Key Points

IRAK1 is hyperactivated in human preterm birth and in mouse and rhesus IUI models.

IRAK1 deletion and inhibition reduces preterm birth.

IRAK1 induces preterm birth by upregulating COX-2.

Background:

Despite widespread recognition that adherence to clinical preventive guidelines improves patient outcomes, clinicians struggle to implement guideline changes in a timely manner. Multiple factors influence guideline adoption and effective implementation. However, few studies evaluate their collective and inter-related effects. This qualitative study provides a comprehensive picture of the interplay between multiple factors on uptake of new or changed preventive guidelines.

Methods:

Semistructured interviews conducted in 2018 with a diverse sample of clinicians and practice leaders sought to understand patient, clinician, practice, health system, environment, and guideline factors of influence. An immersion-crystallization approach was used to identify emergent themes.

Results:

Interviewees expressed motivation to adhere to guidelines but also valued sharing decisions with patients. Personal biases and fears affected both clinician and patient guideline adoption. Practices facilitated implementation through workflow optimization and encouraging a culture of evidence-based practice while a key health system function was to maintain electronic health record alerts. More traditional environmental factors, such as insurance coverage or transportation, were less of a barrier to guideline adoption and implementation than the influence of media and specialists. Various specific guideline characteristics also affected ease of adoption and implementation. Different settings expressed greater health system, practice, or clinician-centric approaches to guideline implementation.

Conclusions:

Guideline uptake is influenced by a complex interplay of multiple levels of factors including the patient, clinician, practice, health system, environment, and guideline levels. Comprehensively understanding all levels of influence for each specific clinical setting may help to determine the optimal intervention(s) for improving uptake of evidence-based guidelines.

Family physician researchers continue to provide assistance to improve family medicine care. Commentaries on social determinants of health lead off this issue. Next, we have several papers on successful interventions by clinicians and/or patients to improve diabetes control, and then other provide information on other practice interventions that make a difference in overall care. Drug advertising continues to mislead. There is costly and nonproductive overuse of specific types of care. Herein is also a Scoping Review of possible indices for determining timely initiation of advance care planning. The issue’s clinical reviews on use of transgender care, cervical myelopathy, and inhaled steroids for chronic obstructive pulmonary disease are pertinent, thorough, and timely.

Background

Clinically significant CKD following surgery for kidney cancer is associated with increased morbidity and mortality, but identifying patients at increased CKD risk remains difficult. Simple methods to stratify risk of clinically significant CKD after nephrectomy are needed.

Methods

To develop a tool for stratifying patients’ risk of CKD arising after surgery for kidney cancer, we tested models in a population-based cohort of 699 patients with kidney cancer in Queensland, Australia (2012–2013). We validated these models in a population-based cohort of 423 patients from Victoria, Australia, and in patient cohorts from single centers in Queensland, Scotland, and England. Eligible patients had two functioning kidneys and a preoperative eGFR ≥60 ml/min per 1.73 m². The main outcome was incident eGFR <45 ml/min per 1.73 m² at 12 months postnephrectomy. We used prespecified predictors—age ≥65 years old, diabetes mellitus, preoperative eGFR, and nephrectomy type (partial/radical)—to fit logistic regression models and grouped patients according to degree of risk of clinically significant CKD (negligible, low, moderate, or high risk).

Results

Absolute risks of stage 3b or higher CKD were <2%, 3% to 14%, 21% to 26%, and 46% to 69% across the four strata of negligible, low, moderate, and high risk, respectively. The negative predictive value of the negligible risk category was 98.9% for clinically significant CKD. The c statistic for this score ranged from 0.84 to 0.88 across derivation and validation cohorts.

Conclusions

Our simple scoring system can reproducibly stratify postnephrectomy CKD risk on the basis of readily available parameters. This clinical tool’s quantitative assessment of CKD risk may be weighed against other considerations when planning management of kidney tumors and help inform shared decision making between clinicians and patients.

Background

Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload.

Methods

To investigate whether lower dialysate sodium during hemodialysis reduces left ventricular mass, we conducted a randomized trial in which patients received either low-sodium dialysate (135 mM) or conventional dialysate (140 mM) for 12 months. We included participants who were aged >18 years old, had a predialysis serum sodium ≥135 mM, and were receiving hemodialysis at home or a self-care satellite facility. Exclusion criteria included hemodialysis frequency >3.5 times per week and use of sodium profiling or hemodiafiltration. The main outcome was left ventricular mass index by cardiac magnetic resonance imaging.

Results

The 99 participants had a median age of 51 years old; 67 were men, 31 had diabetes mellitus, and 59 had left ventricular hypertrophy. Over 12 months of follow-up, relative to control, a dialysate sodium concentration of 135 mmol/L did not change the left ventricular mass index, despite significant reductions at 6 and 12 months in interdialytic weight gain, in extracellular fluid volume, and in plasma B-type natriuretic peptide concentration (ratio of intervention to control). The intervention increased intradialytic hypotension (odds ratio [OR], 7.5; 95% confidence interval [95% CI], 1.1 to 49.8 at 6 months and OR, 3.6; 95% CI, 0.5 to 28.8 at 12 months). Five participants in the intervention arm could not complete the trial because of hypotension. We found no effect on health-related quality of life measures, perceived thirst or xerostomia, or dietary sodium intake.

Conclusions

Dialysate sodium of 135 mmol/L did not reduce left ventricular mass relative to control, despite improving fluid status.

