Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities.

Linezolid is a drug with proven human antitubercular activity whose use is limited to highly drug-resistant patients because of its toxicity. This toxicity is related to its mechanism of action─linezolid inhibits protein synthesis in both bacteria and eukaryotic mitochondria. A highly selective and potent series of oxazolidinones, bearing a 5-aminomethyl moiety (in place of the typical 5-acetamidomethyl moiety of linezolid), was identified. Linezolid-resistant mutants were cross-resistant to these molecules but not vice versa. Resistance to the 5-aminomethyl molecules mapped to an N-acetyl transferase (Rv0133) and these mutants remained fully linezolid susceptible. Purified Rv0133 was shown to catalyze the transformation of the 5-aminomethyl oxazolidinones to their corresponding N-acetylated metabolites, and this transformation was also observed in live cells of Mycobacterium tuberculosis. Mammalian mitochondria, which lack an appropriate N-acetyltransferase to activate these prodrugs, were not susceptible to inhibition with the 5-aminomethyl analogues. Several compounds that were more potent than linezolid were taken into C3HeB/FeJ mice and were shown to be highly efficacious, and one of these (9) was additionally taken into marmosets and found to be highly active. Penetration of these 5-aminomethyl oxazolidinone prodrugs into caseum was excellent. Unfortunately, these compounds were rapidly converted into the corresponding 5-alcohols by mammalian metabolism which retained antimycobacterial activity but resulted in substantial mitotoxicity.

An International, Multidisciplinary Consensus Set of Patient-Centered Outcome Measures for Substance-Related and Addictive Disorders.

Background: In 1990, the United States' Institute of Medicine promoted the principles of outcomes monitoring in the alcohol and other drugs treatment field to improve the evidence synthesis and quality of research. While various national outcome measures have been developed and employed, no global consensus on standard measurement has been agreed for addiction. It is thus timely to build an international consensus. Convened by the International Consortium for Health Outcomes Measurement (ICHOM), an international, multi-disciplinary working group reviewed the existing literature and reached consensus for a globally applicable minimum set of outcome measures for people who seek treatment for addiction. Methods: To this end, 26 addiction experts from 11 countries and 5 continents, including people with lived experience (n = 5; 19%), convened over 16 months (December 2018-March 2020) to develop recommendations for a minimum set of outcome measures. A structured, consensus-building, modified Delphi process was employed. Evidence-based proposals for the minimum set of measures were generated and discussed across eight videoconferences and in a subsequent structured online consultation. The resulting set was reviewed by 123 professionals and 34 people with lived experience internationally. Results: The final consensus-based recommendation includes alcohol, substance, and tobacco use disorders, as well as gambling and gaming disorders in people aged 12 years and older. Recommended outcome domains are frequency and quantity of addictive disorders, symptom burden, health-related quality of life, global functioning, psychosocial functioning, and overall physical and mental health and wellbeing. Standard case-mix (moderator) variables and measurement time points are also recommended. Conclusions: Use of consistent and meaningful outcome measurement facilitates carer-patient relations, shared decision-making, service improvement, benchmarking, and evidence synthesis for the evaluation of addiction treatment services and the dissemination of best practices. The consensus set of recommended outcomes is freely available for adoption in healthcare settings globally.

Contraceptive content shared on social media: an analysis of Twitter.

