Appraising Jackson-based unrestorability to competence to stand trial: The demonstration model.

Under United States law, criminal prosecution may not proceed against a defendant who is incompetent to participate in this process. The vast majority of defendants who are adjudicated incompetent to stand trial (IST) will subsequently regain sufficient capacities to be adjudicated competent to stand trial (CST). However, a small subgroup of defendants do not show sufficient improvement in clinical functioning and functional-legal capacities to regain CST. Under Jackson v. Indiana (1972), such individuals should be adjudicated unrestorably IST, with associated actions (e.g., dropping of criminal charges, civil commitment, transfer to a less restrictive environment or released) specified under the particular jurisdictional statutes. But the present practices associated with the evaluation of unrestorability do not appear well supported by research. In particular, statutorily specified evaluative procedures are overly dependent on prediction in some instances and allow an unnecessarily long restoration period in others. In the present article, we propose and describe an alternative approach-the Demonstration Model-that would address both challenges, providing a more consistent and standard approach to assessing CST and the possibility that a defendant may not recover needed capacities within the foreseeable future. Implementation of this approach can potentially guide restoration planning and intervention, decrease unsupported reliance upon prediction in favor of observing and documenting the results of selected interventions, and provide legal decision-makers with clearer and more transparent evidence, while acknowledging the liberty interests of IST defendants set forth in Jackson. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Phage-Related Ribosomal Protease (Prp) of Staphylococcus aureus: In Vitro Michaelis-Menten Kinetics, Screening for Inhibitors, and Crystal Structure of a Covalent Inhibition Product Complex.

Phage-related ribosomal proteases (Prps) are essential for the assembly and maturation of the ribosome in Firmicutes, including the human pathogens Staphylococcus aureus, Streptococcus pneumoniae, and Clostridium difficile. These bacterial proteases cleave off an N-terminal extension of a precursor of ribosomal protein L27, a processing step that is essential for the formation of functional ribosomes. This essential role of Prp in these pathogens has identified this protease as a potential antibiotic target. In this work, we determine the X-ray crystal structure of a covalent inhibition complex at 2.35 Å resolution, giving the first complete picture of the active site of a functional Prp. We also characterize the kinetic activity and screen for potential inhibitors of Prp. This work gives the most complete characterization of the structure and specificity of this novel class of proteases to date.

Rheumatologic diseases in patients with inborn errors of immunity in the USIDNET registry.

There is a gap in clinical knowledge regarding associations between specific inborn errors of immunity (IEIs) and rheumatologic diseases. This study reports the frequency of rheumatologic conditions in a large cohort of patients with IEI using the USIDNET (United States Immunodeficiency Network) registry. We used the USIDNET registry to conduct the analysis. We included all IEI patients within the registry for whom a diagnosed rheumatologic disease was reported. The total number of patients with IEI in our query was 5058. Among those, 278 (5.49%) patients had a diagnosis of rheumatologic disease. This cohort included 172 (61.8%) female and 106 (38.2%) male patients. Rheumatologic complications were highest in the interferonopathies (66.6%), autoimmune lymphoproliferative syndrome (ALPS) (13.7%), and immunoglobulin G subclass deficiency (IgGSD) (11.11%). Additionally, disease patterns were noted to be different in various IEI disease groups. Inflammatory myopathies were the most common rheumatologic condition in patients with X-linked agammaglobulinemia (1.65%), Sjogren's syndrome was the most common rheumatologic disease reported in ALPS patients (6.85%), and systemic lupus erythematosus was the most common rheumatologic disease in patients with chronic mucocutaneous candidiasis (CMC) (7.41%). Rheumatoid arthritis (RA) report rate was highest in patients with IgGSD (3.70%), specific antibody deficiency (SAD) (3.66%), and ALPS (2.74%). This study reports that rheumatologic diseases are frequently observed in patients with IEI. The frequency of different rheumatologic conditions was variable based on the underlying diagnosis. Clinicians caring for patients with IEI should be vigilant to monitor for rheumatologic complications. Key Points • The rates of reported rheumatologic diseases in the USIDNET registry are different in individual IEIs. • Further studies are needed to guide clinicians for detecting rheumatologic conditions earlier in patients with IEI.

Development of a patient-reported outcomes and experience measure for Orthognathic surgery: validation of the Northwick Park Orthognathic Questionnaire (NOQ).