Clinical Trial registry name and registration number:

The Australian New Zealand Clinical Trials Registry, ACTRN12611000975998.

The kinetics, longevity, and breadth of antibodies to influenza virus neuraminidase (NA) in archival, sequential serum/plasma samples from influenza A virus (IAV) H5N1 infection survivors and from patients infected with the 2009 pandemic IAV (H1N1) virus were determined using an enzyme-linked lectin-based assay. The reverse-genetics-derived H4N1 viruses harboring a hemagglutinin (HA) segment from A/duck/Shan Tou/461/2000 (H4N9) and an NA segment derived from either IAV H5N1 clade 1, IAV H5N1 clade 2.3.4, the 2009 pandemic IAV (H1N1) (H1N1pdm), or A/Puerto Rico/8/1934 (H1N1) virus were used as the test antigens. These serum/plasma samples were also investigated by microneutralization (MN) and/or hemagglutination inhibition (HI) assays. Neuraminidase-inhibiting (NI) antibodies against N1 NA of both homologous and heterologous viruses were observed in H5N1 survivors and H1N1pdm patients. H5N1 survivors who were never exposed to H1N1pdm virus developed NI antibodies to H1N1pdm NA. Seroconversion of NI antibodies was observed in 65% of the H1N1pdm patients at day 7 after disease onset, but an increase in titer was not observed in serum samples obtained late in infection. On the other hand, an increase in seroconversion rate with the HI assay was observed in the follow-up series of sera obtained on days 7, 14, 28, and 90 after infection. The study also showed that NI antibodies are broadly reactive, while MN and HI antibodies are more strain specific.

We previously produced a heavy-chain-only antibody (Ab) VH domain (V_HH)-displayed phage library from two alpacas that had been immunized with ricin toxoid and nontoxic mixtures of the enzymatic ricin toxin A subunit (RTA) and binding ricin toxin B subunit (RTB) (D. J. Vance, J. M. Tremblay, N. J. Mantis, and C. B. Shoemaker, J Biol Chem 288:36538–36547, 2013, https://doi.org/10.1074/jbc.M113.519207). Initial and subsequent screens of that library by direct enzyme-linked immunosorbent assay (ELISA) yielded more than two dozen unique RTA- and RTB-specific V_HHs, including 10 whose structures were subsequently solved in complex with RTA. To generate a more complete antigenic map of ricin toxin and to define the epitopes associated with toxin-neutralizing activity, we subjected the V_HH-displayed phage library to additional "pannings" on both receptor-bound ricin and antibody-captured ricin. We now report the full-length DNA sequences, binding affinities, and neutralizing activities of 68 unique V_HHs: 31 against RTA, 33 against RTB, and 4 against ricin holotoxin. Epitope positioning was achieved through cross-competition ELISAs performed with a panel of monoclonal antibodies (MAbs) and verified, in some instances, with hydrogen-deuterium exchange mass spectrometry. The 68 V_HHs grouped into more than 20 different competition bins. The RTA-specific V_HHs with strong toxin-neutralizing activities were confined to bins that overlapped two previously identified neutralizing hot spots, termed clusters I and II. The four RTB-specific V_HHs with potent toxin-neutralizing activity grouped within three adjacent bins situated at the RTA-RTB interface near cluster II. These results provide important insights into epitope interrelationships on the surface of ricin and delineate regions of vulnerability that can be exploited for the purpose of vaccine and therapeutic development.

In the article "Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment" by Muñoz-Lopetegi et al.,¹ published online March 2, 2020, the y-axis label for figure 5’s right graph should be "CSF anti-GAD65 concentration (IU/mL)." The editorial office regrets the error.

Objective

To describe the presentations, radiologic features, and outcomes of children with autoimmune encephalitis associated with myelin oligodendrocyte glycoprotein antibodies (MOG abs).

Methods

Identification of children fulfilling the diagnostic criteria for possible autoimmune encephalitis (AE) and testing positive for serum MOG abs. Chart review and comprehensive analysis of serum MOG abs using live cell assays and rat brain immunohistochemistry.

Results

Ten children (4 girls, 6 boys) with AE and serum MOG abs were identified. The median age at onset was 8.0 years (range: 4–16 years). Children presented with a combination of encephalopathy (10/10), headache (7/10), focal neurologic signs (7/10), or seizures (6/10). CSF pleocytosis was common (9/10, median 80 white cell count/μL, range: 21–256). Imaging showed cortical and deep gray matter involvement in all in addition to juxtacortical signal alterations in 6/10 children. No involvement of other white matter structures or contrast enhancement was noted. MOG abs were detected in all children (median titer 1:640; range: 1:320–1:10,540). Nine children had a favorable outcome at discharge (modified Rankin scale of < 2). Five of 10 children had up to 3 additional demyelinating relapses associated with persisting MOG abs. One child had NMDA receptor (NMDAR) abs at initial presentation. A second child had a third demyelinating episode with MOG abs with overlapping NMDAR encephalitis.

Discussion

AE associated with serum MOG abs represents a distinct form of autoantibody-mediated encephalitis in children. We therefore recommend including MOG abs testing in the workup of children with suspected AE.

Objective

To determine the characteristic clinical and spinal MRI phenotypes of sarcoidosis-associated myelopathy (SAM), we analyzed a large cohort of patients with this disorder.

