"What if that's your last sleep?" A qualitative exploration of the trauma of incarceration and sleep.

Study Background/Objectives: Sleep is an underexplored factor in the health of people involved in the criminal legal system. This study addresses the paucity of research on how individual, social, and physical environmental factors impact sleep health during and after incarceration by highlighting the voices of people involved in the criminal legal system through a community-engaged qualitative research approach. Methods: We conducted 20 semi-structured interviews with men recently released from prison for a study on trauma and healthcare during incarceration and after release. Interviews were coded and analyzed using reflexive thematic analysis and a critical realist framework. Our research team included people with a history of incarceration who performed central roles in the research process. Results: Three themes emerged from participants' descriptions of sleep during and after incarceration: (1) concerns about health contributing to sleep problems, (2) lack of access to treatment for sleep disorders leading to ongoing sleep problems, and (3) issues of safety contributing to sleep problems during incarceration and after release. Conclusions: This study identifies factors and domains influencing sleep during and after incarceration. By identifying which interpersonal, environmental, and structural factors impact sleep quality, medical and carceral staff are better equipped to ameliorate sleep health disparities within populations with a history of incarceration and those actively bound by the criminal legal system. Future research should examine other factors impacting sleep in incarcerated and recently released populations and develop multi-level interventions to improve sleep health. This paper is part of the Sleep and Circadian Health in the Justice System Collection.

The experiences of families of children with cancer during the COVID-19 pandemic: A qualitative exploration.

OBJECTIVES: The COVID-19 pandemic posed new challenges to physical and psychological well-being. Families with pediatric cancer patients were particularly vulnerable due to changes like children staying at home, hospital policy shifts, and caring for an immunocompromised child. Limited research exists on COVID-19's effects on these families. This study aimed to assess the pandemic's impact and identify psychosocial support gaps. METHODS: Participants (N = 256) were parents of children with cancer recruited via Facebook in partnership with Momcology®, a community-based organization for pediatric cancer, between February and May 2021. Qualitative analyses used open-ended responses about the pandemic's impact on the family. RESULTS: Analysis revealed 6 themes, with positive and negative sentiments: family changes (n = 169; 61% negative), social isolation (n = 154; 100% negative), emotional impact (n = 143; 89% negative), school changes (n = 126; 80% negative), health-care changes (n = 111; 96% negative), and physical health (n = 49; 73% negative). Family changes overarched all themes and included financial strains, at-home schooling, and family bonding. Parents highlighted social isolation and the emotional impact of pandemic-related changes. School changes forced parents to balance remote-work and childcare. Health-care changes limited resources and visitation. Parents reported their children were less active and slept less but had fewer illnesses. SIGNIFICANCE OF RESULTS: Many common pandemic challenges were exacerbated by the stress of caring for a child with cancer. Parents struggled most with loss of social support and feelings of isolation. Careful consideration should be given to providing resources for parents of children with cancer and their families.

Evaluation of a Point-of-Need Molecular Diagnostic Tool Coupled with Rapid DNA Extraction Methods for Visceral Leishmaniasis.