BACKGROUND: Information on social media may affect peoples' contraceptive decision making. We performed an exploratory analysis of contraceptive content on Twitter (recently renamed X), a popular social media platform. METHODS: We selected a random subset of 1% of publicly available, English-language tweets related to reversible, prescription contraceptive methods posted between January 2014 and December 2019. We oversampled tweets for the contraceptive patch to ensure at least 200 tweets per method. To create the codebook, we identified common themes specific to tweet content topics, tweet sources, and tweets soliciting information or providing advice. All posts were coded by two team members, and differences were adjudicated by a third reviewer. Descriptive analyses were reported with accompanying qualitative findings. RESULTS: During the study period, 457,369 tweets about reversible contraceptive methods were published, with a random sample of 4,434 tweets used for final analysis. Tweets most frequently discussed contraceptive method decision-making (26.7%) and side effects (20.5%), particularly for long-acting reversible contraceptive methods and the depot medroxyprogesterone acetate shot. Tweets about logistics of use or adherence were common for short-acting reversible contraceptives. Tweets were frequently posted by contraceptive consumers (50.6%). A small proportion of tweets explicitly requested information (6.2%) or provided advice (4.2%). CONCLUSIONS: Clinicians should be aware that individuals are exposed to information through Twitter that may affect contraceptive perceptions and decision making, particularly regarding long-acting reversible contraceptives. Social media is a valuable source for studying contraceptive beliefs missing in traditional health research and may be used by professionals to disseminate accurate contraceptive information.

Community composition of black flies during and after the 2020 vesicular stomatitis virus outbreak in Southern New Mexico, USA.

BACKGROUND: Vesicular stomatitis virus (VSV), a vector-borne pathogen of livestock, emerges periodically in the western US. In New Mexico (NM), US, most cases occur close to the Rio Grande River, implicating black flies (Simulium spp.) as a possible vector. In 2020, VS cases were reported in NM from April to May, although total black fly abundance remained high until September. We investigated the hypothesis that transience of local VSV transmission results from transient abundance of key, competent black fly species. Additionally, we investigated whether irrigation canals in southern NM support a different community of black flies than the main river. Lastly, to gain insight into the source of local black flies, in 2023 we collected black fly larvae prior to the release of water into the Rio Grande River channel. METHODS: We randomly sub-sampled adult black flies collected along the Rio Grande during and after the 2020 VSV outbreak. We also collected black fly adults along the river in 2021 and 2022 and at southern NM farms and irrigation canals in 2022. Black fly larvae were collected from dams in the area in 2023. All collections were counted, and individual specimens were subjected to molecular barcoding for species identification. RESULTS: DNA barcoding of adult black flies detected four species in 2020: Simulium meridionale (N = 158), S. mediovittatum (N = 83), S. robynae (N = 26) and S. griseum/notatum (N = 1). Simulium robynae was only detected during the VSV outbreak period, S. meridionale showed higher relative abundance, but lower absolute abundance, during the outbreak than post-outbreak period, and S. mediovittatum was rare during the outbreak period but predominated later in the summer. In 2022, relative abundance of black fly species did not differ significantly between the Rio Grande sites and farm and irrigation canals. Intriguingly, 63 larval black flies comprised 56% Simulium vittatum, 43% S. argus and 1% S. encisoi species that were either extremely rare or not detected in previous adult collections. CONCLUSIONS: Our results suggest that S. robynae and S. meridionale could be shaping patterns of VSV transmission in southern NM. Thus, field studies of the source of these species as well as vector competence studies are warranted.

Transdiagnostic symptom of depression and anxiety associated with reduced gray matter volume in prefrontal cortex.

Dimensional models of psychopathology may provide insight into mechanisms underlying comorbid depression and anxiety and improve specificity and sensitivity of neuroanatomical findings. The present study is the first to examine neural structure alterations using the empirically derived Tri-level Model. Depression and anxiety symptoms of 269 young adults were assessed using the Tri-level Model dimensions: General Distress (transdiagnostic depression and anxiety symptoms), Anhedonia-Apprehension (relatively specific depression symptoms), and Fears (specific anxiety symptoms). Using structural MRI, gray matter volumes were extracted for emotion generation (amygdala, nucleus accumbens) and regulation (orbitofrontal, ventrolateral, and dorsolateral prefrontal cortex) regions, often implicated in depression and anxiety. Each Tri-level symptom was regressed onto each region of interest, separately, adjusting for relevant covariates. General Distress was significantly associated with smaller gray matter volumes in bilateral orbitofrontal cortex and ventrolateral prefrontal cortex, independent of Anhedonia-Apprehension and Fears symptom dimensions. These results suggests that prefrontal alterations are associated with transdiagnostic dysphoric mood common across depression and anxiety, rather than unique symptoms of these disorders. Additionally, no regions of interest were associated with Anhedonia-Apprehension or Fears, highlighting the importance of studying transdiagnostic features of depression and anxiety. This has implications for understanding mechanisms of and interventions for depression and anxiety.

