Self-monitoring blood pressure in Pregnancy: Evaluation of health professional experiences of the BUMP trials.

BACKGROUND: The BUMP trials evaluated a self-monitoring of blood pressure intervention in addition to usual care, testing whether they improved detection or control of hypertension for women at risk of hypertension or with hypertension during pregnancy. This process evaluation aimed to understand healthcare professionals' perspectives and experiences of the BUMP trials of self-monitoring of blood pressure during pregnancy. METHODS: Twenty-two in-depth qualitative interviews and an online survey with 328 healthcare professionals providing care for pregnant people in the BUMP trials were carried out across five maternity units in England. RESULTS: Analysis used Normalisation Process Theory to identify factors required for successful implementation and integration into routine practice. Healthcare professionals felt self-monitoring of blood pressure did not over-medicalise pregnancy for women with, or at risk of, hypertension. Most said self-monitored readings positively affected their clinical encounters and professional roles, provided additive information on which to base decisions and enriched their relationships with pregnant people. Self-monitoring of blood pressure shifts responsibilities. Some healthcare professionals felt women having responsibility to decide on timing of monitoring and whether to act on self-monitored readings was unduly burdensome, and resulted in healthcare professionals taking additional responsibility for supporting them. CONCLUSIONS: Despite healthcare professionals' early concerns that self-monitoring of blood pressure might over-medicalise pregnancy, our analysis shows the opposite was the case when used in the care of pregnant people with, or at higher risk of, hypertension. While professionals retained ultimate clinical responsibility, they viewed self-monitoring of blood pressure as a means of sharing responsibility and empowering women to understand their bodies, to make judgements and decisions, and to contribute to their care.

MDM2 Antagonist Idasanutlin Reduces HDAC1/2 Abundance and Corepressor Partners but Not HDAC3.

Histone deacetylases 1-3 (HDAC1, HDAC2, and HDAC3) and their associated corepressor complexes play important roles in regulating chromatin structure and gene transcription. HDAC enzymes are also validated drug targets for oncology and offer promise toward new drugs for neurodegenerative diseases and cardiovascular diseases. We synthesized four novel heterobifunctional molecules designed to recruit the mouse double minute 2 homologue (MDM2) E3 ligase to degrade HDAC1-3 utilizing the MDM2 inhibitor idasanutlin, known as proteolysis targeting chimeras (PROTACs). Idasanutlin inhibits the MDM2-P53 protein-protein interaction and is in clinical trials. Although two MDM2-recruiting heterobifunctional molecules reduced HDAC1 and HDAC2 abundance with complete selectivity over HDAC3 and reduced HDAC1/2 corepressor components LSD1 and SIN3A, we were surprised to observe that idasanutlin alone was also capable of this effect. This finding suggests an association between the MDM2 E3 ligase and HDAC1/2 corepressor complexes, which could be important for designing future dual/bifunctional HDAC- and MDM2-targeting therapeutics, such as PROTACs.

PROTAC chemical probes for histone deacetylase enzymes.

Over the past three decades, we have witnessed the progression of small molecule chemical probes designed to inhibit the catalytic active site of histone deacetylase (HDAC) enzymes into FDA approved drugs. However, it is only in the past five years we have witnessed the emergence of proteolysis targeting chimeras (PROTACs) capable of promoting the proteasome mediated degradation of HDACs. This is a field still in its infancy, however given the current progress of PROTACs in clinical trials and the fact that FDA approved HDAC drugs are already in the clinic, there is significant potential in developing PROTACs to target HDACs as therapeutics. Beyond therapeutics, PROTACs also serve important applications as chemical probes to interrogate fundamental biology related to HDACs via their unique degradation mode of action. In this review, we highlight some of the key findings to date in the discovery of PROTACs targeting HDACs by HDAC class and HDAC isoenzyme, current gaps in PROTACs to target HDACs and future outlooks.

Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs).

