehensive neuropsychological assessment at baseline and were followed up to 2 years. Level II Movement Disorder Society criteria for PD-MCI and PD dementia (PDD) were applied annually. Composite global and domain cognitive z -scores were calculated based on a 10-test neuropsychological battery. RESULTS: Baseline diagnosis of PD-MCI was not associated with a change in global cognitive z -scores. Lower baseline attention and higher executive domain z -scores were associated with greater global cognitive z -score worsening regardless of cognitive diagnosis. Worse baseline domain z -scores in the attention and language domains were associated with progression to MCI or PDD, whereas higher baseline scores in all cognitive domains except executive function were associated with clinical and psychometric reversion to "normal" cognition. CONCLUSIONS: Lower scores on cognitive tests of attention were predictive of worse global cognition over 2 years of follow-up in PD, and lower baseline attention and language scores were associated with progression to MCI or PDD. However, PD-MCI diagnosis per se was not predictive of cognitive decline over 2 years. The association between higher executive domain z -scores and greater global cognitive worsening is probably a spurious result.

Gender, Age and COVID-19 Vaccination Status in African American Adult Faith-Based Congregants in the Southeastern United States.

OBJECTIVES: The COVID-19 pandemic has revealed significant differences in COVID-19 vaccination rates, with African Americans reporting lower rates compared to other racial and ethnic groups. The purpose of these analyses was to assess whether COVID-19 vaccination status differed according to age in a sample of 1,240 African American adult congregants of faith-based organizations ages 18 years or older, and to examine whether this association was moderated by gender. DESIGN: We developed and administered a 75-item cross-sectional survey, the Triad Pastor's Network COVID-19 and COVID-19 Vaccination survey, to assess experiences and perceptions regarding the COVID-19 virus and vaccines. We assessed the association between age and having received > 1 dose of a COVID-19 vaccine using unadjusted and multivariable binary logistic regression models, and the interaction of age and gender with COVID-19 vaccination status in a multivariable model. RESULTS: Approximately 86% of participants reported having received ≥ 1 dose of a COVID-19 vaccine. The mean age (standard deviation) of the sample was 51.33 (16.62) years, and 70.9% of the sample was comprised of women. The age by gender interaction term in the multivariable model was significant (p = 0.005), prompting additional analyses stratified by gender. In women, increased age was significantly associated with higher odds of COVID-19 vaccination (odds ratio = 1.09; 95% Confidence Interval 1.06, 1.11; p < 0.001). In men, the association was not significant (p = 0.44). CONCLUSIONS: Older age was positively associated with COVID-19 vaccination in African American women, but not African American men, which may inform strategies to increase vaccination rates.

Hyperpolarized [1-13C]Acetyl-l-Carnitine Probes Tricarboxylic Acid Cycle Activity In Vivo.

Mitochondrial oxidative phosphorylation (OXPHOS) is sensitive to a variety of biological factors, and dysregulated OXPHOS is observed during the development of numerous pathological conditions. ATP production via OXPHOS is intrinsically dependent on the availability of acetyl-coenzyme A (CoA), which can enter the tricarboxylic acid (TCA) cycle to drive the oxidative pathway. Acetyl-l-carnitine (ALCAR) is an interchangeable endogenous source of acetyl-CoA, and therefore, ALCAR-derived probes are uniquely positioned for the assessment of OXPHOS. In this report, we develop hyperpolarized (HP) [1-13C]ALCAR as a noninvasive probe to investigate cardiac TCA cycle activity in vivo. We initially synthesized the isotopically labeled substrate and demonstrated that the 13C nucleus maintained a suitable T1 value (50.1 ± 0.8 s at 3 T) and polarization levels (21.3 ± 5.3%) to execute in vivo metabolic measurements. HP [1-13C]ALCAR was employed for cardiac analyses of OXPHOS in rats under fed and fasted conditions. [5-13C]Glutamate was successfully detected, and the metabolite was used to analyze the TCA cycle activity in both nutritional states. These assessments were compared to analogous experiments with the HP [1-13C]pyruvate. Our report represents the first study to demonstrate that HP methods using [1-13C]ALCAR enable direct analyses of mitochondrial function and TCA cycle activity, which are fundamental to cardiac cell homeostasis.