A rapid, cost-effective, and simple nucleic acid isolation technique coupled with a point-of-need DNA amplification assay is a desirable goal for programmatic use. For diagnosis of Visceral Leishmaniasis (VL), Recombinase Polymerase Amplification (RPA) rapid tests for the detection of Leishmania DNA are versatile and have operational advantages over qPCR. To facilitate the delivery of the RPA test at point-of-need for VL diagnosis, we compared two rapid DNA extraction methods, SwiftDx (SX) and an in-house Boil and Spin (BS) method, coupled with RPA amplification, versus more widely used methods for DNA extraction and amplification, namely Qiagen (Q) kits and qPCR, respectively. A total of 50 confirmed VL patients and 50 controls, matched for age and gender, were recruited from Mymensingh, Bangladesh, a region highly endemic for VL. Blood samples were collected from each participant and DNA was extracted using Q, SX and BS methods. Following DNA extraction, qPCR and RPA assays were performed to detect L. donovani in downstream analysis. No significant differences in sensitivity of the RPA assay were observed between DNA extraction methods, 94.00% (95% CI: 83.45-98.75%), 90% (95% CI: 78.19-96.67%), and 88% (95% CI: 75.69-95.47%) when using Q, SX, and BS, respectively. Similarly, using qPCR, no significant differences in sensitivity were obtained when using Q or SX for DNA extraction, 94.00% (95% CI: 83.45-98.75%) and 92.00% (80.77-97.78%), respectively. It is encouraging that RPA and qPCR showed excellent agreement (k: 0.919-0.980) when different extraction methods were used and that the DNA impurities using BS had no inhibitory effect on the RPA assay. Furthermore, significantly higher DNA yields were obtained using SX and BS versus Q; however, a significantly higher parasite load was detected using qPCR when DNA was extracted using Q versus SX. Considering the cost, execution time, feasibility, and performance of RPA assay, rapid extraction methods such as the Boil and Spin technique appear to have the potential for implementation in resource-limited endemic settings. Further clinical research is warranted prior to broader application.

sTREM-1 and TNF-α levels are associated with the clinical outcome of leprosy patients.

Leprosy reaction (LR) and physical disability (PD) are the most significant clinical complications of leprosy. Herein, we assessed the circulating serum-sTREM-1 and TNF-α levels and their genetic polymorphisms in leprosy. Serum-sTREM-1 and TNF-α levels were measured in leprosy patients (LP) before treatment (n = 51) and from their household contacts (HHCs; n = 25). DNA samples were genotyped using TREM-1 rs2234246 and TNF-α rs1800629-SNP in 210 LPs and 168 endemic controls. The circulating sTREM-1 and TNF-α levels are higher in the multibacillary form. The ROC curve of the serum-sTREM-1 levels was able to differentiate LR from non-LR and PD from non-PD. Similarly, LPs with serum-sTREM-1 levels >210 pg/ml have 3-fold and 6-fold higher chances of presenting with LR and PD, respectively. Genotypes CC+CT of the TREM-1 were associated with leprosy. Taken together, our analyses indicated that sTREM-1 and TNF-α play an important role in the pathogenesis of leprosy and provide promising biomarkers to assist in the diagnosis of leprosy complications.

Effects of Forest Fragmentation on Connectivity and Genetic Diversity in an Endemic and an Invasive Rodent in Northwestern Madagascar.

Habitat loss and fragmentation are of concern to conservation biologists worldwide. However, not all organisms are affected equally by these processes; thus, it is important to study the effects of living in fragmented habitats on species that differ in lifestyle and habitat requirements. In this study, we examined the dispersal and connectivity patterns of rodents, one endemic (Eliurus myoxinus) and one invasive (Rattus rattus), in two landscapes containing forest fragments and adjacent continuous forest patches in northwestern Madagascar. We generated genetic (RADseq) data for 66 E. myoxinus and 81 R. rattus individuals to evaluate differences in genetic diversity as well as inbreeding and connectivity in two landscapes. We found higher levels of inbreeding and lower levels of genetic diversity in E. myoxinus compared with R. rattus. We observed related dyads both within and between habitat patches and positive spatial autocorrelation at lower distance classes for both species, with a stronger pattern of spatial autocorrelation in R. rattus. Across each site, we identified contrasting migration rates for each species, but these did not correspond to habitat-matrix dichotomies. The relatively low genetic diversity in the endemic E. myoxinus suggests ecological constraints that require further investigation.

A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation.