Structure Guided Discovery of Novel Pan Metallo-ß-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

The use of ß-lactam (BL) and ß-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-ß-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.

Risk factor associations for severe COVID-19, influenza and pneumonia in people with diabetes to inform future pandemic preparations: UK population-based cohort study.

OBJECTIVE: This study aimed to compare clinical and sociodemographic risk factors for severe COVID-19, influenza and pneumonia, in people with diabetes. DESIGN: Population-based cohort study. SETTING: UK primary care records (Clinical Practice Research Datalink) linked to mortality and hospital records. PARTICIPANTS: Individuals with type 1 and type 2 diabetes (COVID-19 cohort: n=43 033 type 1 diabetes and n=584 854 type 2 diabetes, influenza and pneumonia cohort: n=42 488 type 1 diabetes and n=585 289 type 2 diabetes). PRIMARY AND SECONDARY OUTCOME MEASURES: COVID-19 hospitalisation from 1 February 2020 to 31 October 2020 (pre-COVID-19 vaccination roll-out), and influenza and pneumonia hospitalisation from 1 September 2016 to 31 May 2019 (pre-COVID-19 pandemic). Secondary outcomes were COVID-19 and pneumonia mortality. Associations between clinical and sociodemographic risk factors and each outcome were assessed using multivariable Cox proportional hazards models. In people with type 2 diabetes, we explored modifying effects of glycated haemoglobin (HbA1c) and body mass index (BMI) by age, sex and ethnicity. RESULTS: In type 2 diabetes, poor glycaemic control and severe obesity were consistently associated with increased risk of hospitalisation for COVID-19, influenza and pneumonia. The highest HbA1c and BMI-associated relative risks were observed in people aged under 70 years. Sociodemographic-associated risk differed markedly by respiratory infection, particularly for ethnicity. Compared with people of white ethnicity, black and south Asian groups had a greater risk of COVID-19 hospitalisation, but a lesser risk of pneumonia hospitalisation. Risk factor associations for type 1 diabetes and for type 2 diabetes mortality were broadly consistent with the primary analysis. CONCLUSIONS: Clinical risk factors of high HbA1c and severe obesity are consistently associated with severe outcomes from COVID-19, influenza and pneumonia, especially in younger people. In contrast, associations with sociodemographic risk factors differed by type of respiratory infection. This emphasises that risk stratification should be specific to individual respiratory infections.

Activity of ceftolozane/tazobactam, imipenem/relebactam and ceftazidime/avibactam against clinical Gram-negative isolates-SMART United States 2019-21.

Background: Ongoing national and international surveillance efforts are critical components of antimicrobial stewardship, resistance monitoring, and drug development programs. In this report, we summarize the results of ceftolozane/tazobactam, imipenem/relebactam, ceftazidime/avibactam and comparator agent testing against 10 509 Enterobacterales and 2524 Pseudomonas aeruginosa collected by USA clinical laboratories in 2019-21 as part of the SMART global surveillance programme. Methods: MICs were determined by CLSI broth microdilution and interpreted using 2023 CLSI M100 breakpoints. Results: Most Enterobacterales were ceftazidime/avibactam susceptible (>99%), meropenem susceptible (99%) and ceftolozane/tazobactam susceptible (94%). Non-Morganellaceae Enterobacterales were also highly susceptible to imipenem/relebactam (99%). Ceftolozane/tazobactam inhibited 94% of Escherichia coli and 89% of Klebsiella pneumoniae with ceftriaxone non-susceptible/non-carbapenem-resistant phenotypes. Against P. aeruginosa, ceftolozane/tazobactam (97% susceptible) was more active than ceftazidime/avibactam (95%) and imipenem/relebactam (91%). MDR and difficult-to-treat resistance (DTR) phenotypes were identified in 13% and 7% of P. aeruginosa isolates, respectively. Ceftolozane/tazobactam remained active against 78% of MDR P. aeruginosa (13% and 23% higher than ceftazidime/avibactam and imipenem/relebactam, respectively) and against 74% of DTR P. aeruginosa (24% and 37% higher than ceftazidime/avibactam and imipenem/relebactam, respectively). Length of hospital stay at the time of specimen collection, ward type and infection type resulted in percent susceptible value differences of >5% across isolate demographic strata for some antimicrobial agent/pathogen combinations. Conclusions: We conclude that in the USA, in 2019-21, carbapenem (meropenem) resistance remained uncommon in Enterobacterales and ceftolozane/tazobactam was more active than both ceftazidime/avibactam and imipenem/relebactam against P. aeruginosa.

