Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Status and future developments for downstream processing of biological products: Perspectives from the Recovery XIX yield roundtable discussions.

Governments and biopharmaceutical organizations aggressively leveraged expeditious communication capabilities, decision models, and global strategies to make a COVID-19 vaccine happen within a period of 12 months. This was an unusual effort and cannot be transferred to normal times. However, this focus on a single vaccine has also led to other treatments and drug developments being sidelined. Society expects the pharmaceutical industry to provide an uninterrupted supply of medicines. However, it is often overlooked how complex the manufacture of these compounds is and what logistics are required, not to mention the time needed to develop new drugs. The overarching theme, therefore, is patient access and how we can help ensure access and extend it to low- and middle-income countries. Despite unceasing efforts to make medications available to all patient populations, this must never be done at the expense of patient safety. A major fraction of the costs in biopharmaceutical manufacturing are for drug discovery, process development, and clinical studies. Infrastructure costs are very difficult to quantify because they often depend on whether a greenfield facility or an existing, depreciated facility is used or adapted for a new product. To accelerate process development concepts of platform process and prior knowledge are increasingly leveraged. While more traditional protein therapeutics continue to dominate the field, we are also experiencing the exciting emergence and evolution of other therapeutic formats (bispecifics, tetravalent mAbs, antibody-drug conjugates, enzymes, peptides, etc.) that offer unique treatment options for patients. Protein modalities are still dominant, but new modalities are being developed that can be learned from including advanced therapeutics-like cell and gene therapies. The industry must develop a model-based strategy for process development and technologies such as continuous integrated biomanufacturing must be adopted. The overall conclusion is that the pandemic pace was unsustainable, focused on vaccine delivery at the expense of other modalities/disease targets, and had implications for professional and personal life (work-life balance). Routinely reducing development time from 10 years to 1 year is nearly impossible to achieve. Environmental aspects of sustainable downstream processing are also described.

Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads.

Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action. SIGNIFICANCE STATEMENT: Because antimalarial drugs are prone to evolving resistance in the virulent human P. falciparum pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.

The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork.

Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by ß-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.

Competencies for respectful maternity care: Identifying those most important to midwives worldwide.

BACKGROUND: A respectful, person-centered philosophy of maternity care has been emerging over several decades. Research conducted on behalf of the International Confederation of Midwives (ICM) to identify essential competencies for midwifery practice also identified the knowledge, skills, and professional behaviors that should be hallmarks of respectful maternity care practices among the global community of midwives. METHODS: A three-round, online, modified Delphi survey was conducted between April 2016 and October 2016. A total of 895 individuals from 90 of the then-current 105 ICM member countries participated, with good representation across English, French, and Spanish speakers, high-income, medium-income, and low-income countries, and educators and clinicians. RESULTS: A total of 115 respectful maternity care (RMC)-related items were endorsed by participants in Round 1 or 2. These items received average scores of between 90.24% and 99.10%, well above the 85% threshold required to be identified as within the scope of global midwifery practice. These items were compared with the 12 domains of RMC identified by Shakibazadeh and colleagues that defined respectful care during childbirth in health facilities globally, and with similar RMC frameworks, and were found to be highly congruent, thus demonstrating the high value of RMC within the core of midwifery practice. DISCUSSION: ICM survey items were endorsed across all 12 RMC domains proposed by Shakibazadeh et al, and the findings affirmed that across ICM countries and regions, the philosophy of RMC was integrally related to the knowledge, skills, and professional behaviors that emerged as essential for basic midwifery practice.

Efficacy of Aminomethyl Spectinomycins against Complex Upper Respiratory Tract Bacterial Infections.