Methods

Patients diagnosed with SAM at a single center between 2000 and 2018 who met the established criteria for definite and probable neurosarcoidosis were included in a retrospective analysis to identify clinical profiles, CSF characteristics, and MRI lesion morphology.

Results

Of 62 included patients, 33 (53%) were male, and 30 (48%) were African American. SAM was the first clinical presentation of sarcoidosis in 49 patients (79%). Temporal profile of symptom evolution was chronic in 81%, with sensory symptoms most frequently reported (87%). CSF studies showed pleocytosis in 79% and CSF-restricted oligoclonal bands in 23% of samples tested. Four discrete patterns of lesion morphology were identified on spine MRI: longitudinally extensive myelitis (n = 28, 45%), short tumefactive myelitis (n = 14, 23%), spinal meningitis/meningoradiculitis (n = 14, 23%), and anterior myelitis associated with areas of disc degeneration (n = 6, 10%). Postgadolinium enhancement was seen in all but 1 patient during the acute phase. The most frequent enhancement pattern was dorsal subpial enhancement (n = 40), followed by meningeal/radicular enhancement (n = 23) and ventral subpial enhancement (n = 12). In 26 cases (42%), enhancement occurred at locations with coexisting structural changes (e.g., spondylosis).

Conclusions

Recognition of the clinical features (chronically evolving myelopathy) and distinct MRI phenotypes (with enhancement in a subpial and/or meningeal pattern) seen in SAM can aid diagnosis of this disorder. Enhancement patterns suggest that SAM may have a predilection for areas of the spinal cord susceptible to mechanical stress.

Infections due to methicillin-resistant Staphylococcus aureus (MRSA) are present worldwide and represent a major public health concern. The capability of PCR followed by high-resolution melt (HRM) curve analysis for the detection of community-associated and livestock-associated MRSA strains and the identification of staphylococcal protein A (spa) locus was evaluated in 74 MRSA samples which were isolated from the environment, humans, and pigs on a single piggery. PCR-HRM curve analysis identified four spa types among MRSA samples and differentiated MRSA strains accordingly. A nonsubjective differentiation model was developed according to genetic confidence percentage values produced by tested samples, which did not require visual interpretation of HRM curve results. The test was carried out at different settings, and result data were reanalyzed and confirmed with DNA sequencing. PCR-HRM curve analysis proved to be a robust and reliable test for spa typing and can be used as a tool in epidemiological studies.

Q fever, caused by Coxiella burnetii, is a worldwide zoonotic disease that may cause severe forms in humans and requires a specific and prolonged antibiotic treatment. Although current serological and molecular detection tools allow a reliable diagnosis of the disease, culture of C. burnetii strains is mandatory to assess their susceptibility to antibiotics and sequence their genome in order to optimize patient management and epidemiological studies. However, cultivating this fastidious microorganism is difficult and restricted to reference centers, as it requires biosafety level 3 laboratories and relies on cell culture performed by experienced technicians. In addition, the culture yield is low, which results in a small number of isolates being available. In this work, we developed a novel high-content screening (HCS) isolation strategy based on optimized high-throughput cell culture and automated microscopic detection of infected cells with specifically designed algorithms targeting cytopathic effects. This method was more efficient than the shell vial assay, at the level of time dependency, when applied to both frozen specimens (7 isolates recovered by HCS only, sensitivity 91% versus 78% for shell vial) and fresh samples (1 additional isolate using HCS, sensitivity 7% versus 5% for shell vial), for which most strains were recovered more rapidly with the new technique. In addition, detecting positive cultures by an automated microscope reduced the need for expertise and saved 24% of technician working time. Application of HCS to antibiotic susceptibility testing of 12 strains demonstrated that it was as efficient as the standard procedure that combines shell vial culture and quantitative PCR.

Limited treatment options contribute to high morbidity/mortality rates with carbapenem-resistant, Gram-negative bacterial infections. New approaches for carbapenemase-producing organism (CPO) detection may help inform clinician decision-making on patient treatment and infection control. BD Phoenix CPO detect (CPO detect) detects and classifies carbapenemases in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa during susceptibility testing. The clinical performance of CPO detect is reported here. Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa isolates were evaluated across three sites using CPO detect and a composite reference method (RM); the latter was comprised of the modified carbapenem inactivation method and a MIC screen for ertapenem, imipenem, and meropenem. Multiplex PCR testing was also utilized for Ambler class determination. Positive and negative percentages of agreement (PPA and NPA, respectively) between CPO detect and the RM were determined. The PPA and NPA for Enterobacterales were 98.5% (confidence intervals, 96.6%, 99.4%) and 97.2% (95.8%, 98.2%), respectively. The A. baumannii PPA and NPA, respectively, were 97.1% (90.2%, 99.2%) and 97.1% (89.9%, 99.2%). The P. aeruginosa PPA and NPA, respectively, were 95.9% (88.6%, 98.6%) and 92.3% (86.7%, 95.6%). The PPA values for carbapenemase class designations for all organisms combined and Enterobacterales alone, respectively, were 95.3% (90.2%, 97.8%) and 94.6% (88.8%, 97.5%) for class A, 94.0% (88.7%, 96.6%) and 96.4% (90.0%, 98.8%) for class B, and 95.0% (90.1%, 97.6%) and 99.0% (94.4%, 99.8%) for class D carbapenemases. NPA values for all organisms and Enterobacterales alone ranged from 98.5% to 100%. CPO detect provided accurate detection and classification of CPOs for the majority of isolates of Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa tested.