Comorbid psychiatric disease significantly mediates increased rates of alcohol use disorder among patients with inflammatory and pigmentary skin disorders: a case-control study in the All of Us Research Program.

Dermatologic diseases have a well-documented association with depression and anxiety, which are in turn often comorbid with alcohol use disorder (AUD). Nonethleess, the relationship between dermatologic disease and AUD, and the relative contribution of depression and anxiety, are poorly understood. Here, we utilize the National Insittutes of Health All of Us Research Program to investigate the association between inflammatory and pigmentary dermatologic diseases with AUD. Furthermore, we investigate whether comorbid depression and anxiety mediates this relationship. We employed a matched case-control model with multivariable logistic regression. We also employed a mediation analysis. We found an increased odds of AUD among patients with atopic dermatitis, acne/rosacea, hidradenitis suppurativa, psoriasis, and pigmentary disorders (vitiligo, melasma, and post-inflammatory hyperpigmentation). This was partially mediated by anxiety and depression, especially for diseases with a significant cosmetic component. Overall, these findings highlight the profound psychological and physical health effects that inflammatory and pigmentary disease can have on patients, both independently and in combination with comorbid psychiatric disease.

Susceptibility of Gram-negative isolates collected in South Korea to imipenem/relebactam and comparator agents-SMART 2018-21.

Objectives: To evaluate the in vitro susceptibility of recent Gram-negative pathogens collected in South Korean medical centres to imipenem/relebactam and comparator agents. Methods: From 2018 to 2021, six hospitals in South Korea each collected up to 250 consecutive, aerobic or facultative Gram-negative pathogens per year from patients with bloodstream, intra-abdominal, lower respiratory tract and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted by 2023 CLSI breakpoints. Most isolates that were imipenem/relebactam, imipenem or ceftolozane/tazobactam non-susceptible were screened for ß-lactamase genes by PCR or WGS. Results: Of all non-Morganellaceae Enterobacterales (NME) isolates (n = 4100), 98.8% were imipenem/relebactam susceptible. Most NME were also susceptible to imipenem alone (94.7%) and meropenem (97.3%); percent susceptible values for non-carbapenem ß-lactam comparators were lower (68%-80%). Imipenem/relebactam retained activity against 96.4%, 70.8% and 70.6% of MDR, difficult-to-treat resistant (DTR) and meropenem-non-susceptible NME, respectively, and inhibited 93.1% of KPC-carrying and 95.5% of ESBL-carrying NME. Of imipenem/relebactam-resistant NME, 21/25 (84.0%) carried an MBL or an OXA-48-like carbapenemase. Of all Pseudomonas aeruginosa isolates (n = 738), 82.8% were imipenem/relebactam susceptible; percent susceptible values for all ß-lactam comparators, including carbapenems (imipenem, meropenem) were 61.5%-74.7%. Less than 20% of MDR and DTR isolates, and 41% of meropenem-non-susceptible P. aeruginosa isolates were imipenem/relebactam susceptible. Of imipenem/relebactam-resistant P. aeruginosa isolates, 61.6% carried an MBL and 37.0% did not possess any acquired ß-lactamase genes. Conclusions: Based on in vitro data, imipenem/relebactam, if licensed in South Korea, may be a viable treatment option for many hospitalized patients infected with common Gram-negative pathogens including NME exhibiting MDR, DTR and carbapenem resistance and many ß-lactam-resistant phenotypes of P. aeruginosa.