Effectiveness of Area-to-Value Legends and Grid Lines in Contiguous Area Cartograms.

A contiguous area cartogram is a geographic map in which the area of each region is proportional to numerical data (e.g., population size) while keeping neighboring regions connected. In this study, we investigated whether value-to-area legends (square symbols next to the values represented by the squares' areas) and grid lines aid map readers in making better area judgments. We conducted an experiment to determine the accuracy, speed, and confidence with which readers infer numerical data values for the mapped regions. We found that, when only informed about the total numerical value represented by the whole cartogram without any legend, the distribution of estimates for individual regions was centered near the true value with substantial spread. Legends with grid lines significantly reduced the spread but led to a tendency to underestimate the values. Comparing differences between regions or between cartograms revealed that legends and grid lines slowed the estimation without improving accuracy. However, participants were more likely to complete the tasks when legends and grid lines were present, particularly when the area units represented by these features could be interactively selected. We recommend considering the cartogram's use case and purpose before deciding whether to include grid lines or an interactive legend.

Localization of deep brain stimulation trajectories via automatic mapping of microelectrode recordings to MRI.

Objective. Suboptimal electrode placement during subthalamic nucleus deep brain stimulation (STN DBS) surgery may arise from several sources, including frame-based targeting errors and intraoperative brain shift. We present a computer algorithm that can accurately localize intraoperative microelectrode recording (MER) tracks on preoperative magnetic resonance imaging (MRI) in real-time, thereby predicting deviation between the surgical plan and the MER trajectories.Approach. Random forest (RF) modeling was used to derive a statistical relationship between electrophysiological features on intraoperative MER and voxel intensity on preoperative T2-weighted MR imaging. This model was integrated into a larger algorithm that can automatically localize intraoperative MER recording tracks on preoperative MRI in real-time. To verify accuracy, targeting error of both the planned intraoperative trajectory ('planned') and the algorithm-derived trajectory ('calculated') was estimated by measuring deviation from the final DBS lead location on postoperative high-resolution computed tomography ('actual').Main results. MR imaging and MERs were obtained from 24 STN DBS implant trajectories. The cross-validated RF model could accurately distinguish between gray and white matter regions along MER trajectories (AUC 0.84). When applying this model within the localization algorithm, thecalculatedMER trajectory estimate was found to be significantly closer to theactualDBS lead when compared to theplannedtrajectory recorded during surgery (1.04 mm vs 1.52 mm deviation,p< 0.002), with improvement shown in 19/24 cases (79%). When applying the algorithm to simulated DBS trajectory plans with randomized targeting error, up to 4 mm of error could be resolved to <2 mm on average (p< 0.0001).Significance. This work presents an automated system for intraoperative localization of electrodes during STN DBS surgery. This neuroengineering solution may enhance the accuracy of electrode position estimation, particularly in cases where high-resolution intraoperative imaging is not available.

Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition.

Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, resembling developmental connection specificity. These results offer confidence in stem cell-based therapy for epilepsy as a safe and reliable treatment for patients suffering from intractable epilepsy.

Gene expression differentials driven by mass rearing and artificial selection in black soldier fly colonies.

The micro-evolutionary forces that shape genetic diversity during domestication have been assessed in many plant and animal systems. However, the impact of these processes on gene expression, and consequent functional adaptation to artificial environments, remains under-investigated. In this study, whole-transcriptome dynamics associated with the early stages of domestication of the black soldier fly (BSF), Hermetia illucens, were assessed. Differential gene expression (DGE) was evaluated in relation to (i) generational time within the cultured environment (F2 vs. F3), and (ii) two selection strategies [no artificial selective pressure (NS); and selection for greater larval mass (SEL)]. RNA-seq was conducted on 5th instar BSF larvae (n = 36), representing equal proportions of the NS (F2 = 9; F3 = 9) and SEL (F2 = 9; F3 = 9) groups. A multidimensional scaling plot revealed greater gene expression variability within the NS and F2 subgroups, while the SEL group clustered separately with lower levels of variation. Comparisons between generations revealed 898 differentially expressed genes (DEGs; FDR-corrected p < 0.05), while between selection strategies, 213 DEGs were observed (FDR-corrected p < 0.05). Enrichment analyses revealed that metabolic, developmental, and defence response processes were over-expressed in the comparison between F2 and F3 larvae, while metabolic processes were the main differentiating factor between NS and SEL lines. This illustrates the functional adaptations that occur in BSF colonies across generations due to mass rearing; as well as highlighting genic dynamics associated with artificial selection for production traits that might inform future selective breeding strategies.