Clostridioides difficile infection (CDI) is one of the most common health care-associated infections that can cause significant morbidity and mortality. CDI diagnosis involves laboratory testing in conjunction with clinical assessment. The objective of this study was to assess the performance of various C. difficile tests and to compare clinical characteristics, Xpert C. difficile/Epi (PCR) cycle threshold (C_T), and Singulex Clarity C. diff toxins A/B (Clarity) concentrations between groups with discordant test results. Unformed stool specimens from 200 hospitalized adults (100 PCR positive and 100 negative) were tested by cell cytotoxicity neutralization assay (CCNA), C. diff Quik Chek Complete (Quik Chek), Premier Toxins A and B, and Clarity. Clinical data, including CDI severity and CDI risk factors, were compared between discordant test results. Compared to CCNA, PCR had the highest sensitivity at 100% and Quik Chek had the highest specificity at 100%. Among clinical and laboratory data studied, prevalences of leukocytosis, prior antibiotic use, and hospitalizations were consistently higher across all subgroups in comparisons of toxin-positive to toxin-negative patients. Among PCR-positive samples, the median C_T was lower in toxin-positive samples than in toxin-negative samples; however, C_T ranges overlapped. Among Clarity-positive samples, the quantitative toxin concentration was significantly higher in toxin-positive samples than in toxin-negative samples as determined by CCNA and Quik Chek Toxin A and B. Laboratory tests for CDI vary in sensitivity and specificity. The quantitative toxin concentration may offer value in guiding CDI diagnosis and treatment. The presence of leukocytosis, prior antibiotic use, and previous hospitalizations may assist with CDI diagnosis, while other clinical parameters may not be consistently reliable.

The number of onsite clinical microbiology laboratories in hospitals is decreasing, likely related to the business model for laboratory consolidation and labor shortages, and this impacts a variety of clinical practices, including that of banking isolates for clinical or epidemiologic purposes. To determine the impact of these trends, infectious disease (ID) physicians were surveyed regarding their perceptions of offsite services. Clinical microbiology practices for retention of clinical isolates for future use were also determined. Surveys were sent to members of the Infectious Diseases Society of America’s (IDSA) Emerging Infections Network (EIN). The EIN is a sentinel network of ID physicians who care for adult and/or pediatric patients in North America and who are members of IDSA. The response rate was 763 (45%) of 1,680 potential respondents. Five hundred forty (81%) respondents reported interacting with the clinical microbiology laboratory. Eighty-six percent of respondents thought an onsite laboratory very important for timely diagnostic reporting and ongoing communication with the clinical microbiologist. Thirty-five percent practiced in institutions where the core microbiology laboratory has been moved offsite, and an additional 7% (n = 38) reported that movement of core laboratory functions offsite was being considered. The respondents reported that only 24% of laboratories banked all isolates, with the majority saving isolates for less than 30 days. Based on these results, the trend toward centralized core laboratories negatively impacts the practice of ID physicians, potentially delays effective implementation of prompt and targeted care for patients with serious infections, and similarly adversely impacts infection control epidemiologic investigations.

Human herpesvirus 6 (HHV-6) is an important cause of meningitis and meningoencephalitis. As testing for HHV-6 in cerebrospinal fluid (CSF) is more readily available using the FilmArray Meningitis/Encephalitis panel (FA-ME; BioFire Diagnostics, Salt Lake City, UT), we aimed to determine the clinical significance of detecting HHV-6 in order to identify true infections and to ensure appropriate antiviral initiation. Chart review on 25 patients positive for HHV-6 by FA-ME was performed to determine clinical presentation, comorbidity, treatment, and outcome. The presence of chromosomally integrated HHV-6 (ciHHV-6) DNA was also investigated. Of 1,005 children tested by FA-ME, HHV-6 was detected in 25 (2.5%). Five patients were diagnosed with either HHV-6 meningitis or meningoencephalitis based on HHV-6 detection in CSF, clinical presentation, and radiographic findings. Detection of HHV-6 by FA-ME led to discontinuation of acyclovir within 12.0 h in all 12 patients empirically treated with acyclovir. Six of the 12 patients were started on ganciclovir therapy within 6.8 h; 4 of these were treated specifically for HHV-6 infection, whereas therapy was discontinued in the remaining 2 patients. CSF parameters were not generally predictive of HHV-6 positivity. The presence of ciHHV-6 was confirmed in 3 of 18 patients who could be tested. Five of the 25 patients included in the study were diagnosed with HHV-6 meningitis/meningoencephalitis. FA-ME results led to discontinuation of empirical antiviral treatment in 12 patients and appropriate initiation of ganciclovir in 4 patients. In our institution, detection of HHV-6 using FA-ME led to faster establishment of disease etiology and optimization of antimicrobial therapy.

