Growth-differentiation factor 15 (GDF15) is an inflammatory cytokine involved in energy homeostasis. Its circulating levels are acutely increased by the type 2 diabetes medication metformin, resulting in reduced appetite and weight loss. We identified a genetic variant at the GDF15 gene to proxy a small, lifelong increase in circulating GDF15 levels, and leveraged it in colocalization and Mendelian randomization analyses to investigate the effects of chronically elevated GDF15 levels on body mass index (BMI) and type 2 diabetes liability. The results provide human genetic evidence supporting that chronically elevated GDF15 levels increase BMI. There was no genetic evidence to support bi-directional effects, or that chronically elevated GDF15 levels directly affect liability to type 2 diabetes. Our results contrast the BMI lowering effects of an acute increase in GDF15 levels observed after metformin use. These findings have direct implications for informing pharmacological strategies aimed at targeting GDF15 levels for weight loss.
Anti-tumor necrosis factor alpha (TNFα) agents are effective in diseases including Crohn’s disease (CD) but may cause cytopenias. The mechanisms involved in anti-TNFα agents induced thrombocytopenia are scarce. We report a 73-year-old male with Crohn’s disease for which he currently used adalimumab, an anti-TNFα agent. He had received mesalazine and infliximab before the treatment of adalimumab. No comorbidities were present. Routine laboratory tests revealed a deep thrombocytopenia (thrombocytes 24x10*9/L) after which adalimumab was discontinued. Bleeding symptoms included cutaneous hematomas and mild epistaxis. Direct monoclonal antibody-specific immobilization of platelet antigens (MAIPA assay) revealed autoantibodies specific to glycoprotein IIb/IIIa (GPIIb/IIIa) and glycoprotein V (GPV) platelet receptors. There was no bone marrow suppression. Other causes of the thrombocytopenia were ruled out. The platelet count normalized after adalimumab discontinuation. No further interventions were required. Monitoring thrombocyte levels after initiating anti-TNFα agents is recommended, which could lead to prevention of this potential fatal phenomenon.
Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus’ entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anti-coagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. Methods and intervention The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) meta-trial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the meta-trial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes. Analysis We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. Trial registration, ethics and dissemination The meta-trial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board.
This themed issue follows a meeting held at the Royal College of Physicians in London in November 2019 entitled “Avoiding harm from overprescribing: how to reduce waste and dependence on prescription drugs.” Here we summarize the existing challenges faced by healthcare professionals and attempt to present solutions to the expanding problem associated with a vast therapeutic arsenal and increasing medical complexity.
Aim: Efavirenz is still widely used as the preferred first-line antiretroviral agent in the middle- and low- income countries, including Malaysia. The efavirenz population pharmacokinetic profile among HIV-positive smokers is still unknown. We aimed to assess the association of smoking with efavirenz and the differences in HIV clinical outcomes. Methods: A total of 154 stable HIV-positive patients on efavirenz in northern Malaysia were recruited with a sparse sampling for this multicentre prospective cohort study. The association between smoking and efavirenz pharmacokinetic parameters was determined using the non-linear mixed-effect model (NONMEM). A mixture model of clearance was adopted to describe the metaboliser status because genetic data is unavailable. The effect of smoking on HIV clinical markers (CD4, CD4 / CD8 ratio and viral blips) for at least two years after the antiretroviral initiation was also investigated. Results: Our data were best fitted with a one-compartment mixture model with first-order absorption without lag time. Smoking significantly associated with higher clearance (CL/F) (β = 1.39; 95% confidence interval (CI): 1.07 to 1.91), while weight affected both CL/F and volume (V/F). From the mixture model, 20% of patients were in the slow clearance group, which mimic the genotype distribution of slow metaboliser. An efavirenz dose reduction is not recommended for smokers ≥60kg with normal metabolism rate. Smoking significantly associated with slower normalisation of CD4 and CD4 / CD8 ratio. Conclusion: HIV-positive smokers presented with significantly higher efavirenz clearance and unfavourable clinical outcomes. Close monitoring of adherence and clinical response among smokers is warranted.