RNA vaccines possess significant clinical promise in counteracting human diseases caused by infectious or cancerous threats. Self-amplifying replicon RNA (repRNA) has been thought to offer the potential for enhanced potency and dose sparing. However, repRNA is a potent trigger of innate immune responses in vivo, which can cause reduced transgene expression and dose-limiting reactogenicity, as highlighted by recent clinical trials. Here, we report that multivalent repRNA vaccination, necessitating higher doses of total RNA, could be safely achieved in mice by delivering multiple repRNAs with a localizing cationic nanocarrier formulation (LION). Intramuscular delivery of multivalent repRNA by LION resulted in localized biodistribution accompanied by significantly upregulated local innate immune responses and the induction of antigen-specific adaptive immune responses in the absence of systemic inflammatory responses. In contrast, repRNA delivered by lipid nanoparticles (LNPs) showed generalized biodistribution, a systemic inflammatory state, an increased body weight loss, and failed to induce neutralizing antibody responses in a multivalent composition. These findings suggest that in vivo delivery of repRNA by LION is a platform technology for safe and effective multivalent vaccination through mechanisms distinct from LNP-formulated repRNA vaccines.

A Systematic Review of Electronic Community Resource Referral Systems.

INTRODUCTION: Community Resource Referral Systems delivered electronically through healthcare information technology systems (e.g., electronic medical records) have become more common in efforts to address patients' unmet health-related social needs. Community Resource Referral System connects patients with social supports such as food assistance, utility support, transportation, and housing. This systematic review identifies barriers and facilitators that influence the Community Resource Referral System's implementation in the U.S. by identifying and synthesizing peer-reviewed literature over a 15-year period. METHODS: This systematic review was conducted following PRISMA guidelines. A search was conducted on five scientific databases to capture the literature published between January 2005 and December 2020. Data analysis was conducted from August 2021 to July 2022. RESULTS: This review includes 41 articles of the 2,473 initial search results. Included literature revealed that Community Resource Referral Systems functioned to address a variety of health-related social needs and were delivered in different ways. Integrating the Community Resource Referral Systems into clinic workflows, maintenance of community-based organization inventories, and strong partnerships between clinics and community-based organizations facilitated implementation. The sensitivity of health-related social needs, technical challenges, and associated costs presented as barriers. Overall, electronic medical records-integration and automation of the referral process was reported as advantageous for the stakeholders. DISCUSSION: This review provides information and guidance for healthcare administrators, clinicians, and researchers designing or implementing electronic Community Resource Referral Systems in the U.S. Future studies would benefit from stronger implementation science methodological approaches. Sustainable funding mechanisms for community-based organizations, clear stipulations regarding how healthcare funds can be spent on health-related social needs, and innovative governance structures that facilitate collaboration between clinics and community-based organizations are needed to promote the growth and sustainability of Community Resource Referral Systems in the U.S.

The relationship of chronic disease conditions to mental and physical health among cancer survivors.

PURPOSE: This study examined the relationship between the presence of chronic disease conditions and mental and physical health among cancer survivors in the United States. METHODS: We conducted a cross-sectional analysis utilizing survey data from the 2016-2017 Behavioral Risk Factor Surveillance System (BRFSS) on 65,673 eligible cancer survivors. The primary outcomes of interest were self-rated metal/physical health in the past 30 days. Descriptive statistics and multivariate logistic regression were used to examine the mentioned association. RESULTS: 15.3% and 24.8% of survivors reported having several days of poor mental and physical health (14-30 days compared to 0-13 days), and 42.4% of survivors reported having one to two chronic diseases. In multivariate analysis, survivors with one to two chronic diseases were more likely to report several days of poor mental (OR, 2.74; 95% CI, 2.22-3.38) and physical (OR, 1.95; 95% CI, 1.72-2.22) health. Survivors with 3+ chronic diseases had markedly higher odds of having several days of poor mental (OR, 6.41; 95% CI, 5.19-7.91) and physical health (OR, 4.71; 95% CI, 4.16-5.34). Among survivors with at least one chronic disease, older age, insured, and more perceived social/emotional support were negatively associated with mental health (p value <0.05). Similarly, older age was related to fewer days of poor physical health (p value <0.05) regardless of chronic disease conditions. CONCLUSION: Having chronic diseases was associated with more days of poor mental and physical health among cancer survivors. Integrated, extensive care should include mental/physical health components and chronic disease management in cancer survivorship care.