On 31 December 2019, the World Health Organization was informed of a cluster of cases of pneumonia of unknown etiology in Wuhan, China. Subsequent investigations identified a novel coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), from the affected patients. Highly sensitive and specific laboratory diagnostics are important for controlling the rapidly evolving SARS-CoV-2-associated coronavirus disease 2019 (COVID-19) epidemic. In this study, we developed and compared the performance of three novel real-time reverse transcription-PCR (RT-PCR) assays targeting the RNA-dependent RNA polymerase (RdRp)/helicase (Hel), spike (S), and nucleocapsid (N) genes of SARS-CoV-2 with that of the reported RdRp-P2 assay, which is used in >30 European laboratories. Among the three novel assays, the COVID-19-RdRp/Hel assay had the lowest limit of detection in vitro (1.8 50% tissue culture infective doses [TCID₅₀]/ml with genomic RNA and 11.2 RNA copies/reaction with in vitro RNA transcripts). Among 273 specimens from 15 patients with laboratory-confirmed COVID-19 in Hong Kong, 77 (28.2%) were positive by both the COVID-19-RdRp/Hel and RdRp-P2 assays. The COVID-19-RdRp/Hel assay was positive for an additional 42 RdRp-P2-negative specimens (119/273 [43.6%] versus 77/273 [28.2%]; P < 0.001), including 29/120 (24.2%) respiratory tract specimens and 13/153 (8.5%) non-respiratory tract specimens. The mean viral load of these specimens was 3.21 x 10⁴ RNA copies/ml (range, 2.21 x 10² to 4.71 x 10⁵ RNA copies/ml). The COVID-19-RdRp/Hel assay did not cross-react with other human-pathogenic coronaviruses and respiratory pathogens in cell culture and clinical specimens, whereas the RdRp-P2 assay cross-reacted with SARS-CoV in cell culture. The highly sensitive and specific COVID-19-RdRp/Hel assay may help to improve the laboratory diagnosis of COVID-19.

ABSTRACTBackground:The focused assessment with sonography for HIV-associated tuberculosis (TB) (FASH) ultrasound protocol has been increasingly used to help clinicians diagnose TB. We sought to quantify the diagnostic utility of FASH for TB among individuals with HIV in Malawi.Methods:Between March 2016 and August 2017, 210 adults with HIV who had 2 or more signs and symptoms that were concerning for TB (fever, cough, night sweats, weight loss) were enrolled from a public HIV clinic in Lilongwe, Malawi. The treating clinicians conducted a history, physical exam, FASH protocol, and additional TB evaluation (laboratory diagnostics and chest radiography) on all participants. The clinician made a final treatment decision based on all available information. At the 6-month follow-up visit, we categorized participants based on clinical outcomes and diagnostic tests as having probable/confirmed TB or unlikely TB; association of FASH with probable/confirmed TB was calculated using Fisher's exact tests. The impact of FASH on empiric TB treatment was determined by asking the clinicians prospectively about whether they would start treatment at 2 time points in the baseline visit: (1) after the initial history and physical exam; and (2) after history, physical exam, and FASH protocol.Results:A total of 181 participants underwent final analysis, of whom 56 were categorized as probable/confirmed TB and 125 were categorized as unlikely TB. The FASH protocol was positive in 71% (40/56) of participants with probable/confirmed TB compared to 24% (30/125) of participants with unlikely TB (odds ratio=7.9, 95% confidence interval=3.9,16.1; P<.001). Among those classified as confirmed/probable TB, FASH increased the likelihood of empiric TB treatment before obtaining any other diagnostic studies from 9% (5/56) to 46% (26/56) at the point-of-care. For those classified as unlikely TB, FASH increased the likelihood of empiric treatment from 2% to 4%.Conclusion:In the setting of HIV coinfection in Malawi, FASH can be a helpful tool that augments the clinician's ability to make a timely diagnosis of TB.

Background:

The number of medical undergraduate and postgraduate students completing palliative care clinical rotations in Canadian medical schools is currently unknown. The aim of this study was to assess the proportion of Canadian medical trainees completing clinical rotations in palliative care and to determine whether changes took place between 2008 and 2018.

Methods:

In this descriptive study, all Canadian medical schools (n = 17) were invited to provide data at the undergraduate and postgraduate levels (2007/08–2015/16 and 2007/08–2017/18, respectively). Information collected included the number, type and length of palliative care clinical rotations offered and the total number of medical trainees or residents enrolled at each school.

Results:

All 17 Canadian medical schools responded to the request for information. At the undergraduate level, palliative care clinical rotations were not offered in 2 schools, mandatory in 2 and optional in 13. Three schools that offered optional rotations were unable to provide complete data and were therefore excluded from further analyses. In 2015/16, only 29.7% of undergraduate medical students completed palliative care clinical rotations, yet this was a significant improvement compared to 2011/12 (13.6%, p = 0.02). At the postgraduate level, on average, 57.9% of family medicine trainees completed such rotations between 2007/08 and 2016/17. During the same period, palliative care clinical rotations were completed by trainees in specialty or subspecialty programs in anesthesiology (34.2%), geriatric medicine (64.4%), internal medicine (30.9%), neurology (28.2%) and psychiatry (64.5%).

Interpretation:

Between 2008 and 2018, a large proportion of Canadian medical trainees graduated without the benefit of a clinical rotation in palliative care. Without dedicated clinical exposure to palliative care, many physicians will enter practice without vital palliative care competencies.