The most frequent ailment for which antibiotics are prescribed is otitis media (ear infections), which is most commonly caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae Treatment of otitis media is complicated by the fact that the bacteria in the middle ear typically form biofilms, which can be recalcitrant to antibiotic treatment. Furthermore, bacterial respiratory infections can be greatly exacerbated by viral coinfection, which is particularly evidenced by the synergy between influenza and S. pneumoniae In this study, we sought to ascertain the in vivo efficacy of aminomethyl spectinomycin lead 1950, an effective antibacterial agent both in vitro and in vivo against Streptococcus pneumoniae in the context of complex respiratory infections and acute otitis media. A single dose of 1950 significantly reduced bacterial burden in the respiratory tract for all three pathogens, even when species were present in a coinfection model. Additionally, a single dose of 1950 effectively reduced pneumococcal acute otitis media from the middle ear. The agent 1950 also proved efficacious in the context of influenza-pneumococcal super infection. These data further support the development of this family of compounds as potential therapeutic agents against the common causes of complex upper respiratory tract infections and acute otitis media.

Activation of 6-Alkoxy-Substituted Methylenecyclopropane Nucleoside Analogs Requires Enzymatic Modification by Adenosine Deaminase-Like Protein 1.

To determine the mechanism of action of third-generation methylenecyclopropane nucleoside analogs (MCPNAs), DNA sequencing of herpes simplex virus 1 (HSV-1) isolates resistant to third-generation MCPNAs resulted in the discovery of G841S and N815S mutations in HSV-1 UL30. Purified HSV-1 UL30 or human cytomegalovirus (HCMV) UL54 was then subjected to increasing concentrations of MBX-2168-triphosphate (TP), with results demonstrating a 50% inhibitory concentration (IC50) of ∼200 µM, indicating that MBX-2168-TP does not inhibit the viral DNA polymerase. Further metabolic studies showed the removal of a moiety on the guanine ring of MBX-2168. Therefore, we hypothesized that enzymatic removal of a moiety at the 6-position of the guanine ring of third-generation MCPNAs is an essential step in activation. To test this hypothesis, pentostatin (deoxycoformycin [dCF]), an adenosine deaminase-like protein 1 (ADAL-1) inhibitor, was coincubated with MBX-2168. The results showed that dCF antagonized the effect of MBX-2168, with a >40-fold increase in the 50% effective concentration (EC50) at 50 µM dCF (EC50 of 63.1 ± 8.7 µM), compared with MBX-2168 alone (EC50 of 0.2 ± 0.1 µM). Purified ADAL-1 demonstrated time-dependent removal of the moiety on the guanine ring of MBX-2168-monophosphate (MP), with a Km of 17.5 ± 2.4 µM and a Vmax of 0.12 ± 0.04 nmol min-1 Finally, synguanol-TP demonstrated concentration-dependent inhibition of HSV-1 UL30 and HCMV UL54, with IC50s of 0.33 ± 0.16 and 0.38 ± 0.11 µM, respectively. We conclude that ADAL-1 is the enzyme responsible for removing the moiety from the guanine ring of MBX-2168-MP prior to conversion to a TP, the active compound that inhibits the viral DNA polymerase.

Hospital nurse-staffing models and patient- and staff-related outcomes.