Association between asthma, rhinitis and atopic dermatitis with leprosy: A case-control study.

Background Considering the cross-regulation of Th1 and Th2 responses, we hypothesised that atopic diseases (Th2) inhibit the protective Th1 immune response to Mycobacterium leprae and exacerbates leprosy. Objective In this study, we aimed to evaluate the association between leprosy and atopic diseases. Methods To evaluate the association of atopic diseases with leprosy, we conducted a case-control study that included leprosy patients (n = 333) and their household contacts (n = 93). The questionnaire from the International Study of Asthma and Allergies in Childhood, which is validated in several countries for epidemiological diagnosis of atopic diseases, was applied to determine the occurrence of atopic diseases, allergic rhinitis, asthma, and atopic dermatitis among leprosy patients and the household contacts. Results Considering clinical and epidemiological data, among the leprosy group 51.6% (n = 172) were determined to have at least one atopic disease, while atopy was observed less frequently at 40.86% among household contacts (n = 38). When two or more atopic diseases were assessed, the frequency was significantly higher among the leprosy patients than in the household contacts (21.9% vs. 11.8%; P-value = 0.03). Likewise, the frequency of asthma was significantly higher among leprosy patients (21%) than in the household contacts (10.8%; P-value = 0.02). Thus, our analyses revealed an association of atopic diseases with leprosy, with a significant linear increase in the occurrence of leprosy with an increase in the number of atopic diseases (P-value = 0.01). Limitation Due to the difficulties in recruiting household contacts that have prolonged contact with patients, but are not genetically related to the patient, the household contacts group is smaller than the leprosy patient group. Conclusion The data reveal an association between atopic diseases and leprosy outcomes. This knowledge could improve the treatment of leprosy patients with co-incident atopic diseases.

Racial/Ethnic Disparity in the Relationship of Mental and Physical Health With Colorectal Cancer Screening Utilization Among Breast and Prostate Cancer Survivors.

PURPOSE: We examined colorectal cancer (CRC) screening utilization among non-Hispanic White, non-Hispanic Black (NHB), non-Hispanic other (NHO)/Hispanic cancer survivors. We also determined whether experiencing poor physical and/or mental health affects CRC screening utilization in breast and prostate cancers across different racial/ethnic groups. METHODS: Data from years 2016, 2018, and 2020 of the Behavioral Risk Factor Surveillance System on 3,023 eligible treatment-utilizing cancer survivors with complete treatment were used. We performed descriptive statistics and multivariable logistic regression to examine the mentioned association. RESULTS: Among 3,023 eligible survivors, 67.7% of NHO/Hispanic survivors demonstrated lower CRC screening use compared with non-Hispanic White (82%) and NHB (89%) survivors (P < .001). In multivariable analysis, having frequent (14-30 days) poor mental health was associated with lower odds of receiving CRC screening among NHB (odds ratio [OR], 0.32; 95% CI, 0.11 to 0.95) and NHO/Hispanic (OR, 0.39; 95% CI, 0.18 to 0.81) survivors. Similar results in physical health were also found in NHB (OR, 0.34; 95% CI, 0.13 to 0.91) and NHO/Hispanic (OR, 0.22; 95% CI, 0.05 to 0.91) groups. Among those experienced both frequent poor mental and physical health, NHB/NHO/Hispanic were less likely to be screened for CRC (OR, 0.05; 95% CI, 0.02 to 0.10). CONCLUSION: NHO/Hispanic survivors demonstrated lower CRC screening use. Frequent poor mental and/or physical health was strongly associated with lower CRC screening use among NHB and NHO/Hispanic survivors. Our study suggests that cancer survivorship care considering mental and physical health status may improve adherence to CRC screening recommendation (for secondary cancer prevention) for NHB, NHO, and Hispanic survivors.