S100A8/A9 is implicated in inflammation mechanisms related to atherosclerosis and plaque vulnerability, but it remains unclear whether S100A8/A9 is associated with the prognosis of ischemic stroke. The aim of this study was to investigate these associations in 2 independent multicenter cohorts.Plasma S100A8/A9 concentrations at baseline were measured among 4785 patients with ischemic stroke from 2 independent cohorts: Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke (IIPAIS) and China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite outcome of death or major disability at 3 months after ischemic stroke. Secondary outcomes were major disability, death, and a composite outcome of death or vascular events.Among the combined participants of IIPAIS and CATIS, the adjusted odds ratios associated with the highest quartile of plasma S100A8/A9 were 2.11 (95% CI, 1.66–2.68) for the primary outcome and 1.62 (95% CI, 1.27–2.07) for the secondary outcome of major disability; adjusted hazard ratios were 4.14 (95% CI, 2.10–8.15) for the secondary outcome of death and 2.08 (95% CI, 1.38–3.13) for the composite outcome of death or vascular events. Each SD increase of log-transformed S100A8/A9 was associated with 28% (95% CI, 18%–39%; P < 0.001) increased risk of the primary outcome. Multivariable-adjusted spline regression analyses showed a linear association between plasma S100A8/A9 concentrations and primary outcome (P < 0.001 for linearity). Subgroup analyses further confirmed these associations.High plasma S100A8/A9 concentrations at baseline were independently associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that S100A8/A9 might have a role as a prognostic marker of ischemic stroke.

The measurement of neuron-specific enolase (NSE) in serum is frequently requested for diagnosis, risk stratification, and treatment monitoring of neuroblastoma (NB) in the pediatric population. However, authoritative clinical practice guidelines advise about the poor diagnostic performance of NSE.We critically appraised the available literature evaluating the diagnostic and prognostic value of NSE in the management of NB, paying special attention to the definition of appropriate threshold levels. In addition, we discuss the interfering conditions causing artifactual increases of NSE concentrations in serum and potentially influencing the clinical evaluation of patients with suspected NB.No definitive evidence supports the use of serum NSE for diagnosis and monitoring of NB. The risk of obtaining false-positive NSE results associated with confounders (e.g., sample hemolysis) and other pathophysiologic conditions (e.g., inflammation) is remarkable and hampers the diagnostic value of this test. NSE may be helpful to define the risk of death of patients with NB, mainly in the advanced stages of disease. However, further studies validating currently marketed immunoassays and defining threshold values useful for this scope are warranted.

Dramatically rising costs in drug development are in large part because of the high failure rates in clinical phase trials. The poor correlation of animal studies to human toxicity and efficacy have led many developers to question the value of requiring animal studies in determining which drugs should enter in-human trials. Part 1 of this 2-part series examined some of the data regarding the lack of concordance between animal toxicity studies and human trials, as well as some of the potential reasons behind it. This second part of the series focuses on some alternatives to animal trials (hereafter referred to as animal research) as well as current regulatory discussions and developments regarding such alternatives.

In low-dose computed tomography (LDCT) screening for lung cancer, all three main conditions for overdiagnosis in cancer screening are present: 1) a reservoir of slowly or nongrowing lung cancer exists; 2) LDCT is a high-resolution imaging technology with the potential to identify this reservoir; and 3) eligible screening participants have a high risk of dying from causes other than lung cancer. The degree of overdiagnosis in cancer screening is most validly estimated in high-quality randomised controlled trials (RCTs), with enough follow-up time after the end of screening to avoid lead-time bias and without contamination of the control group.

Nine RCTs investigating LDCT screening were identified. Two RCTs were excluded because lung cancer incidence after the end of screening was not published. Two other RCTs using active comparators were also excluded. Therefore, five RCTs were included: two trials were at low risk of bias, two of some concern and one at high risk of bias. In a meta-analysis of the two low risk of bias RCTs including 8156 healthy current or former smokers, 49% of the screen-detected cancers were overdiagnosed. There is uncertainty about this substantial degree of overdiagnosis due to unexplained heterogeneity and low precision of the summed estimate across the two trials.

Key points

Nine randomised controlled trials (RCTs) on low-dose computed tomography screening were identified; five were included for meta-analysis but only two of those were at low risk of bias.

In a meta-analysis of recent low risk of bias RCTs including 8156 healthy current or former smokers from developed countries, we found that 49% of the screen-detected cancers may be overdiagnosed.

There is uncertainty about the degree of overdiagnosis in lung cancer screening due to unexplained heterogeneity and low precision of the point estimate.

If only high-quality RCTs are included in the meta-analysis, the degree of overdiagnosis is substantial.

Educational aims

To appreciate that low-dose computed tomography screening for lung cancer meets all three main conditions for overdiagnosis in cancer screening: a reservoir of indolent cancers exists in the population; the screening test is able to "tap" this reservoir by detecting biologically indolent cancers as well as biologically important cancers; and the population being screened is characterised by a relatively high competing risk of death from other causes

To learn about biases that might affect the estimates of overdiagnosis in randomised controlled trials in cancer screening

The diagnostic process of idiopathic interstitial pneumonias (IIPs) is complex and the underlying mechanisms that participate in these diseases still need to be fully understood. In 2015, the European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-Associated Interstitial Lung Disease introduced the term "interstitial pneumonia with autoimmune features" (IPAF) to identify subjects with IIP and features suggesting background autoimmunity but not characterisable connective tissue disease (CTD) [1]. The need for a proper clinical, serological and morphological assessment of IIP was highlighted to identify potential subjects with IPAF and CTD-ILD. However, the measurement of anti-neutrophil cytoplasmic antibodies (ANCAs) is not included in the definition of IPAF and ANCA serological testing is only recommended in idiopathic pulmonary fibrosis (IPF) when a clinical suspicion of vasculitis exists [2]. As current research evaluates the prognostic relevance of autoimmune features in IIP, the clinical importance of ANCA positivity still needs to be determined.