Warfarin has existed for more than seven decades and has been the anticoagulant of choice for many thromboembolic disorders. The recent introduction of direct acting oral anticoagulants (DOACs) has however caused a shift in preference by healthcare professionals all over the world. DOACs have been found to be at least as effective as warfarin in prevention of stroke in patients with atrial fibrillation and in treatment of venous thromboembolism. In sub-Saharan Africa, however, the widespread use of DOACs has been hampered mainly by their higher acquisition costs. As the drugs come off patent, their use in sub-Saharan Africa is likely to increase. However, very few trials have been conducted in African settings, and safety concerns will need to be addressed with further study before widespread adoption into clinical practice.
Aim: Two recommendations for hemodialysis in lithium poisoning, one from the Extracorporeal TReatments in Poisoning (EXTRIP) workgroup and a single center retrospective one (Paris), differ. We compared outcomes in lithium poisoning based on these criteria with a primary outcome of worsening neurological symptoms in patients where EXTRIP and Paris criteria were discordant. Methods: Poison center data were queried for lithium poisoned patients for whom hemodialysis was either recommended or performed. Patients were categorized according to EXTRIP and Paris criteria and excluded if the peak lithium concentration was <1.2 mmol/L or if neurological follow-up was unavailable. Comparative analyses were only performed when both criteria could be assessed. Results: 219 patients were analyzed. Paris criteria were applied in 70 and EXTRIP criteria in 178. 42 patients were excluded because Paris criteria could not be applied. When Paris and EXTRIP both supported hemodialysis, 50/57 (88%) of patients who received hemodialysis improved, as did all 3 who did not receive hemodialysis. When Paris and EXTRIP opposed hemodialysis, all non-dialyzed patients did well. Among the 86 patients for whom EXTRIP supported hemodialysis but Paris did not, 4/19 (21%) patients not dialyzed deteriorated (p=0.02; OR=8.7, 95%CI=1.5-51.8), one of whom died. All 8 patients for whom Paris criteria supported hemodialysis but EXTRIP did not were dialyzed and improved. Conclusion: When the EXTRIP and Paris criteria are discordant, EXTRIP criteria outperforms the Paris criteria at identifying potentially ill patients who might benefit from hemodialysis.
Nitrous oxide is an increasingly popular recreational drug. However recurrent or prolonged use can be associated with nitrous oxide toxicity, with numerous reports of harm documented in the literature. Nitrous oxide irreversibly binds and inactivates vitamin B12, which is an important co-factor in metabolic pathways involved in DNA and myelin synthesis. Toxicity is therefore associated with vitamin B12 deficiency-related syndromes, primarily involving haematological and neurological systems. As a ‘legal high’, nitrous oxide use has attracted repeated health warnings from experts. An awareness and understanding of the pathophysiology and management of nitrous oxide toxicity is therefore important for clinicians. We discuss the case of a 29-year old man presenting with nitrous oxide-induced sensorimotor neuropathy and review the existing literature surrounding toxicity.
Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD) but the direct renal effects of IL-6 inhibition are not established. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR-Egger methods. There was no evidence for an association of genetically proxied inhibition of IL-6 signalling (scaled per unit decrease in natural log transformed C-reactive protein) with log eGFR (0.002, 95% confidence interval -0.004 – 0.008), BUN (0.088, 95% confidence interval -0.003 – 0.019) and CKD (odds ratio 1.018, 95% confidence interval 0.899 – 1.153). These findings suggest that inhibition of IL-6 signalling is unlikely to have a direct effect on renal function.
Routinely collected data has been increasingly used to evaluate and monitor long-term opioid therapy (LTOT) patterns, with very little guidance on how to measure LTOT from these data sources. We conducted a systematic review of studies published between Jan 2000 and Jul 2019 to catalogue LTOT definitions, the rationale for definitions, and LTOT rates in observational research using routinely collected data in non-surgical settings. We screened 4,056 abstracts, 209 full-text manuscripts and included 126 studies; mostly from the US (82%) and published between 2015 and 2019 (68%). We identified 78 definitions of LTOT, commonly operationalised as 90 days of use within a year (21%). Studies often used multiple criteria to derive definitions (63%), mostly based on measures of duration, such as supply days/days of use (67%), episode length (21%), or prescription fills within specified time periods (9%). Definitions were based on previous publications (63%), clinical judgment (17%), or empirical data (3%); 10% of studies applied more than one definition. LTOT definition was not provided with enough details for replication in 14 studies and 37 studies did not specify the opioids evaluated. Rates of LTOT ranged from 0.2% to 57% according to study design, population and definition used. We observed a substantial rise in studies evaluating LTOT with large variability in the definitions used and poor reporting of the rationale and implementation of the definitions. This variation impacts on research reproducibility, comparability of findings and the development of strategies aiming to curb therapy that is not guideline-recommended.