Orthognathic surgery aims to correct dentoskeletal and facial discrepancies. The expected benefits are functional, cosmetic, and psychological. In a previous publication, this group assessed the determinants of patient satisfaction to formulate the Northwick Park Orthognathic Questionnaire (NOQ). The aim of the present study was to validate this questionnaire. A total of 118 postoperative patients prospectively completed the NOQ, 30 of whom completed the questionnaire a second time. The mean completion rate was 87.6 ± 10%. Response reproducibility was high: 92% of patients gave identical responses (range 81-100%). The intra-class correlation coefficient (ICC) was 0.96 (0.96 ± 0.072). Average test-retest scores for each domain were as follows (range in parenthesis): reasons for treatment 93% (60-100%), preoperative experience 96% (81-100%), preparation for surgery 95% (81-100%), inpatient experience 89% (55-100%), post-discharge experience 83% (55-100%), benefits of treatment 92% (71-100%), overall patient education 91% (62-100%). Internal validity using Cronbach's alpha was 0.72 (standard deviation 0.23, range 0.5-1). The results confirm the consistency of responses and the reliability of the information collected with the NOQ. The NOQ is a novel questionnaire and a valid metric to quantify a patient's perception of their experience. Its adoption may aid in making targeted improvements to patient care.

The stoned age: Sex differences in the effects of adolescent cannabinoid exposure on prefrontal cortex structure and function in animal models.

Cannabis is the most used drug during adolescence, which is a period of enhanced cortical plasticity and synaptic remodeling that supports behavioral, cognitive, and emotional maturity. In this chapter, we review preclinical studies indicating that adolescent exposure to cannabinoids has lasting effects on the morphology and synaptic organization of the prefrontal cortex and associated circuitry, which may lead to cognitive dysfunction later in life. Additionally, we reviewed sex differences in the effects of adolescent cannabinoid exposure with a focus on brain systems that support cognitive functioning. The body of evidence indicates enduring sex-specific effects in behavior and organization of corticolimbic circuitry, which appears to be influenced by species, strain, drug, route of administration, and window/pattern of drug exposure. Caution should be exercised when extrapolating these results to humans. Adopting models that more closely resemble human cannabis use will provide more translationally relevant data concerning the long-term effects of cannabis use on the adolescent brain.

Development of Genetically Encoded Biosensors for Reporting the Methyltransferase-Dependent Biosynthesis of Semisynthetic Macrolide Antibiotics.

Clarithromycin is an improved semisynthetic analogue of the naturally occurring macrolide, erythromycin. The subtle modification of a methyl group on the C-6 hydroxyl group endows the molecule with improved acid stability and results in a clinically useful antibiotic. Here, we show that the effector specificity of the biosensor protein, MphR, can be evolved to selectively recognize clarithromycin and therefore report on the production of this molecule in vivo. In addition, a crystal structure of the evolved variant reveals the molecular basis for selectivity and provides a guide for the evolution of a new metabolic function using this biosensor.

Type I interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression.

Interferons (IFNs) are key regulators of a number of inflammatory conditions in which neutrophils play an important role in pathology, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), where type I IFNs are implicated in disease pathology. However, IFNs are usually generated in vivo together with other cytokines that also have immunoregulatory functions, but such interactions are poorly defined experimentally. We measured the effects of type I (IFN-α) IFN, elevated in both RA and SLE, on the functions of healthy neutrophils incubated in vitro in the absence and presence of proinflammatory cytokines typically elevated in inflammatory diseases [tumour necrosis factor (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF)]. IFN-α alone had no effect on neutrophil apoptosis; however, it abrogated the anti-apoptotic effect of GM-CSF (18 h, P < 0·01). The enhanced stability of the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and delayed activation of caspase activation normally regulated by GM-CSF were blocked by IFN-α: this effect was mediated, in part, by activation of p38 mitogen-activated protein kinase (MAPK). IFN-α alone also primed reactive oxygen species (ROS) production and maintained the transient priming effect of TNF-α for up to 4 h: it also down-regulated GM-CSF- and TNF-α-activated expression of chemokine (C-X-C motif) ligand (CXCL)1, CXCL2, CXCL3, CXCL8, CCL3 and CCL4 but, in contrast, increased the expression of CXCL10. These novel data identify complex regulatory signalling networks in which type I IFNs profoundly alter the response of neutrophils to inflammatory cytokines. This is likely to have important consequences in vivo and may explain the complexity and heterogeneity of inflammatory diseases such as RA, in which multiple cytokine cascades have been activated.