BACKGROUND: Nurses comprise the largest component of the health workforce worldwide and numerous models of workforce allocation and profile have been implemented. These include changes in skill mix, grade mix or qualification mix, staff-allocation models, staffing levels, nursing shifts, or nurses' work patterns. This is the first update of our review published in 2011. OBJECTIVES: The purpose of this review was to explore the effect of hospital nurse-staffing models on patient and staff-related outcomes in the hospital setting, specifically to identify which staffing model(s) are associated with: 1) better outcomes for patients, 2) better staff-related outcomes, and, 3) the impact of staffing model(s) on cost outcomes. SEARCH METHODS: CENTRAL, MEDLINE, Embase, two other databases and two trials registers were searched on 22 March 2018 together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised trials, non-randomised trials, controlled before-after studies and interrupted-time-series or repeated-measures studies of interventions relating to hospital nurse-staffing models. Participants were patients and nursing staff working in hospital settings. We included any objective reported measure of patient-, staff-related, or economic outcome. The most important outcomes included in this review were: nursing-staff turnover, patient mortality, patient readmissions, patient attendances at the emergency department (ED), length of stay, patients with pressure ulcers, and costs. DATA COLLECTION AND ANALYSIS: We worked independently in pairs to extract data from each potentially relevant study and to assess risk of bias and the certainty of the evidence. MAIN RESULTS: We included 19 studies, 17 of which were included in the analysis and eight of which we identified for this update. We identified four types of interventions relating to hospital nurse-staffing models:- introduction of advanced or specialist nurses to the nursing workforce;- introduction of nursing assistive personnel to the hospital workforce;- primary nursing; and- staffing models.The studies were conducted in the USA, the Netherlands, UK, Australia, and Canada and included patients with cancer, asthma, diabetes and chronic illness, on medical, acute care, intensive care and long-stay psychiatric units. The risk of bias across studies was high, with limitations mainly related to blinding of patients and personnel, allocation concealment, sequence generation, and blinding of outcome assessment.The addition of advanced or specialist nurses to hospital nurse staffing may lead to little or no difference in patient mortality (3 studies, 1358 participants). It is uncertain whether this intervention reduces patient readmissions (7 studies, 2995 participants), patient attendances at the ED (6 studies, 2274 participants), length of stay (3 studies, 907 participants), number of patients with pressure ulcers (1 study, 753 participants), or costs (3 studies, 617 participants), as we assessed the evidence for these outcomes as being of very low certainty. It is uncertain whether adding nursing assistive personnel to the hospital workforce reduces costs (1 study, 6769 participants), as we assessed the evidence for this outcome to be of very low certainty. It is uncertain whether primary nursing (3 studies, > 464 participants) or staffing models (1 study, 647 participants) reduces nursing-staff turnover, or if primary nursing (2 studies, > 138 participants) reduces costs, as we assessed the evidence for these outcomes to be of very low certainty. AUTHORS' CONCLUSIONS: The findings of this review should be treated with caution due to the limited amount and quality of the published research that was included. We have most confidence in our finding that the introduction of advanced or specialist nurses may lead to little or no difference in one patient outcome (i.e. mortality) with greater uncertainty about other patient outcomes (i.e. readmissions, ED attendance, length of stay and pressure ulcer rates). The evidence is of insufficient certainty to draw conclusions about the effectiveness of other types of interventions, including new nurse-staffing models and introduction of nursing assistive personnel, on patient, staff and cost outcomes. Although it has been seven years since the original review was published, the certainty of the evidence about hospital nurse staffing still remains very low.

Aminomethyl Spectinomycins as Therapeutics for Drug-Resistant Gonorrhea and Chlamydia Coinfections.

Bacterial sexually transmitted infections are widespread and common, with Neisseria gonorrhoeae (gonorrhea) and Chlamydia trachomatis (chlamydia) being the two most frequent causes. If left untreated, both infections can cause pelvic inflammatory disease, infertility, ectopic pregnancy, and other sequelae. The recommended treatment for gonorrhea is ceftriaxone plus azithromycin (to empirically treat chlamydial coinfections). Antibiotic resistance to all existing therapies has developed in gonorrheal infections. The need for new antibiotics is great, but the pipeline for new drugs is alarmingly small. The aminomethyl spectinomycins, a new class of semisynthetic analogs of the antibiotic spectinomycin, were developed on the basis of a computational analysis of the spectinomycin binding site of the bacterial 30S ribosome and structure-guided synthesis. The compounds display particular potency against common respiratory tract pathogens as well as the sexually transmitted pathogens that cause gonorrhea and chlamydia. Here, we demonstrate the in vitro potencies of several compounds of this class against both bacterial species; the compounds displayed increased potencies against N. gonorrhoeae compared to that of spectinomycin and, significantly, demonstrated activity against C. trachomatis that is not observed with spectinomycin. Efficacies of the compounds were compared to those of spectinomycin and gentamicin in a murine model of infection caused by ceftriaxone/azithromycin-resistant N. gonorrhoeae; the aminomethyl spectinomycins significantly reduced the colonization load and were as potent as the comparator compounds. In summary, data produced by this study support aminomethyl spectinomycins as a promising replacement for spectinomycin and antibiotics such as ceftriaxone for treating drug-resistant gonorrhea, with the added benefit of treating chlamydial coinfections.

Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models.

Objectives: New drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment of tuberculosis (TB) in humans. The spectinamides are narrow-spectrum semisynthetic analogues of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead 1599, have been previously shown to exhibit a promising therapeutic profile in mice as single agents. Here we explore the in vivo activity of lead spectinamides when combined with other agents. Methods: The efficacy of 1599 or 1810 was tested in combination in three increasingly advanced TB mouse models. Mice were infected by aerosol and allowed to establish acute or chronic infection, followed by treatment (≤4 weeks) with the spectinamides alone or in two- and three-drug combination regimens with existing and novel therapeutic agents. Bacteria were enumerated from lungs by plating for cfu. Results: Herein we show the following: (i) 1599 exhibits additive or synergistic activity with most of the first-line agents; (ii) 1599 in combination with rifampicin and pyrazinamide or with bedaquiline and pyrazinamide promotes significantly improved efficacy in the high-dose aerosol model; (iii) 1599 enhances efficacy of rifampicin or pyrazinamide in chronically infected BALB/c mice; and (iv) 1599 is synergistic when administered in combination with rifampicin and pyrazinamide in the C3HeB/FeJ mouse model showing caseous necrotic pulmonary lesions. Conclusions: Spectinamides were effective partner agents for multiple anti-TB agents including bedaquiline, rifampicin and pyrazinamide. None of these in vivo synergistic interactions was predicted from in vitro MIC chequerboard assays. These data support further development of the spectinamides as combination partners with existing and experimental anti-TB agents.

Acute flaccid paralysis incidence and Zika virus surveillance, Pacific Islands.

PROBLEM: The emergence of Zika virus has challenged outbreak surveillance systems in many at-risk, low-resource countries. As the virus has been linked with Guillain-Barré syndrome, routine data on the incidence of acute flaccid paralysis (AFP) may provide a useful early warning system for the emergence of Zika virus. APPROACH: We documented all Zika virus outbreaks and cases in 21 Pacific Islands and territories for the years 2007 to 2015. We extracted data from the Global Polio Eradication Initiative database on the reported and expected annual incidence of AFP in children younger than 15 years. Using a Poisson probability test, we tested the significance of unexpected increases in AFP in years correlating with Zika virus emergence. Data were analysed separately for each Pacific Island country and territory. LOCAL SETTING: In most Pacific Island countries, early warning surveillance for acute public health threats such as Zika virus is hampered by poor health infrastructure, insufficient human resources and geographical isolation. RELEVANT CHANGES: Only one example was found (Solomon Islands in 2015) of a significant increase in reported AFP cases correlating with Zika virus emergence. LESSONS LEARNT: We found no conclusive evidence that routinely reported AFP incidence data in children were useful for detecting emergence of Zika virus in this setting. More evidence may be needed from adult populations, who are more likely to be affected by Guillain-Barré syndrome. Reporting of AFP may be deficient in regions certified as polio-free.

Exploring the strategies that midwives in British Columbia use to promote normal birth.