Land use and dingo baiting are correlated with the density of kangaroos in rangeland systems.

Rangelands worldwide have been subject to broadscale modification, such as widespread predator control, introduction of permanent livestock water and altered vegetation to improve grazing. In Australia, these landscape changes have resulted in kangaroos (i.e. large macropods) populations increasing over the past 200 years. Kangaroos are a key contributor to total grazing pressure and in conjunction with livestock and feral herbivores have been linked to land degradation. We used 22 years of aerial survey data to investigate whether the density of 3 macropod species in the southern rangelands of Western Australia was associated with: (i) land use, including type of livestock, total livestock, density of feral goats, type of land tenure, and kangaroo commercial harvest effort; (ii) predator management, including permitted dingo control effort, estimated dingo abundance, and presence of the State Barrier Fence (a dingo exclusion fence); and (iii) environmental variables: ruggedness, rainfall, fractional cover, and total standing dry matter. Red kangaroos (Osphranter rufus) were most abundant in flat, open vegetation, on pastoral land, where area permitted for dingo control was high, and numbers were positively associated with antecedent rainfall with a 12-month delay. Western grey kangaroos (Macropus fuliginosus) were most abundant on flat, agricultural land, but less abundant in areas with high permitted dingo control. Euros (Osphranter robustus) were most abundant in rugged pastoral land with open vegetation, where permitted dingo control was high. While environmental variables are key drivers of landscape productivity and kangaroo populations, anthropogenic factors such as land use and permitted dingo control are strongly associated with kangaroo abundance.

Methodology to geometrically age human body models to average and subject-specific anthropometrics, demonstrated using a small stature female model assessed in a side impact.

The aged population has been associated with an increased risk of injury in car-crash, creating a critical need for improved assessment of safety systems. Finite element human body models (HBMs) have been proposed, but require representative geometry of the aged population and high mesh quality. A new hybrid Morphing-CAD methodology was applied to a 26-year-old (YO) 5th percentile female model to create average 75YO and subject-specific 86YO HBMs. The method achieved accurate morphing targets while retaining high mesh quality. The three HBMs were integrated into a side sled impact test demonstrating similar kinematic response but differing rib fracture patterns.

Filarial infections in lemurs: Evidence for a wide geographical distribution and low host specificity among lemur species.

The relevance of emerging infectious diseases continues to grow worldwide as human activities increasingly extend into formerly remote natural areas. This is particularly noticeable on the island of Madagascar. As closest relatives to humans on the island, lemurs are of particular relevance as a potential origin of zoonotic pathogen spillover. Knowledge of pathogens circulating in lemur populations is, however, very poor. Particularly little is known about lemur hemoparasites. To infer host range, ecological and geographic spread of the recently described hemoparasitic nematode Lemurfilaria lemuris in northwestern Madagascar, a total of 942 individuals of two mouse lemur species (Microcebus murinus [n = 207] and Microcebus ravelobensis [n = 433]) and two rodent species (the endemic Eliurus myoxinus [n = 118] and the invasive Rattus rattus [n = 184]) were captured in two fragmented forest landscapes (Ankarafantsika National Park and Mariarano Classified Forest) in northwestern Madagascar for blood sample examination. No protozoan hemoparasites were detected by microscopic blood smear screening. Microfilaria were present in 1.0% (2/207) of M. murinus and 2.1% (9/433) of M. ravelobensis blood samples but not in rodent samples. Internal transcribed spacer 1 (ITS-1) sequences were identical to an unnamed Onchocercidae species previously described to infect a larger lemur species, Propithecus verreauxi, about 650 km further south. In contrast to expectations, L. lemuris was not detected. The finding of a pathogen in a distantly related host species, at a considerable geographic distance from the location of its original detection, instead of a microfilaria species previously described for one of the studied host species in the same region, illustrates our low level of knowledge of lemur hemoparasites, their host ranges, distribution, modes of transmission, and their zoonotic potential. Our findings shall stimulate new research that will be of relevance for both conservation medicine and human epidemiology.