Pulmonary manifestations and management of COVID-19 pediatric patients admitted in a tertiary government hospital

@#Background. Coronavirus Disease 2019 (COVID-19) presents with respiratory signs and symptoms in children. Presently, there are no local studies on the pulmonary manifestations and management of COVID-19 among children. Objective. Our study aimed to identify and describe the presenting respiratory signs and symptoms, oxygenation status, radiologic findings, blood gas analysis, and pulmonary interventions among children admitted for COVID-19. We also analyzed the clinical and radiologic variables associated with mortality. Methodology. This is a retrospective study using data obtained from a review of medical records from April 1, 2020, to June 30, 2020, at a tertiary government institution in the Philippines. All pediatric patients (0-18 years) hospitalized for probable or confirmed COVID-19 during the said time period were included in this study. Univariate and multivariate logistic regression was applied to determine factors affecting mortality. Results. A total of 25 pediatric patients with a mean age of 7 years old (age range: 11 days to 18 years) were admitted for COVID-19. Cough (44%) and dyspnea (24%) were the most common presenting respiratory symptoms, while tachypnea (68%), crackles (36%), and peripheral oxygen desaturation (36%) were the most common respiratory signs. Indeterminate findings for COVID-19 such as multifocal or diffuse ground-glass opacities and/or consolidations were the most common radiographic abnormalities. Invasive ventilatory support was administered to 6 cases of severe COVID-19 and 4 critical cases. There were no variables that correlated significantly with mortality. Conclusion. Respiratory signs and symptoms were prominent in our cohort of children admitted due to COVID-19. Mechanical ventilation was required in more severe cases. Larger prospective studies may help identify variables that significantly correlate with poor outcomes among children with COVID-19.

A novel toolkit for the prediction of clinical outcomes following mechanical thrombectomy.

AIM: To develop a robust toolkit to aid decision-making for mechanical thrombectomy (MT) based on readily available patient variables that could accurately predict functional outcome following MT. MATERIALS AND METHODS: Data from patients with anterior circulation stroke who underwent MT between October 2009 and January 2018 (n=239) were identified from our MT database. Patient explanatory variables were age, sex, National Institutes of Health Stroke Scale (NIHSS), Alberta Stroke Program Early CT Score (ASPECTS), collateral score, and Glasgow Coma Scale. Five models were developed from the data to predict five outcomes of interest: model 1: prediction of survival: modified Rankin Scale (mRS) of 0-5 (alive) or 6 (dead); model 2: prediction of good/poor outcome: mRS of 0-3 (good), or 4-6 (poor); model 3: prediction of good/poor outcome: mRS of 0-2 (good), or 3-6 (poor); model 4: prediction of mRS category: mRS of 0-2 (no disability), 3 (minor disability), 4-5 (severe disability) or 6 (dead); model 5: prediction of the exact mRs score (mRs as a continuous variable). The accuracy and discriminative power of each predictive model were tested. RESULTS: Prediction of survival was 87% accurate (area under the curve [AUC] 0.89). Prediction of good/poor outcome was 91% accurate (AUC 0.94) for Model 2 and 95% accurate (AUC 0.98) for Model 3. Prediction of mRS category was 76% accurate, and increased to 98% using the "one-score-out rule". Prediction of the exact mRS value was accurate to an error of 0.89. CONCLUSIONS: This novel toolkit provided accurate estimations of outcome for MT.

APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNFα expression and signalling.