Purpose:

Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action.

Experimental Design:

We evaluated the anti-MM activity of the fully human BCMAxCD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated.

Results:

We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957–mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect.

Conclusions:

JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.

Omadacycline is a broad-spectrum aminomethylcycline approved in October 2018 by the U.S. Food and Drug Administration for treating acute bacterial skin and skin structure infections and community-acquired pneumonia as both an oral and intravenous once-daily formulation. In this report, the activities of omadacycline and comparators were tested against 49,000 nonduplicate bacterial isolates collected prospectively during 2016 to 2018 from medical centers in Europe (24,500 isolates, 40 medical centers [19 countries]) and the United States (24,500 isolates, 33 medical centers [23 states and all 9 U.S. census divisions]). Omadacycline was tested by broth microdilution following the methods in Clinical and Laboratory Standards Institute document M07 (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard, 11th ed., 2018). Omadacycline (MIC_50/90, 0.12/0.25 mg/liter) inhibited 98.6% of Staphylococcus aureus isolates at ≤0.5 mg/liter, including 96.3% of methicillin-resistant S. aureus isolates and 99.8% of methicillin-susceptible S. aureus isolates. Omadacycline potency was comparable for Streptococcus pneumoniae (MIC_50/90, 0.06/0.12 mg/liter), viridans group streptococci (MIC_50/90, 0.06/0.12 mg/liter), and beta-hemolytic streptococci (MIC_50/90, 0.12/0.25 mg/liter), regardless of species and susceptibility to penicillin, macrolides, or tetracycline. Omadacycline was active against all Enterobacterales tested (MIC_50/90, 1/8 mg/liter; 87.5% of isolates were inhibited at ≤4 mg/liter) except Proteus mirabilis (MIC_50/90, 16/>32 mg/liter) and indole-positive Proteus spp. (MIC_50/90, 8/32 mg/liter) and was most active against Escherichia coli (MIC_50/90, 0.5/2 mg/liter), Klebsiella oxytoca (MIC_50/90, 1/2 mg/liter), and Citrobacter spp. (MIC_50/90, 1/4 mg/liter). Omadacycline inhibited 92.4% of Enterobacter cloacae species complex and 88.5% of Klebsiella pneumoniae isolates at ≤4 mg/liter. Omadacycline was active against Haemophilus influenzae (MIC_50/90, 0.5/1 mg/liter), regardless of β-lactamase status, and against Moraxella catarrhalis (MIC_50/90, ≤0.12/0.25 mg/liter). The potent activity of omadacycline against Gram-positive and -negative bacteria indicates that omadacycline merits further study in serious infections in which multidrug resistance and mixed Gram-positive and Gram-negative bacterial infections may be a concern.

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.

Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC₉₀, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC₉₀, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC₉₀ values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC₉₀ values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

The comparative efficacy of ceftazidime-avibactam and meropenem-vaborbactam for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections remains unknown. This was a multicenter, retrospective cohort study of adults with CRE infections who received ceftazidime-avibactam or meropenem-vaborbactam for ≥72 hours from February 2015 to October 2018. Patients with a localized urinary tract infection and repeat study drug exposures after the first episode were excluded. The primary endpoint was clinical success compared between treatment groups. Secondary endpoints included 30- and 90-day mortality, adverse events (AE), 90-day CRE infection recurrence, and development of resistance in patients with recurrent infection. A post hoc subgroup analysis was completed comparing patients who received ceftazidime-avibactam monotherapy, ceftazidime-avibactam combination therapy, and meropenem-vaborbactam monotherapy. A total of 131 patients were included (ceftazidime-avibactam, n = 105; meropenem-vaborbactam, n = 26), 40% of whom had bacteremia. No significant difference in clinical success was observed between groups (62% versus 69%; P = 0.49). Patients in the ceftazidime-avibactam arm received combination therapy more often than patients in the meropenem-vaborbactam arm (61% versus 15%; P < 0.01). No difference in 30- and 90-day mortality resulted, and rates of AE were similar between groups. In patients with recurrent infection, development of resistance occurred in three patients that received ceftazidime-avibactam monotherapy and in no patients in the meropenem-vaborbactam arm. Clinical success was similar between patients receiving ceftazidime-avibactam and meropenem-vaborbactam for treatment of CRE infections, despite ceftazidime-avibactam being used more often as a combination therapy. Development of resistance was more common with ceftazidime-avibactam monotherapy.

Nacubactam is a novel β-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine β-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae. The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential β-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].)

The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.)

The aim of this work was to evaluate the pharmacokinetics of amikacin in Mexican patients with different renal functions receiving once-daily dosing regimens and the influence of clinical and demographical covariates that may influence the optimization of this antibiotic. A prospective study was performed in a total of 63 patients with at least one determination of amikacin plasma concentration. Population pharmacokinetic (PK) parameters were estimated by nonlinear mixed-effects modeling; validations were performed for dosing recommendation purposes based on PK/pharmacodynamic simulations. The concentration-versus-time data were best described by a one-compartment open model with proportional interindividual variability associated with amikacin clearance (CL) and volume of distribution (V); residual error followed a homoscedastic trend. Creatinine clearance (CL_CR) and ideal body weight (IBW) demonstrated significant influence on amikacin CL and V, respectively. The final model [CL (liters/h) = 7.1 x (CL_CR/130)^0.84 and V (liters) = 20.3 x (IBW/68)^2.9] showed a mean prediction error of 0.11 mg/liter (95% confidence interval, –3.34, 3.55) in the validation performed in a different group of patients with similar characteristics. There is a wide variability in amikacin PK parameters in Mexican patients. This leads to inadequate dosing regimens, especially in patients with augmented renal clearance (CL_CR of >130 ml/min). Optimization based on the final population PK model in Mexican patients may be useful, since reliability and clinical applicability have been demonstrated in this study.