BACKGROUND: Rates of normal birth have been declining steadily over the past 20 years, despite the evidence of the benefits to mother and baby. This is most obvious in steadily increasing caesarean section rates across countries and studies of the factors involved suggest it may be more to do with the organization of maternity care and the preferences of healthcare providers than changes in maternal or demographic conditions. The proportion of women in British Columbia (BC) receiving care from a midwife continues to grow and there is a particular focus on promoting and supporting normal pregnancy and birth in the midwifery philosophy of care. In BC, women receiving care from a midwife are less likely to have a caesarean section and other birth interventions. METHODS: An interpretive approach, based on interpretive phenomenology was used to explore the experiences of midwives in BC of normal birth and the strategies that they use to keep birth normal. Fourteen experienced midwives were purposively selected from across the range of practice, geographical, and rural/urban contexts to participate in depth interviews. Data were analyzed using Thematic Network Analysis. RESULTS: Seven key themes were identified in the data: working with women from the early pregnancy, informing choice, the birth environment, careful watching and waiting, managing early labour, helping the woman to cope with labour, and tools in the tool kit. CONCLUSIONS: Midwives in BC work closely with women from early pregnancy to prepare them for a normal birth, and as "instruments of care" they adopt a range of approaches to support women to achieve this. The emphasis on continuity of care in the BC model of midwifery care plays a vital role in this.

Effect of Chlorhexidine Bathing Every Other Day on Prevention of Hospital-Acquired Infections in the Surgical ICU: A Single-Center, Randomized Controlled Trial.

OBJECTIVE: To test the hypothesis that compared with daily soap and water bathing, 2% chlorhexidine gluconate bathing every other day for up to 28 days decreases the risk of hospital-acquired catheter-associated urinary tract infection, ventilator-associated pneumonia, incisional surgical site infection, and primary bloodstream infection in surgical ICU patients. DESIGN: This was a single-center, pragmatic, randomized trial. Patients and clinicians were aware of treatment-group assignment; investigators who determined outcomes were blinded. SETTING: Twenty-four-bed surgical ICU at a quaternary academic medical center. PATIENTS: Adults admitted to the surgical ICU from July 2012 to May 2013 with an anticipated surgical ICU stay for 48 hours or more were included. INTERVENTIONS: Patients were randomized to bathing with 2% chlorhexidine every other day alternating with soap and water every other day (treatment arm) or to bathing with soap and water daily (control arm). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was a composite outcome of catheter-associated urinary tract infection, ventilator-associated pneumonia, incisional surgical site infection, and primary bloodstream infection. Of 350 patients randomized, 24 were excluded due to prior enrollment in this trial and one withdrew consent. Therefore, 325 were analyzed (164 soap and water versus 161 chlorhexidine). Patients acquired 53 infections. Compared with soap and water bathing, chlorhexidine bathing every other day decreased the risk of acquiring infections (hazard ratio = 0.555; 95% CI, 0.309-0.997; p = 0.049). For patients bathed with soap and water versus chlorhexidine, counts of incident hospital-acquired infections were 14 versus 7 for catheter-associated urinary tract infection, 13 versus 8 for ventilator-associated pneumonia, 6 versus 3 for incisional surgical site infections, and 2 versus 0 for primary bloodstream infection; the effect was consistent across all infections. The absolute risk reduction for acquiring a hospital-acquired infection was 9.0% (95% CI, 1.5-16.4%; p = 0.019). Incidences of adverse skin occurrences were similar (18.9% soap and water vs 18.6% chlorhexidine; p = 0.95). CONCLUSIONS: Compared with soap and water, chlorhexidine bathing every other day decreased the risk of acquiring infections by 44.5% in surgical ICU patients.

Closing the gap in Australian Aboriginal infant immunisation rates -- the development and review of a pre-call strategy.