Receipt of follow-up care plans on colorectal cancer screening among breast, prostate, and lung cancer survivors.

PURPOSE: Our study aimed to examine whether receipt of follow-up care plans is associated with greater guideline-concordant CRC screening stratified by breast, prostate, and lung cancer survivors. METHODS: We used data from years 2016, 2018, and 2020 of the Behavioral Risk Factor Surveillance System on 3339 eligible treatment-utilizing cancer survivors with complete treatment. We performed descriptive statistics and multivariable logistic regression to examine the mentioned association. RESULTS: We observed that 83.9% of breast and 88.2% of prostate cancer survivors with follow-care plans received CRC screening (p-value < 0.001). The lowest CRC screening use was observed among lung cancer (70.8%). In multivariable analysis, receipt of follow-up care plans was strongly associated with greater odds of receiving CRC screening in breast (OR, 2.67; 95% CI: 1.71-4.16) and prostate (OR, 3.81; 95% CI: 2.30-6.31) cancer survivors. Regardless of provider type, 84 to 88% reduced likelihood of receipt of CRC screening when they received follow-up care plans among lung cancer survivors. Among those without follow-up care plans, breast (OR, 0.29; 95% CI: 0.09-0.92) and lung (OR, 0.05; 95% CI: 0.01-0.25) cancer survivors who received care from general practices were less likely to receive CRC screening compared to those who received care from non-general practices. CONCLUSIONS: Receipt of follow-up care plans was associated with greater CRC screening use in breast and prostate cancers. Lung cancer survivors demonstrated lower screening use despite receipt of follow-up care plans. IMPLICATION FOR CANCER SURVIVORS: Patient and provider communication regarding CRC screening recommendation should be included in their follow-up care plans.

Leishmaniasis Vaccines: Applications of RNA Technology and Targeted Clinical Trial Designs.

Leishmania parasites cause a variety of discrete clinical diseases that present in regions where their specific sand fly vectors sustain transmission. Clinical and laboratory research indicate the potential of immunization to prevent leishmaniasis and a wide array of vaccine candidates have been proposed. Unfortunately, multiple factors have precluded advancement of more than a few Leishmania targeting vaccines to clinical trial. The recent maturation of RNA vaccines into licensed products in the context of COVID-19 indicates the likelihood of broader use of the technology. Herein, we discuss the potential benefits provided by RNA technology as an approach to address the bottlenecks encountered for Leishmania vaccines. Further, we outline a variety of strategies that could be used to more efficiently evaluate Leishmania vaccine efficacy, including controlled human infection models and initial use in a therapeutic setting, that could prioritize candidates before evaluation in larger, longer and more complicated field trials.

Retraction: Teixeira et al. RADseq Data Suggest Occasional Hybridization between Microcebus murinus and M. ravelobensis in Northwestern Madagascar. Genes 2022, 13, 913.

The published article [...].

Cortical bone continuum damage mechanics constitutive model with stress triaxiality criterion to predict fracture initiation and pattern.

A primary objective of finite element human body models (HBMs) is to predict response and injury risk in impact scenarios, including cortical bone fracture initiation, fracture pattern, and the potential to simulate post-fracture injury to underlying soft tissues. Current HBMs have been challenged to predict the onset of failure and bone fracture patterns owing to the use of simplified failure criteria. In the present study, a continuum damage mechanics (CDM) model, incorporating observed mechanical response (orthotropy, asymmetry, damage), was coupled to a novel phenomenological effective strain fracture criterion based on stress triaxiality and investigated to predict cortical bone response under different modes of loading. Three loading cases were assessed: a coupon level notched shear test, whole bone femur three-point bending, and whole bone femur axial torsion. The proposed material model and fracture criterion were able to predict both the fracture initiation and location, and the fracture pattern for whole bone and specimen level tests, within the variability of the reported experiments. There was a dependence of fracture threshold on finite element mesh size, where higher mesh density produced similar but more refined fracture patterns compared to coarser meshes. Importantly, the model was functional, accurate, and numerically stable even for relatively coarse mesh sizes used in contemporary HBMs. The proposed model and novel fracture criterion enable prediction of fracture initiation and resulting fracture pattern in cortical bone such that post-fracture response can be investigated in HBMs.