Introduction: Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment, benznidazole (BZN) and nifurtimox (NF). Treating CD infected patients, especially children and women of reproductive age, is vital in order to prevent long term sequelae such as heart and gastrointestinal disfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Finally, treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response. Areas covered: This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Conclusion: Early diagnosis and treatment of CD, especially in pediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drugs development.
Aim To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle. Methods In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability, and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography (OCT), clinical photography, thermal imaging, and laser speckle contrast imaging (LSCI) to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device. Results While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 101-point VAS scale). Initial absorption rate and bioavailability were higher after i.d. adalimumab (Tmax=95h(47-120); F=129%(6.46%)) compared to s.c. adalimumab (Tmax=120h(96-221)). In 50% and 83% of the subjects anti-adalimumab antibodies were detected after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (p<0.0001). Cytokine secretion after whole blood LPS challenge was comparable between administration routes. Conclusion Intradermal of adalimumab using hollowing microneedles was perceived as more painful, and less accepted than s.c. administration, however, yields a higher bioavailability with similar safety and pharmacodynamic effects.
Comment on “The changing face of paracetamol toxicity and new regimens for an old antidote acetylcysteine”Dear Editor,We have with interest read the recently published commentary by Isbister and Chiew1 in which current approaches for the treatment of paracetamol (PCM) poisoning with N-acetylcysteine (NAC) were described. While we appreciate the authors’ valuable comments on the challenges in managing this common poisoning, we noticed the omission of the Danish NAC regimen.NAC has been established as a highly efficient antidote in preventing PCM-induced hepatotoxicity when administered within 8 h of PCM ingestion.2 Treatment delays because of pending laboratory results do not harmfully affect the outcome if NAC is administered within 8 h. However, it is frequent occurring that patients get treated beyond that time in e.g. the UK,3 thus potentially decreasing the efficacy of NAC.In Denmark a 20-hour two-bag regime has been used for more than seven years.4 All patients suspected of poisoning with more than 6 g PCM are treated with NAC without risk stratification according to a nomogram. Patients deliberately poisoning themselves with PCM may not report reliable information of the time of ingestion and dose of PCM. If a nomogram is used without an accurate time of ingestion, the estimation of the risk of hepatotoxicity is unreliable. It is well documented that patients have been withheld treatment with NAC due to misinterpretation of the nomogram resulting in hepatotoxicity.5Concomitant overdosing of several drugs that delay the time to peak PCM concentration is common and may result in crossing from below to above the treatment line5 leaving line crossers who required treatment untreated. The same is relevant in cases of massive PCM overdosing alone (drug bezoar) or poisonings with extended-release PCM formulations (late PCM peak).6 Furthermore, it is well-known that the half-life of PCM in liver injury exceeds the expected 4 h used for treatment decision in the nomogram, thus further questioning the reliability of the nomogram as a risk stratification tool for patients suffering from liver diseases. Although the Danish regime further reduces the risk of hepatoxicity, because of incorrectly withheld or delayed NAC treatment compared to other regimes based on a nomogram, it comes at a cost of more patients being treated.We believe that all approaches deserve mention in order to identify the most effective and safe approach to this poisoning. Therefore, we should consider the effectiveness, duration