Neutrophils are key players in the pathophysiological process underlying inflammatory conditions not only by release of tissue-damaging cytotoxic enzymes, reactive oxygen species (ROS) but also by secretion of important immunomodulatory chemokines and cytokines. Here, we report the effects of the novel agent APPA, undergoing formal clinical development for treatment of osteoarthritis, and its constituent components, apocynin (AP) and paeonol (PA) on a number of neutrophil functions, including effects on TNFα- expression and signalling. Neutrophils were treated with APPA (10-1000 µg/mL) prior to the measurement of cell functions, including ROS production, chemotaxis, apoptosis and surface receptor expression. Expression levels of several key genes and proteins were measured after incubation with APPA and the chromatin re-modelling agent, R848. APPA did not significantly affect phagocytosis, bacterial killing or expression of surface receptors, while chemotactic migration was affected only at the highest concentrations. However, APPA down-regulated neutrophil degranulation and ROS levels, and decreased the formation of neutrophil extracellular traps. APPA also decreased cytokine-stimulated gene expression, inhibiting both TNFα- and GM-CSF-induced cell signalling. APPA was as effective as infliximab in down-regulating chemokine and IL-6 expression following incubation with R848. Whilst APPA does not interfere with neutrophil host defence against infections, it does inhibit neutrophil degranulation, and cytokine-driven signalling pathways (e.g. autocrine signalling and NF-κB activation), processes that are associated with inflammation. These observations may explain the mechanisms by which APPA exerts anti-inflammatory effects and suggests a potential therapeutic role in inflammatory diseases in which neutrophils and TNFα signalling are important in pathology, such as rheumatoid arthritis.

Correction: Evidence-Based Guideline on Laparoscopy in Pregnancy: Commissioned by the British Society for Gynaecological Endoscopy (BSGE) Endorsed by the Royal College of Obstetricians & Gynaecologists (RCOG).

[This corrects the article on p. 5 in vol. 11, PMID: 31695854.].

Evidence-Based Guideline on Laparoscopy in Pregnancy: Commissioned by the British Society for Gynaecological Endoscopy (BSGE) Endorsed by the Royal College of Obstetricians & Gynaecologists (RCOG).

Laparoscopy is widely utilised to diagnose and treat acute and chronic, gynaecological and general surgical conditions. It has only been in recent years that laparoscopy has become an acceptable surgical alternative to open surgery in pregnancy. To date there is little clinical guidance pertaining to laparoscopic surgery in pregnancy. This is why the BSGE commissioned this guideline. MEDLINE, EMBASE, CINAHL and the Cochrane library were searched up to February 2017 and evidence was collated and graded following the NICE-approved process. The conditions included in this guideline are laparoscopic management of acute appendicitis, acute gall bladder disease and symptomatic benign adnexal tumours in pregnancy. The intended audience for this guideline is obstetricians and gynaecologists in secondary and tertiary care, general surgeons and anaesthetists. However, only laparoscopists who have adequate laparoscopic skills and who perform complex laparoscopic surgery regularly should undertake laparoscopy in pregnant women, since much of the evidence stems from specialised centres.

The 2017-19 activity at Mount Agung in Bali (Indonesia): Intense unrest, monitoring, crisis response, evacuation, and eruption.

After 53 years of quiescence, Mount Agung awoke in August 2017, with intense seismicity, measurable ground deformation, and thermal anomalies in the summit crater. Although the seismic unrest peaked in late September and early October, the volcano did not start erupting until 21 November. The most intense explosive eruptions with accompanying rapid lava effusion occurred between 25 and 29 November. Smaller infrequent explosions and extrusions continue through the present (June 2019). The delay between intense unrest and eruption caused considerable challenges to emergency responders, local and national governmental agencies, and the population of Bali near the volcano, including over 140,000 evacuees. This paper provides an overview of the volcanic activity at Mount Agung from the viewpoint of the volcano observatory and other scientists responding to the volcanic crisis. We discuss the volcanic activity as well as key data streams used to track it. We provide evidence that magma intruded into the mid-crust in early 2017, and again in August of that year, prior to intrusion of an inferred dike between Mount Agung and Batur Caldera that initiated an earthquake swarm in late September. We summarize efforts to forecast the behavior of the volcano, to quantify exclusion zones for evacuations, and to work with emergency responders and other government agencies to make decisions during a complex and tense volcanic crisis.

Oncology Association of Naturopathic Physicians: Principles of Care Guidelines.