BACKGROUND: Improving timely immunisation is key to closing the inequitable gap in immunisation rates between Aboriginal children and non-Indigenous children. Aboriginal Immunisation Officers were employed in Hunter New England Local Health District (HNELHD), New South Wales (NSW), Australia, to telephone the families of all Aboriginal infants prior to the due date for their first scheduled vaccination. METHODS: Aboriginal Immunisation Officers contacted the families of Aboriginal children born in the Hunter New England Local Health District (HNELHD) by telephone before their due immunisation date (pre-call) to provide the rationale for timely immunisation, and to facilitate contact with culturally safe local immunisation services if this was required. The impact of this strategy on immunisation coverage rates is reviewed. RESULTS: For the period March 2010 to September 2014 there was a significant increase in immunisation coverage rate for Aboriginal children at 12 months of age in HNELHD (p < 0.0001). The coverage in the rest of NSW Aboriginal children also increased but not significantly (p = 0.218). Over the full study period there was a significant decrease in the immunisation coverage gap between Aboriginal children and non-Indigenous children in HNELHD (p < 0.0001) and the rest of NSW (p = 0.004). The immunisation coverage gap between Aboriginal and non-Indigenous infants decreased at a significantly faster rate in HNELHD than the rest of NSW (p = 0.0001). By the end of the study period in 2014, immunisation coverage in HNELHD Aboriginal infants had surpassed that of non-Indigenous infants by 0.8 %. CONCLUSIONS: The employment of Aboriginal immunisation officers may be associated with closing of the gap between Aboriginal and non-Indigenous infants' immunisation coverage in HNELHD and NSW. The pre-call telephone strategy provided accelerated benefit in closing this gap in HNELHD.

Flutracking weekly online community survey of influenza-like illness annual report, 2015.

Flutracking is a national online community influenza-like illness (ILI) surveillance system that monitors weekly ILI activity and impact in the Australian community. This article reports on the 2015 findings from Flutracking. From 2014 to 2015 there was a 38.5% increase in participants to 27,824 completing at least 1 survey with a peak weekly response of 25,071 participants. The 2015 Flutracking national ILI weekly fever and cough percentages peaked in late August at 5.0% in the unvaccinated group, in the same week as the national counts of laboratory confirmed influenza peaked. A similar percentage of Flutracking participants took two or more days off from work or normal duties in 2015 (peak level 2.3%) compared with 2014 (peak level 2.5%) and the peak weekly percentage of participants seeking health advice was 1.6% in both 2014 and 2015. Flutracking fever and cough peaked in the same week as Influenza Complications Alert Network surveillance system influenza hospital admissions. The percentage of Flutracking participants aged 5 to 19 years with cough and fever in 2015 was the highest since 2011. The 2015 season was marked by a transition to predominantly influenza B strain circulation, which particularly affected younger age groups. However, for those aged 20 years and over, the 2015 national Flutracking influenza season was similar to 2014 in community ILI levels and impact.

Elevated amniotic fluid lactate predicts labor disorders and cesarean delivery in nulliparous women at term.

OBJECTIVE: We sought to assess amniotic fluid lactate (AFL) at diagnosis of spontaneous labor at term (≥37 weeks) as a predictor of labor disorders (dystocia) and cesarean delivery (CD). STUDY DESIGN: This was a single-institution, prospective cohort study of 905 singleton, cephalic, term (≥37 weeks) nulliparous women in spontaneous labor. A standard management of labor (active management of labor) including a standard oxytocin regimen up to a maximum dose of 30 mU/min was applied. AFL was measured using a point-of-care device (LMU061; ObsteCare, Stockholm, Sweden). Labor arrest in the first stage of labor was defined as the need for oxytocin when cervical dilatation was <1 cm/h over 2 hours and in the second stage of labor by poor descent and rotation over 1 hour. Standard statistical analysis included analysis of variance, Pearson correlations, and binary logistic regression. Unsupervised decision tree analysis with 10-fold cross-validation was used to identify AFL thresholds. RESULTS: AFL was normally distributed and did not correlate with age, body mass index, or gestation. Unsupervised decision tree analysis demonstrated that AFL could be divided into 3 groups: 0-4.9 mmol/L (n = 118), 5.0-9.9 mmol/L (n = 707), and ≥10.0 mmol/L (n = 80). Increasing AFL was associated with higher total oxytocin dose (P = .001), labor disorders (P = .005), and CD (P ≤ .001). Multivariable regression analysis demonstrated that women with AFL ≥5.0-9.9 mmol/L (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.06-2.39) and AFL ≥10.0 mmol/L (OR, 1.72; 95% CI, 1.01-2.93) were independent predictors of a labor disorder. AFL ≥5.0-9.9 mmol/L did not predict CD but multivariable analysis confirmed that AFL ≥10.0 mmol/L was an independent predictor of CD (OR, 3.35; 95% CI, 1.73-6.46). AFL ≥5.0-9.9 mmol/L had a sensitivity of 89% in predicting a labor disorder and a sensitivity of 93% in predicting CD with a 97% negative predictive value. AFL ≥10.0 mmol/L was highly specific but lacked sensitivity for CD. There was no difference in birthweight of infants according to labor disorder and delivery method. CONCLUSION: AFL at diagnosis of labor in spontaneously laboring single cephalic nulliparous term women is an independent predictor of a labor disorder and CD. These data suggest that women with AFL between 5.0-9.9 mmol/L with a labor disorder may be amenable to correction using the active management of labor protocol.