and safety of choice of treatment including the incidence of anaphylactoid reactions to NAC while assuring that nobody is wrongly withhold NAC treatment. Not to mention, that the abovementioned approach is associated with a comparable incidence of anaphylactoid reactions when compared to other approaches.4,7 It is worth mentioning that the primary factor limiting a faster delivery of the antidote is the development of anaphylactoid reactions. It is to be shown if pre-administrations of antihistamines can reduce the dose-dependent side-effect leading to development of faster NAC regimes7.We declare no competing interests.Alaa Daoud (orcid: 0000-0002-8714-4028)a,b, Kim Peder Dalhoffa,b, Tonny Studsgaard Petersen (orcid: 0000-0002-9974-2738)a,baDepartment of Clinical Medicine, Faculty of Health and Medical science, Copenhagen University, Copenhagen, DenmarkbDepartment of Clinical Pharmacology and The Danish Poison Information Centre, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark*Correspondence to Alaa Daoud, Alaa.Ahmed.Daoud@regionh.dk1. Isbister GK, Chiew A. The changing face of paracetamol toxicity and new regimens for an old antidote acetylcysteine. British Journal of Clinical Pharmacology . n/a(n/a). doi:10.1111/bcp.144952. Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J . 1979;2(6198):1097-1100. doi:10.1136/bmj.2.6198.10973. The College of Emergency Medicine. Paracetamol Overdose Clinical Audit 2013-14. Accessed September 7, 2020. https://www.rcem.ac.uk/docs/Previous%20Audits/CEM8120-Paracetamol%20Overdose%20national%20report.pdf4. Daoud A, Dalhoff KP, Christensen MB, Bøgevig S, Petersen TS. Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine. Clinical Toxicology . 2020;58(7):698-704. doi:10.1080/15563650.2019.16758865. Mutsaers A, Green JP, Sivilotti MLA, et al. Changing nomogram risk zone classification with serial testing after acute acetaminophen overdose: a retrospective database analysis. Clinical Toxicology . 2019;57(6):380-386. doi:10.1080/15563650.2018.15293206. Bizovi KE, Aks SE, Paloucek F, Gross R, Keys N, Rivas J. Late Increase in Acetaminophen Concentration After Overdose of Tylenol Extended Relief. Annals of Emergency Medicine . 1996;28(5):549-551. doi:10.1016/S0196-0644(96)70119-17. Mullins ME, Yu M, O’Grady L, Khan S, Schwarz ES. Adverse reactions in patients treated with the one-bag method of N-acetylcysteine for acetaminophen ingestion. Toxicology Communications . 2020;4(1):49-54. doi:10.1080/24734306.2020.1770498
Introduction Irrational medicine use is proportionately higher in low and middle-income countries like Sierra Leone. This study aims at exploring the structure, functions, and challenges of Drug, and Therapeutics Committees (DTC) recently piloted in Sierra Leone. Method A two-phase mixed-method study design was used in this study. Firstly, a cross-sectional survey using an online questionnaire to assess the structure, indicators, and challenges of DTC . In phase two, a semi-structured interview was used to get deeper insights into the key issues that emerged from the survey. Participants were mainly pharmacists in-charge at the hospitals where the DTC program hasbeen established. MS Excel 2019 and NVivo version 12 were respectively used for data management and analysis. Results DTCs mostly had a minimum of ten members consisting of a mix of both medical and hospital administrative staff. The main functions of DTC are ensuring rational medicines use, monitoring, and reporting adverse drug reactions. All but one hospital had subcommittees that are either effective or nonfunctional. The main challenges in DTC functions and maintenance were funding (n=6), DTC decision implementation (n=4), and unmotivated members (n=4). Strategies suggested to improve DTC at public hospitals and nationwide include; resource allocation, monitoring, and evaluating DTC functions and capacity building of its members. Conclusion DTC present a compelling opportunity towards achieving rational medicines use at the hospital level in Sierra Leone. Nonetheless, lack of funding, operational resources, are significant limitations. Policymakers must note these drawbacks whilst expanding DTC programs to other hospitals in Sierra Leone.