Thalamic Segmentation and Neural Activation Modeling Based on Individual Tissue Microstructure in Deep Brain Stimulation for Essential Tremor.

OBJECTIVE: Thalamic deep brain stimulation (DBS) is the primary surgical therapy for essential tremor (ET). Thalamic DBS traditionally uses an atlas-based targeting approach, which, although nominally accurate, may obscure individual anatomic differences from population norms. The objective of this study was to compare this traditional atlas-based approach with a novel quantitative modeling methodology grounded in individual tissue microstructure (N-of-1 approach). MATERIALS AND METHODS: The N-of-1 approach uses individual patient diffusion tensor imaging (DTI) data to perform thalamic segmentation and volume of tissue activation (VTA) modeling. For each patient, the thalamus was individually segmented into 13 nuclei using DTI-based k-means clustering. DBS-induced VTAs associated with tremor suppression and side effects were then computed for each patient with finite-element electric-field models incorporating DTI microstructural data. Results from N-of-1 and traditional atlas-based modeling were compared for a large cohort of patients with ET treated with thalamic DBS. RESULTS: The size and shape of individual N-of-1 thalamic nuclei and VTAs varied considerably across patients (N = 22). For both methods, tremor-improving therapeutic VTAs showed similar overlap with motor thalamic nuclei and greater motor than sensory nucleus overlap. For VTAs producing undesirable sustained paresthesia, 94% of VTAs overlapped with N-of-1 sensory thalamus estimates, whereas 74% of atlas-based segmentations overlapped. For VTAs producing dysarthria/motor contraction, the N-of-1 approach predicted greater spread beyond the thalamus into the internal capsule and adjacent structures than the atlas-based method. CONCLUSIONS: Thalamic segmentation and VTA modeling based on individual tissue microstructure explain therapeutic stimulation equally well and side effects better than a traditional atlas-based method in DBS for ET. The N-of-1 approach may be useful in DBS targeting and programming, particularly when patient neuroanatomy deviates from population norms.

Perceived social support declines after deep brain stimulation surgery in patients with Parkinson's disease.

INTRODUCTION: The Social Provisions Scale (SPS) measures a person's perceived social support. We evaluated the perceived social support in Parkinson's disease (PD) patients before and after subthalamic nucleus (STN) deep brain stimulation (DBS) and its impact on clinical outcomes following DBS. METHODS: We analyzed 55 PD patients who underwent STN DBS surgery and completed the SPS, PDQ-39, and MDS-UPDRS Parts I-IV before and 6-12 months after surgery. Some patients also completed global cognitive, mood and apathy scales. Caregivers completed the CBI at each visit. Linear regression models and linear mixed models evaluated the association between the SPS baseline score, MDS-UPDRS and PDQ-39 scores, the association between MDS-UPDRS, CBI and the SPS follow-up score, and the association between SPS, global cognition and other psychological variables. RESULTS: DBS implantation improved MDS-UPDRS I-IV and PDQ-39 scores. Perceived social support declined after DBS (baseline SPS total 82.55 ± 7.52 vs. follow-up SPS total 78.83 ± 9.02, p = 0.0001). Baseline SPS total score was not significantly associated with the MDS-UPDRS or PDQ-39 scores at follow-up. MDS-UPDRS scores and the CBI at follow-up had no significant association with SPS total score at follow-up. Measures of global cognition, mood and apathy were associated with the SPS before and after DBS, and the association was independent of STN DBS. CONCLUSION: After STN DBS, PD patients experienced a decrease in perceived social support, but baseline perceived social support did not impact clinical outcomes. It is important to further identify factors that may contribute to this perception of worsened social support.

Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson's Disease.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized. OBJECTIVES: To use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD. METHODS: We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest. RESULTS: Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD. CONCLUSIONS: Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Antimicrobial resistance of Neisseria gonorrhoeae isolated from patients attending sexually transmitted infection clinics in Urban Hospitals, Lusaka, Zambia.

BACKGROUND: Neisseria gonorrhoeae, the causative agent for sexually transmitted infection (STI) gonorrhoea, has emerged with a significant public health impact on acquiring resistance to antimicrobials available for treatment. The resistance of N. gonorrhoeae limit treatment options and contributed to high morbidity associated with gonorrhoea. Data on antimicrobial resistance (AMR) profiles in N. gonorrhoeae is scares in Zambia. This study aimed to determine the antibiotic susceptibilities in N. gonorrhoeae isolates from Lusaka, Zambia. METHODS: A prospective cross-sectional study was conducted on 630 STI patients who presented with urethral or vaginal discharge from 2019 to 2020. Urethral and endocervical secretions were cultured on Modified Thayer Martin agar and incubated at 36 °C ± 1 °C in 5% CO2 for 24 h. Identification of N. gonorrhoeae isolates was achieved by Gram stain, oxidase, nitrocefin disk, BactiCard Neisseria, and Viteck® Compact. The AMR profiles were determined using E-test. Statistical significant was determined by Pearson's Chi-square test, Mann-Whitney U test, or logistic regression with p-values of < 0.05 indicating significance. RESULTS: A total of 630 patients were recruited of which 46% (290/630) with the median of 29 years and interquartile range (IQR) of 19-39 years were male. The median of the females was 26 years and IQR of 15-37 years. Neisseria gonorrhoeae was isolated from 19.4% (122/630) patients of which 72.9% (89/122) were male, with highest prevalence of isolation in the age category of 25-34 years. The prevalence of resistance was high to penicillin (85.2%), tetracycline (68.9%) and ciprofloxacin (59.8%) with MIC90 of 32 µg/mL, 8 µg/mL, and 8 µg/mL respectively. The isolates had reduced susceptibility to cefixime (1.6%), spectinomycin (4.9%) and (4.9%) for azithromycin. All isolates were susceptible to ceftriaxone. Risk factors associated with AMR were douching in females (AOR 6.69, 95% CI; 1.11-40.31, p = 0.039), female gender (AOR 7.64, 95% CI; 1.11-52.33, p = 0.048), HIV-positivity (AOR 26.59, 95% CI; 3.67-192.7, p = 0.005), no condom use or unprotected sex (AOR 5.48, 95% CI; 1.17-22.75 p = 0.026), sex trading (AOR 4.19, 95% CI; 1.55-11.33, p = 0.010), and over-counter treatment of ciprofloxacin (AOR 3.44, 95% CI; 1.17-22.75, p = 0.023). CONCLUSION: The N. gonorrhoeae resistance to penicillin, tetracycline and ciprofloxacin was high necessitating revision of the treatment guidelines. However, no resistance to ceftriaxone was detected. Therefore, monitoring of antibiotic resistance remains critical in Zambia.

Indolactam Dipeptides as Nanomolar Gli Inhibitors.

The Gli transcription factors within the Hedgehog (Hh) signaling pathway play essential roles in human development. However, the reactivation of Gli proteins in adult tissue is tumorigenic and drives the progression of several cancers, including the majority of basal cell carcinomas. Here we describe a novel set of indolactam dipeptides that target protein kinase C (PKC), exploiting the unique capacity of PKC isozymes to act as regulators of Gli. We devised an efficient synthetic route for the indolactam-based natural product (-)-pendolmycin and a series of analogues, and we evaluated these analogues in mechanistically distinct Gli reporter assays. The lead compound from these studies, N-hexylindolactam V, exhibits superior Gli suppression relative to clinical inhibitors and blocks the growth of Gli-dependent basal cell carcinoma cells. More broadly, our structure-activity studies provide inroads for the development of novel Gli antagonists and new avenues for combating Gli-driven cancers.