Venlafaxine for neuropathic pain in adults.

BACKGROUND: Neuropathic pain, which is caused by nerve damage, is increasing in prevalence worldwide. This may reflect improved diagnosis, or it may be due to increased incidence of diabetes-associated neuropathy, linked to increasing levels of obesity. Other types of neuropathic pain include post-herpetic neuralgia, trigeminal neuralgia, and neuralgia caused by chemotherapy. Antidepressant drugs are sometimes used to treat neuropathic pain; however, their analgesic efficacy is unclear. A previous Cochrane review that included all antidepressants for neuropathic pain is being replaced by new reviews of individual drugs examining chronic neuropathic pain in the first instance. Venlafaxine is a reasonably well-tolerated antidepressant and is a serotonin reuptake inhibitor and weak noradrenaline reuptake inhibitor. Although not licensed for the treatment of chronic or neuropathic pain in most countries, it is sometimes used for this indication. OBJECTIVES: To assess the analgesic efficacy of, and the adverse effects associated with the clinical use of, venlafaxine for chronic neuropathic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via The Cochrane Library, and MEDLINE and EMBASE via Ovid up to 14 August 2014. We reviewed the bibliographies of any randomised trials identified and review articles, contacted authors of one excluded study and searched www.clinicaltrials.gov to identify additional published or unpublished data. We also searched the meta-Register of controlled trials (mRCT) (www.controlled-trials.com/mrct) and the WHO International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) for ongoing trials but did not find any relevant trials. SELECTION CRITERIA: We included randomised, double-blind studies of at least two weeks' duration comparing venlafaxine with either placebo or another active treatment in chronic neuropathic pain in adults. All participants were aged 18 years or over and all included studies had at least 10 participants per treatment arm. We only included studies with full journal publication. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data using a standard form and assessed study quality. We intend to analyse data in three tiers of evidence as described by Hearn 2014, but did not find any first-tier evidence (ie evidence meeting current best standards, with minimal risk of bias) or second-tier evidence, that was considered at some risk of bias but with adequate participant numbers (at least 200 in the comparison). Third-tier evidence is that arising from studies with small numbers of participants; studies of short duration, studies that are likely to be of limited clinical utility due to other limitations, including selection bias and attrition bias; or a combination of these. MAIN RESULTS: We found six randomised, double-blind trials of at least two weeks' duration eligible for inclusion. These trials included 460 participants with neuropathic pain, with most participants having painful diabetic neuropathy. Four studies were of cross-over design and two were parallel trials. Only one trial was both parallel design and placebo-controlled. Mean age of participants ranged from 48 to 59 years. In three studies (Forssell 2004, Jia 2006 and Tasmuth 2002), only mean data were reported. Comparators included placebo, imipramine, and carbamazepine and duration of treatment ranged from two to eight weeks. The risk of bias was considerable overall in the review, especially due to the small size of most studies and due to attrition bias. Four of the six studies reported some positive benefit for venlafaxine. In the largest study by Rowbotham, 2004, 56% of participants receiving venlafaxine 150 to 225 mg achieved at least a 50% reduction in pain intensity versus 34% of participants in the placebo group and the number needed to treat for an additional beneficial outcome was 4.5. However, this study was subject to significant selection bias. Known adverse effects of venlafaxine, including somnolence, dizziness, and mild gastrointestinal problems, were reported in all studies but were not particularly problematic and, overall, adverse effects were equally prominent in placebo or other active comparator groups. AUTHORS' CONCLUSIONS: We found little compelling evidence to support the use of venlafaxine in neuropathic pain. While there was some third-tier evidence of benefit, this arose from studies that had methodological limitations and considerable risk of bias. Placebo effects were notably strong in several studies. Given that effective drug treatments for neuropathic pain are in current use, there is no evidence to revise prescribing guidelines to promote the use of venlafaxine in neuropathic pain. Although venlafaxine was generally reasonably well tolerated, there was some evidence that it can precipitate fatigue, somnolence, nausea, and dizziness in a minority of people.