Aim Patients on anti-tuberculosis (anti-TB) therapy are at risk of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) and cytokeratin-18 (K18) are exploratory DILI biomarkers. To explore their utility in this global context, circulating miR-122 and K18 concentrations were measured in UK and Ugandan populations on anti-TB therapy for mycobacterial infection. Methods European patients receiving anti-TB therapy were recruited at the Royal Infirmary of Edinburgh, UK (ALISTER-ClinicalTrials.gov Identifier: NCT03211208). African patients with HIV-TB coinfection, receiving anti-TB and anti-retroviral therapy (ART), were recruited at the Infectious Diseases Institute, Kampala, Uganda (SAEFRIF-NCT03982277). Serial blood samples, demographic and clinical data were collected. MiR-122 was quantified using PCR. K18 was quantified using the M65 ELISA. Results The study had 235 participants (healthy volunteers (n=28); ALISTER: active TB (n=30), latent TB (n=88), non-tuberculous mycobacterial infection (n=25); SAEFRIF: HIV-TB coinfection (n=64)). In the absence of DILI, there was no difference in miR-122 and K18 across the groups. Both miR-122 and K18 correlated with alanine transaminase activity (ALT) (miR-122: r=0.52, 95%CI=0.42-0.61, P<0.0001. K18: r=0.42, 95%CI=0.34-0.49, P<0.0001). There were two DILI cases: baseline ALT was 18 and 28 IU/L, peak ALT 431 and 194 IU/L; baseline K18 58 and 219 U/L, peak K18 1247 and 3490 U/L; baseline miR-122 4 and 17 fM, peak miR-122 60 and 336 fM, respectively. Conclusion In European and African patients treated with anti-TB therapy miR-122 and K18 correlated with ALT and increased with DILI. Further work should determine the diagnostic and prognostic utility of miR-122 and K18 in this global context-of-use.
Aims: Hypophosphatemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside/ferric derisomaltose (IIM), which are used to treat iron deficiency. To determine frequency, severity, duration and risk factors of incident hypophosphatemia after treatment with FCM and IIM. Methods: A systematic literature search for articles indexed in EMBASE, PubMed and Web of Science in years 2005 to 2020 was carried out using the search terms ‘ferric carboxymaltose’ OR ‘iron isomaltoside’. Prospective clinical trials reporting outcomes on hypophosphatemia rate, mean nadir serum phosphate and/or change in mean serum phosphate from baseline were selected. Hypophosphatemia rate and severity were compared for studies on IIM vs. FCM after stratification for chronic kidney disease. Meta-regression analysis was used to investigate risk factors for hypophosphatemia. Results: Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphatemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%), and significantly greater mean decreases in serum phosphate (0.40 versus 0.06 mmol/L). Hypophosphatemia persisted at the end of the study periods (maximum 3 months) in up to 45% of patients treated with FCM. Meta-regression analysis identified low baseline serum ferritin and transferrin saturation, and normal kidney function as significant predictors of hypophosphatemia. Conclusion: FCM is associated with a high risk of hypophosphatemia, which does not resolve for at least 3 months in a large proportion of affected patients. More severe iron deficiency and normal kidney function are risk factors for hypophosphatemia.
The development of specific drug therapy for children was a paradigm changing event that transformed paediatric medical practice. However a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child health care being used “off label” rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US FDA and followed by the European Union’s EMA have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labeling for new drugs, there has been much less progress with older drugs. As well while the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labeling in other jurisdictions. This impacts on a number of issues beyond labeling, including the availability of child-friendly formulations. Finally the impact of Brexit on paediatric drug studies in the UK remains unclear and subject to on-going negotiations between the UK government and the European Union.
Timely intravenous (IV) to oral antimicrobial switch (IV-oral-switch) is a key antimicrobial stewardship (AMS) strategy. A retrospective audit was undertaken to determine concordance with IV-oral-switch guidelines in the context of a long-standing, tightly regulated AMS program. Data from 107 general medical and surgical patients in an Australian hospital were analysed. Median duration of IV antimicrobial courses before switching to oral therapy was 3 days (interquartile range, 2.25-5.00). Timely IV-oral-switch occurred in 57% (n=61) of patients. The median delay to switching was 0 days (IQR 0 to 1.25). In most courses (92/106, 86.8%), the choice of oral alternative after switching was appropriate. In 45% (47/105) of courses, total duration of therapy (IV plus oral) exceeded the recommended duration by >1.0 day. Excessive IV antimicrobial duration was uncommon at a hospital with a tightly regulated AMS program. Total duration of therapy was identified as an AMS target for improvement.