Inadequate (Ax) Transbronchial Lung Transplant Biopsies-Scope and the Potential Contributing Factors.

BACKGROUND: Transbronchial biopsy is the cornerstone for the evaluation of graft function after lung transplant and a standard of care to diagnose acute cellular rejection. However, the yield from these biopsies is variable, with about 15% to 50% of samples being judged as nondiagnostic, leading to additional procedures. The factors contributing to the nondiagnostic sampling have not been delineated, and the discordance in sample assessment between the bronchoscopist and pathologist has not been quantified. METHODS: A retrospective cohort of patients who had bronchoscopies with biopsies for surveillance and graft assessment at a large-volume transplant center was studied. The occurrence of nondiagnostic alveolar sampling was assessed, and the patient demographics and procedural characteristics were compared with the diagnostic group. RESULTS: We included 128 patients in our study and found the inadequacy rate for alveolar tissue sampling to be 15.5%. The median number of passes made by the bronchoscopist was 9, and the number of samples assessed by the bronchoscopist was 8, with a median of 6 adequate samples identified by the pathologist. The frequency of previous biopsies, history of prior inadequate samples, need for a higher number of pass attempts, presence of airway abnormalities, and the use of general anesthesia increased the odds of inadequate sampling. CONCLUSIONS: Patients with the identified factors may be at risk of inadequate sampling on transbronchial biopsies. The bronchoscopist could consider getting additional samples to avoid a nondiagnostic alveolar sample. Further multicenter studies would help to elucidate other contributing factors.

Major stress in early childhood strengthens the association between peripheral inflammatory activity and corticostriatal responsivity to reward.

BACKGROUND: Severe, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. METHODS: 180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood - C-reactive protein, tumor necrosis factor-a, and interleukins-6, -8, and -10 - and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. RESULTS: Stress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants' age, sex, racial and ethnic identity, family income, and depressive symptoms. CONCLUSIONS: Collectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling.

Seeking help for mental health during the COVID-19 pandemic: A longitudinal analysis of adults' experiences with digital technologies and services.

The COVID-19 pandemic brought about dramatic changes in how patients access healthcare from its outset. Lockdown restrictions and remote working led to a proliferation of digital technologies and services, which also impacted mental health provisions. Against the backdrop of new and changing support services, along with an unprecedented emphasis on mental health, relatively little is known about how adults sought out and received support for their mental health during this period. With a sample of 27,574 adults assessed longitudinally online over 12 months of the pandemic in the UK, we analysed reports of help-seeking for mental health, as well as sources of treatment or support and the perceived helpfulness of treatments received. We observed that the proportions of participants who reported seeking help remained relatively consistent throughout the 12-month period (ranging from 12.6% to 17.0%). Online talking therapies were among the most frequently sought sources (15.3%), whereas online self-guided treatments were among the least frequently sought sources (5%). Telephone lines, both NHS and non-governmental, had marked treatment 'gaps'. These treatment gaps, where individuals sought treatment but did not receive it, were especially evident for men and older adults. Our findings underscore online talking therapies as being a widely-sought and helpful source of mental health support. This is important given the current global need for accessible treatment options.

Seasonal Patterns in Tetracycline-Associated Hyperpigmentation Among Patients With Acne Vulgaris.