Gauging the skin resident Leishmania parasites through a loop mediated isothermal amplification (LAMP) assay in post-kala-azar dermal leishmaniasis.

Despite the availability of highly sensitive polymerase chain reaction (PCR)-based methods, the dearth of remotely deployable diagnostic tools circumvents the early and accurate detection of individuals with post-kala-azar dermal leishmaniasis (PKDL). Here, we evaluate a design-locked loop-mediated isothermal amplification (LAMP) assay to diagnose PKDL. A total of 76 snip-skin samples collected from individuals with probable PKDL (clinical presentation and a positive rK39 rapid diagnostic test (RDT)) were assessed by microscopy, qPCR, and LAMP. An equal number of age and sex-matched healthy controls were included to determine the specificity of the LAMP assay. The LAMP assay with a Qiagen DNA extraction (Q-LAMP) showed a promising sensitivity of 72.37% (95% CI: 60.91-82.01%) for identifying the PKDL cases. LAMP assay sensitivity declined when the DNA was extracted using a boil-spin method. Q-qPCR showed 68.42% (56.75-78.61%) sensitivity, comparable to LAMP and with an excellent agreement, whereas the microscopy exhibited a weak sensitivity of 39.47% (28.44-51.35%). When microscopy and/or qPCR were considered the gold standard, Q-LAMP exhibited an elevated sensitivity of 89.7% (95% CI: 78.83-96.11%) for detection of PKDL cases and Bayesian latent class modeling substantiated the excellent sensitivity of the assay. All healthy controls were found to be negative. Notwithstanding the optimum efficiency of the LAMP assay towards the detection of PKDL cases, further optimization of the boil-spin method is warranted to permit remote use of the assay.

Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents.

Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative molecules were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic analysis of these analogs may lead to a next generation POA analog for treating TB.

ß-Lactamase-Mediated Fragmentation: Historical Perspectives and Recent Advances in Diagnostics, Imaging, and Antibacterial Design.

The discovery of ß-lactam (BL) antibiotics in the early 20th century represented a remarkable advancement in human medicine, allowing for the widespread treatment of infectious diseases that had plagued humanity throughout history. Yet, this triumph was followed closely by the emergence of ß-lactamase (BLase), a bacterial weapon to destroy BLs. BLase production is a primary mechanism of resistance to BL antibiotics, and the spread of new homologues with expanded hydrolytic activity represents a pressing threat to global health. Nonetheless, researchers have developed strategies that take advantage of this defense mechanism, exploiting BLase activity in the creation of probes, diagnostic tools, and even novel antibiotics selective for resistant organisms. Early discoveries in the 1960s and 1970s demonstrating that certain BLs expel a leaving group upon BLase cleavage have spawned an entire field dedicated to employing this selective release mechanism, termed BLase-mediated fragmentation. Chemical probes have been developed for imaging and studying BLase-expressing organisms in the laboratory and diagnosing BL-resistant infections in the clinic. Perhaps most promising, new antibiotics have been developed that use BLase-mediated fragmentation to selectively release cytotoxic chemical "warheads" at the site of infection, reducing off-target effects and allowing for the repurposing of putative antibiotics against resistant organisms. This Review will provide some historical background to the emergence of this field and highlight some exciting recent reports that demonstrate the promise of this unique release mechanism.