Patient use of integrative oncology (the inclusion of nonconventional treatments alongside the conventional standard of care) continues to grow, with some studies showing its use in cancer patients to be as high as 91%. Naturopathic physicians are primary care providers who use integrative therapies to deliver patient-centred care. The Oncology Association of Naturopathic Physicians (oncanp) was formed in 2004 as a specialty association for naturopathic physicians providing integrative cancer care (nd oncs). Currently, the membership encompasses more than 400 naturopathic physicians and students, 115 of whom are board-certified Fellows of the American Board of Naturopathic Oncology. In 2016, oncanp established a committee comprising recognized experts in the field of naturopathic oncology to develop a Principles of Care (poc) guideline. The committee first undertook a review of existing standard-of-care and best-practice guidelines in the field of oncology and then adapted those concepts into a draft document. The draft document was then reviewed by naturopathic physicians, medical and radiation oncologists, naturopathic policy experts, and finally the oncanp membership at large. The poc document presented here provides clear guidelines for nd oncs on how best to deliver patient-centred care in the areas of assessment, treatment planning, care management, interprofessional collaboration, and survivorship care. This naturopathic oncology poc document can be a valuable resource for nd oncs and other oncology care providers to further an understanding of the naturopathic and integrative oncology care model and its potential for collaboration.

Fourier transform infrared spectra of cells on glass coverslips. A further step in spectral pathology.

Over the last few years, great effort has been placed on developing Fourier Transform Infrared (FTIR) microspectroscopy as a tool to help in the histopathological diagnosis of cancer. The ever increasing workload in pathology departments is calling for a technique that could identify the presence of cancer cells in cytology and tissue samples in an objective, fast and automated way. However, pathologists use glass slides which absorb infrared (IR) radiation thus removing important mid-IR spectral data in the fingerprint region (proteins, DNA, RNA; 1800 cm-1 to 900 cm-1). To this purpose, we hypothesised whether using thinner glass slides, i.e., glass coverslips, would allow us to obtain spectral data not only from the lipid region (3100 cm-1 to 2700 cm-1) but also from the fingerprint region. To this purpose, we studied peripheral blood mononuclear cells (PBMC), a leukaemia cell line (K562) and a lung cancer cell line (CALU-1). Cells were placed on DAKO coverslips and their FTIR spectra obtained at MIRAS beamline, Alba synchrotron light source (Barcelona, Catalonia). The data presented here not only shows for the first time that it is possible to obtain spectral data from most of the amide I region (1800 cm-1 to 1570 cm-1) of cells placed on glass coverslips but more important, principal component analysis was able to separate between the three types of cells for both the lipid and the amide I regions. The methodology here described is a further step in the application of FTIR microspectroscopy in histopathology departments.

Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach.

This article reviews intravenous vitamin C (IV C) in cancer care and offers a rational approach to enable medical oncologists and integrative practitioners to safely provide IV C combined with oral vitamin C to patients. The use of IV C is a safe supportive intervention to decrease inflammation in the patient and to improve symptoms related to antioxidant deficiency, disease processes, and side effects of standard cancer treatments. A proposed rationale, together with relevant clinical safety considerations for the application of IV C in oncologic supportive care, is provided.

Cigarette smoke modifies neutrophil chemotaxis, neutrophil extracellular trap formation and inflammatory response-related gene expression.

BACKGROUND AND OBJECTIVE: Cigarette smoking is a major risk factor for periodontitis, and smoking perturbs neutrophil reactive oxygen species production. This study tested the hypothesis that cigarette smoke extract (CSE) and its components/metabolites nicotine, cotinine and thiocyanate (SCN-), may influence neutrophil functions. MATERIAL AND METHODS: Chemotaxis was assessed in neutrophils pre-treated with CSE using real-time video microscopy. Neutrophil extracellular trap (NET) release in response to CSE, nicotine, cotinine, SCN- as well as to phorbol 12-myristate-13-acetate and hypochlorous acid following pre-treatment with CSE, nicotine, cotinine or SCN- was assessed using fluorescence-based assays. The impact of CSE and SCN- treatment on neutrophil respiratory burst- and inflammation-related gene expression (NFKBIE, DNAJB1, CXCL8, NCF1, NCF2, CYBB) was determined by real-time polymerase chain reaction. RESULTS: Both CSE and SCN- pre-treatment inhibited phorbol 12-myristate-13-acetate-stimulated NET release. Additionally, SCN- inhibited hypochlorous acid-stimulated NET formation, while SCN- alone stimulated NET release. Overall, neutrophils pre-treated with CSE exhibited reduced speed, velocity and directionality relative to untreated neutrophils. Although CSE and SCN- promoted DNAJB1 expression, increased redox-related gene expression was only detected in response to SCN-. CONCLUSION: These results suggest that CSE can alter ex vivo neutrophil activation by mechanisms independent of SCN- and nicotine, and SCN- may contribute to the perturbed innate immune responses observed in smokers.