BACKGROUND: Oral tetracyclines (TCNs) are commonly prescribed for acne, but they have been shown to increase the risk of hyperpigmentation, particularly in the setting of sun exposure. OBJECTIVE: We evaluated seasonal trends in TCN-associated hyperpigmentation incidence in addition to Google search trends for hyperpigmentation-related terms. METHODS: We performed a retrospective review of acne patients seen at Massachusetts General Brigham and Women’s Hospital between 1992 and 2022. We calculated the incidence of new hyperpigmentation diagnoses for each drug cohort. We also analyzed search volume of hyperpigmentation-related terms extracted from Google Trends. RESULTS: Seasonal differences in new hyperpigmentation diagnoses were identified among acne patients prescribed doxycycline (P=0.016), with peak incidence in April. In the control group of patients who had never received a TCN, diagnoses peaked in May. There were no significant seasonal differences among patients prescribed minocycline (P=0.885). There was greater search volume for hyperpigmentation-related terms in spring and summer compared to fall and winter (P<0.001). Limitations of this study include its retrospective nature and reliance on prescription and diagnosis coding data. CONCLUSIONS: Our findings support the seasonal periodicity of acne-related hyperpigmentation, underscoring the importance of photoprotection counseling for patients with acne. Additionally, doxycycline may be associated with an earlier onset of hyperpigmentation, suggesting a potential benefit of considering minocycline or other alternatives to doxycycline. J Drugs Dermatol. 2023;22(11):e9-e11    doi:10.36849/JDD.7409e.

Recent UK type 2 diabetes treatment guidance represents a near whole population indication for SGLT2-inhibitor therapy.

Recent type 2 diabetes guidance from the UK's National Institute for Health and Care Excellence (NICE) proposes offering SGLT2-inhibitor therapy to people with established atherosclerotic cardiovascular disease (ASCVD) or heart failure, and considering SGLT2-inhibitor therapy for those at high-risk of cardiovascular disease defined as a 10-year cardiovascular risk of > 10% using the QRISK2 algorithm. We used a contemporary population-representative UK cohort of people with type 2 diabetes to assess the implications of this guidance. 93.1% of people currently on anti-hyperglycaemic treatment are now recommended or considered for SGLT2-inhibitor therapy under the new guidance, with the majority (59.6%) eligible on the basis of QRISK2 rather than established ASCVD or heart failure (33.6%). Applying these results to the approximately 2.20 million people in England currently on anti-hyperglycaemic medication suggests 1.75 million people will now be considered for additional SGLT2-inhibitor therapy, taking the total cost of SGLT2-inhibitor therapy in England to over £1 billion per year. Given that older people, those of non-white ethnic groups, and those at lower cardiovascular disease risk were underrepresented in the clinical trials which were used to inform this guidance, careful evaluation of the impact and safety of increased SGLT2-inhibitor prescribing across different populations is urgently required. Evidence of benefit should be weighed against the major cost implications for the UK National Health Service.

Cancer-associated fibroblasts in early-stage lung adenocarcinoma correlate with tumor aggressiveness.

Lung adenocarcinoma (LUAD) is the predominant type of lung cancer in the U.S. and exhibits a broad variety of behaviors ranging from indolent to aggressive. Identification of the biological determinants of LUAD behavior at early stages can improve existing diagnostic and treatment strategies. Extracellular matrix (ECM) remodeling and cancer-associated fibroblasts play a crucial role in the regulation of cancer aggressiveness and there is a growing need to investigate their role in the determination of LUAD behavior at early stages. We analyzed tissue samples isolated from patients with LUAD at early stages and used imaging-based biomarkers to predict LUAD behavior. Single-cell RNA sequencing and histological assessment showed that aggressive LUADs are characterized by a decreased number of ADH1B+ CAFs in comparison to indolent tumors. ADH1B+ CAF enrichment is associated with distinct ECM and immune cell signatures in early-stage LUADs. Also, we found a positive correlation between the gene expression of ADH1B+ CAF markers in early-stage LUADs and better survival. We performed TCGA dataset analysis to validate our findings. Identified associations can be used for the development of the predictive model of LUAD aggressiveness and novel therapeutic approaches.

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review.

BACKGROUND: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy. METHODS: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review. RESULTS: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes. CONCLUSIONS: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.