In this study, the plasmid content of clinical and commensal strains was analyzed and compared. The replicon profile was similar in both populations, except for L, M, A/C, and N (detected only in clinical strains) and HI1 (only in commensal strains). Although I1 and F were the most frequent replicons, only IncI1, sequence type 12 (ST12) was associated with bla_CMY-2 in both populations. In contrast, the widespread resistant IncF plasmids were not linked to a single epidemic plasmid.

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 μg/ml; the mean NTZ maximum concentration (C_max) in plasma was 10.2 μg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis. Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.)

To obtain the optimal dosage regimen in patients receiving extracorporeal membrane oxygenation (ECMO), we developed a population pharmacokinetics model for cefpirome and performed pharmacodynamic analyses. This prospective study included 15 patients treated with cefpirome during ECMO. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF) at predose and 0.5 to 1, 2 to 3, 4 to 6, 8 to 10, and 12 h after cefpirome administration. The population pharmacokinetic model was developed using nonlinear mixed effects modeling and stepwise covariate modeling. Monte Carlo simulation was used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) according to the MIC distribution. Cefpirome pharmacokinetics were best described by a two-compartment model. Covariate analysis indicated that serum creatinine concentration (SCr) was negatively correlated with clearance, and the presence of ECMO increased clearance and the central volume of distribution. The simulations showed that patients with low SCr during ECMO-ON had lower PTA than patients with high SCr during ECMO-OFF; so, a higher dosage of cefpirome was required. Cefpirome of 2 g every 8 h for intravenous bolus injection or 2 g every 12 h for extended infusion over 4 h was recommended with normal kidney function receiving ECMO. We established a population pharmacokinetic model for cefpirome in patients with ECMO, and appropriate cefpirome dosage regimens were recommended. The impact of ECMO could be due to the change in patient status on consideration of the small population and uncertainty in covariate relationships. Dose optimization of cefpirome may improve treatment success and survival in patients receiving ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.)

Nine hundred Haemophilus influenzae clinical isolates from 83 U.S. and European medical centers were tested for susceptibility by reference broth microdilution methods against ceftolozane-tazobactam and comparators. Results were stratified by β-lactamase production and infection type. Overall, ceftolozane-tazobactam MIC_50/90 values were 0.12/0.25 mg/liter, and 99.0% of isolates were inhibited at the susceptible breakpoint of ≤0.5 mg/liter; the highest MIC value was only 2 mg/liter. Our results support using ceftolozane-tazobactam to treat H. influenzae infections.

Hypervirulent Klebsiella pneumoniae strains are the major cause of liver abscesses throughout East Asia, and these strains are usually antibiotic susceptible. Recently, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains have emerged due to hypervirulent strains acquiring antimicrobial resistance determinants or the transfer of a virulence plasmid into a classic MDR strain. In this study, we characterized the clinical and microbiological properties of K. pneumoniae liver abscess (KPLA) caused by MDR-HV strains in Taiwan. Patients with community onset KPLA were retrospectively identified at Taipei Veterans General Hospital during January 2013 to May 2018. Antimicrobial resistance mechanisms, capsular types, and sequence types were determined. MDR-HV strains and their parental antimicrobial-susceptible strains further underwent whole-genome sequencing (WGS) and in vivo mice lethality tests. Thirteen MDR-HV strains were identified from a total of 218 KPLA episodes. MDR-HV strains resulted in similar outcomes to antimicrobial-susceptible strains. All MDR-HV strains were traditional hypervirulent clones carrying virulence capsular types. The major resistance mechanisms were the overexpression of efflux pumps and/or the acquisition of ESBL or AmpC β-lactamase genes. WGS revealed that two hypervirulent strains had evolved to an MDR phenotype due to mutation in the ramR gene and the acquisition of an SHV-12-bearing plasmid, respectively. Both these MDR-HV strains retained high virulence compared to their parental strains. The spread of MDR-HV K. pneumoniae strains in the community raises significant public concerns, and measures should be taken to prevent the further acquisition of carbapenemase and other resistance genes among these strains in order to avoid the occurrence of untreatable KPLA.

Pemigatinib was effective in patients with cholangiocarcinomas with FGFR2 fusions or rearrangements.

The FGFR2b inhibitor bemarituzumab was effective in high-FGFR2b gastroesophageal adenocarcinoma.

Patients with HPV16⁺ cervical cancer and high T-cell responses to an HPV16 vaccine survived longer.

As the COVID-19 pandemic worsens, the clinical cancer community is grappling with how to continue providing access to experimental but potentially lifesaving therapies while keeping immunocompromised patients safe. To that end, cancer centers are making changes to their clinical trial programs, while pharmaceutical companies are deciding how—or whether—trials should continue.