The CDK inhibitor purvalanol A induces neutrophil apoptosis and increases the turnover rate of Mcl-1: potential role of p38-MAPK in regulation of Mcl-1 turnover.

Human neutrophils are terminally differentiated cells that do not replicate and yet express a number of enzymes, notably cell cycle-dependent kinases (CDKs), that are associated normally with control of DNA synthesis and cell cycle progression. In neutrophils, CDKs appear to function mainly to regulate apoptosis, although the mechanisms by which they regulate this process are largely unknown. Here we show that the CDK2 inhibitor, purvalanol A, induces a rapid decrease in myeloid cell leukaemia factor-1 (Mcl-1) levels in human neutrophils and peripheral blood mononuclear cells (PBMCs), but only induces apoptosis in neutrophils which are dependent upon expression on this protein for survival. This rapid decrease in cellular Mcl-1 protein levels was due to a purvalanol A-induced decrease in stability, with the half-life of the protein decreasing from approximately 2 h in control cells to just over 1 h after addition of the CDK2 inhibitor: it also blocked the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent stabilization of Mcl-1. Purvanalol A blocked GM-CSF-stimulated activation of extracellular-regulated kinase (Erk) and signal transducer and activator of transcription (STAT)-3, and stimulated an additive activation of protein kinase B (Akt) with GM-CSF. Purvalanol A alone stimulated a rapid and sustained activation of p38-mitogen-activated protein kinase (MAPK) and the pan p38-MAPK inhibitor, BIRB796, partly blocked the purvalanol A-induced apoptosis and Mcl-1 loss. These novel effects of purvalanol A may result, at least in part, from blocking GM-CSF-mediated Erk activation. In addition, we propose that purvalanol A-induced activation of p38-MAPK is, at least in part, responsible for its rapid effects on Mcl-1 turnover and acceleration of neutrophil apoptosis.

Evaluation of mericon E. coli O157 Screen Plus and mericon E. coli STEC O-Type Pathogen Detection Assays in Select Foods: Collaborative Study, First Action 2017.05.

QIAGEN mericon Escherichia coli O157 Screen Plus and mericon E. coli Shiga toxin-producing E. coli (STEC) O-Type Pathogen Detection Assays use Real-Time PCR technology for the rapid, accurate detection of E. coli O157 and the "big six" (O26, O45, O103, O111, O121, O145) (non-O157 STEC) in select food types. Using a paired study design, the assays were compared with the U.S. Department of Agriculture, Food Safety Inspection Service Microbiology Laboratory Guidebook Chapter 5.09 reference method for the detection of E. coli O157:H7 in raw ground beef. Both mericon assays were evaluated using the manual and an automated DNA extraction method. Thirteen technicians from five laboratories located within the continental United States participated in the collaborative study. Three levels of contamination were evaluated. Statistical analysis was conducted according to the probability of detection (POD) statistical model. Results obtained for the low-inoculum level test portions produced a difference between laboratories POD (dLPOD) value with a 95% confidence interval of 0.00 (-0.12, 0.12) for the mericon E. coli O157 Screen Plus with manual and automated extraction and mericon E. coli STEC O-Type with manual extraction and -0.01 (-0.13, 0.10) for the mericon E. coli STEC O-Type with automated extraction. The dLPOD results indicate equivalence between the candidate methods and the reference method.

New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn?

BACKGROUND: Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made. AIMS: This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms. SOURCES: A review of the published literature via MEDLINE database was performed. Relevant clinical trials were identified with the aid of the clinicaltrials.gov registry. Further data were ascertained from review of abstracts from recent international meetings and pharmaceutical companies. CONTENT: Data on the mechanism of action, microbiological spectrum, clinical efficacy and development of resistance are reported for new agents that have activity against Gram-negative organisms. This includes the ß-lactam/ß-lactamase inhibitor combinations ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam and aztreonam/avibactam; cefiderocol, a siderophore cephalosporin; plazomicin and eravacycline. IMPLICATIONS: The development of new agents with activity against multidrug-resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-ß-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa, but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development.