This study reviews the available evidence on which patient features (such as age, sex, and blood test results) are associated with different outcomes for two recently introduced type 2 diabetes medications: SGLT2-inhibitors and GLP1-receptor agonists. Understanding what individual characteristics are associated with different response patterns may help clinical providers and people living with diabetes make more informed decisions about which type 2 diabetes treatments will work best for an individual. We focus on three outcomes: blood glucose levels (raised blood glucose is the primary symptom of diabetes and a primary aim of diabetes treatment is to lower this), heart disease, and kidney disease. We identified some potential factors that reduce effects on blood glucose levels, including poorer kidney function for SGLT2-inhibitors and lower production of the glucose-lowering hormone insulin for GLP1-receptor agonists. We did not identify clear factors that alter heart and kidney disease outcomes for either medication. Most of the studies had limitations, meaning more research is needed to fully understand the factors that influence treatment outcomes in type 2 diabetes.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Susceptibility of gram-negative isolates collected in Taiwan to imipenem/relebactam and comparator agents - SMART 2018-2021.

BACKGROUND: Imipenem/relebactam (IMR) was approved for patient use in Taiwan in 2023. We evaluated the in vitro susceptibility of recent Gram-negative pathogens collected in Taiwan hospitals to IMR and comparators with a focus on carbapenem-resistant and KPC-carrying non-Morganellaceae Enterobacterales (NME), and carbapenem-resistant Pseudomonas aeruginosa (CRPA). METHODS: From 2018 to 2021, eight hospitals in Taiwan each collected up to 250 consecutive, aerobic or facultative, Gram-negative pathogens per year from patients with bloodstream, intraabdominal, lower respiratory tract, and urinary tract infections. MICs were determined using Clinical Laboratory Standards Institute (CLSI) broth microdilution. Most isolates that were IMR-, imipenem-, or ceftolozane/tazobactam-nonsusceptible were screened for ß-lactamase genes by PCR or whole-genome sequencing. RESULTS: Ninety-eight percent of NME (n = 5063) and 94% of P. aeruginosa (n = 1518) isolates were IMR-susceptible. Percent susceptible values for non-carbapenem ß-lactam comparators, including piperacillin/tazobactam, were 68-79% for NME isolates, while percent susceptible values for all ß-lactam comparators, including meropenem, were 73-81% for P. aeruginosa. IMR retained activity against 93% of multidrug-resistant (MDR) NME and 70% of MDR P. aeruginosa. Sixty-five percent of carbapenem-resistant NME and 81% of KPC-positive NME (n = 80) were IMR-susceptible. IMR inhibited 70% of CRPA (n = 287). Fifty percent of IMR-nonsusceptible NME tested for ß-lactamase carriage had an MBL or OXA-48-like enzyme, whereas most (95%) IMR-nonsusceptible P. aeruginosa examined did not carry acquired ß-lactamase genes. CONCLUSION: Based on our in vitro data, IMR may be a useful option for the treatment of hospitalized patients in Taiwan with infections caused by common Gram-negative pathogens, including carbapenem-resistant NME, KPC-positive NME, and CRPA.

Label-free microfluidic isolation of functional and viable lymphocytes from peripheral blood mononuclear cells.

The separation of peripheral blood mononuclear cells (PBMCs) into constituent blood cell types is a vital step to obtain immune cells for autologous cell therapies. The ability to separate PBMCs using label-free microfluidic techniques, based on differences in biomechanical properties, can have a number of benefits over other conventional techniques, including lower cost, ease of use, and avoidance of animal-derived labeling antibodies. Here, we report a microfluidic device that uses compressive diagonal ridges to separate PBMCs into highly pure samples of viable and functional lymphocytes. The technique utilizes the differences in the biophysical properties of PBMC sub-populations to direct the lymphocytes and monocytes into separate outlets. The biophysical properties of the monocytes and lymphocytes from healthy donors were first characterized using atomic force microscopy. Lymphocytes were found to be significantly stiffer than monocytes, with a mean cell stiffness of 1495 and 931 Pa, respectively. The differences in biophysical properties resulted in distinct trajectories through the microchannel terminating at different outlets, resulting in a lymphocyte sample with purity and viability both greater than 96% with no effect on the cells' ability to produce interferon gamma, a cytokine crucial for innate and adaptive immunity.