Flutracking weekly online community survey of influenza-like illness: 2013 and 2014.

Flutracking is a national online community influenza-like illness (ILI) surveillance system that monitors weekly ILI activity and field vaccine effectiveness. This article reports on the 2013 and 2014 findings from Flutracking. From 2013 to 2014 there was a 14.0% increase in participants who completed at least 1 survey to 21,021 participants. By the end of the 2013 and 2014 seasons, respectively 59.7% and 59.1% of all participants had received the seasonal influenza vaccine. The 2013 Flutracking national ILI weekly incidence peaked in late August at 4.3% in the unvaccinated group, 1 week earlier than national counts of laboratory confirmed influenza. The 2014 Flutracking national ILI weekly incidence also peaked in late August at 4.7% in the unvaccinated group, in the same week as national counts of laboratory confirmed influenza. A lower percentage of Flutracking participants took two or more days off from work or normal duties in 2013 (peak level 1.6%) compared with 2014 (peak level 2.5%) and sought health advice in 2013 (peak level of 1.1%) compared with 2014 (peak of 1.6%). Flutracking ILI surveillance suggests that 2014 was a moderately more intense season than 2013 and similar to 2012.

Synthesis and antibacterial evaluation of new, unsymmetrical triaryl bisamidine compounds.

Herein we describe the synthesis and antibacterial evaluation of a new, unsymmetrical triaryl bisamidine compound series, [Am]-[indole]-[linker]-[HetAr/Ar]-[Am], in which [Am] is an amidine or amino group, [linker] is a benzene, thiophene or pyridine ring, and [HetAr/Ar] is a benzimidazole, imidazopyridine, benzofuran, benzothiophene, pyrimidine or benzene ring. When the [HetAr/Ar] unit is a 5,6-bicyclic heterocycle, it is oriented such that the 5-membered ring portion is connected to the [linker] unit and the 6-membered ring portion is connected to the [Am] unit. Among the 34 compounds in this series, compounds with benzofuran as the [HetAr/Ar] unit showed the highest potencies. Introduction of a fluorine atom or a methyl group to the triaryl core led to the more potent analogs. Bisamidines are more active toward bacteria while the monoamidines are more active toward mammalian cells (as indicated by low CC50 values). Importantly, we identified compound P12a (MBX 1887) with a relatively narrow spectrum against bacteria and a very high CC50 value. Compound P12a has been scaled up and is currently undergoing further evaluations for therapeutic applications.

Small molecule inhibitors of anthrax lethal factor toxin.

This manuscript describes the preparation of new small molecule inhibitors of Bacillus anthracis lethal factor. Our starting point was the symmetrical, bis-quinolinyl compound 1 (NSC 12155). Optimization of one half of this molecule led to new LF inhibitors that were desymmetrized to afford more drug-like compounds.