The class I histone deacetylase (HDAC) enzymes;HDAC1,2 and 3 form the catalytic engine of at least seven structurally distinct multiprotein complexes in cells. These molecular machines play a vital role in the regulation of chromatin accessibility and gene activity via the removal of acetyl moieties from lysine residues within histone tails. Their inhibition via small molecule inhibitors has beneficial effects in a number of disease types, including the clinical treatment of hematological cancers. We have previously reported a library of proteolysis targeting chimeras (PROTACs) incorporating a benzamide-based HDAC ligand (from CI-994), with an alkyl linker and ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase that degrade HDAC1-3 at submicromolar concentrations. Here we report the addition of two novel PROTACs (JPS026 and JPS027), which utilize a ligand for the cellular inhibitor of apoptosis (IAP) family of E3 ligases. We found that both VHL (JPS004)- and IAP (JPS026)-based PROTACs degrade HDAC1-3 and induce histone acetylation to a similar degree. However, JPS026 is significantly more potent at inducing cell death in HCT116 cells than is JPS004. RNA sequencing analysis of PROTAC-treated HCT116 cells showed a distinct gene expression signature in which cell cycle and DNA replication machinery are repressed. Components of the mTORC1 and -2 complexes were also reduced, leading to an increase in FOXO3 and downstream target genes that regulate autophagy and apoptosis. In summary, a novel combination of HDAC and IAP ligands generates a PROTAC with a potent ability to stimulate apoptosis and differential gene expression in human cancer cells.

A 'click' chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras.

Click chemistry was utilised to prepare a library of PROTACs based on entinostat a class I histone deacetylase (HDAC) inhibitor in clinical trials. A novel PROTAC JMC-137 was identified as a HDAC1/2 and HDAC3 degrader in HCT116 cells. However, potency was compromised compared to previously identified class I HDAC PROTACs highlighting the importance in the choice of HDAC ligand, functional group for linker attachment and positioning in PROTAC design.

Impact of the COVID-19 pandemic on cardiovascular heart disease medication use: time-series analysis of England's prescription data during the COVID-19 pandemic (January 2019 to October 2020).

BACKGROUND: Management of high blood pressure (BP) typically requires adherence to medication regimes. However, it is known that the COVID-19 pandemic both interrupted access to some routine prescriptions and changed some patient health behaviours. AIM: This study, therefore, retrospectively investigated prescription reimbursement of cardiovascular (CVD) medicines as a proxy measure for patient adherence and access to medicines during the pandemic. METHODS: A cohort study of all primary care patients in England prescribed CVD medicines. The exposure was to the global pandemic. Prescriptions were compared before and after the pandemic's onset. Statistical variation was the outcome of interest. RESULTS: Descriptive statistics show changes to monthly prescriptions, with wide confidence intervals indicating varying underlying practice. Analysis of variance reveals statistically significant differences for bendroflumethiazide, potassium-sparing diuretics, nicorandil, ezetimibe, ivabradine, ranolazine, colesevelam and midodrine. After the pandemic began (March-October 2020), negative parameters are observed for ACE inhibitors, beta-blockers, calcium channel blockers, statins, antiplatelet, antithrombotics, ARBs, loop diuretics, doxazosin, bendroflumethiazide, nitrates and indapamide, indicating decelerating monthly prescription items (statistically significant declines of calcium channel blockers, antithrombotic, adrenoreceptor blockers and diuretics) of CVD medicines within the general population. Many data points are not statistically significant, but fluctuations remain clinically important for the large population of patients taking these medications. CONCLUSION: A concerning decline in uptake of CVD therapies for chronic heart disease was observed. Accessible screening and treatment alongside financial relief on prescription levies are needed. A video abstract is (4 min 51 s) available: https://bit.ly/39gvEHi.

Self-monitoring of blood pressure in pregnancy: A mixed methods evaluation of a national roll-out in the context of a pandemic.

OBJECTIVE: To evaluate how English maternity units implemented self-monitoring of blood pressure (SMBP) in pregnancy in response to the COVID-19 pandemic. DESIGN: Mixed methods including surveys, anonymised patient data and in-depth interviews with women. SETTING: Maternity units across England. PARTICIPANTS: 45 maternity units completed a survey about the implementation of SMBP (supported by the provision of guidance and blood pressure monitors) during the pandemic, 166 women completed a survey about their experiences of SMBP, and 23 women took part in in-depth interviews. Clinical data from 627 women undertaking SMBP were available from 13 maternity units. RESULTS: SMBP was predominantly used to provide additional BP monitoring for hypertensive or high-risk pregnant women. Overall maternity units and women were positive about its use in terms of reducing the need for additional face-to-face contacts and giving women more control and insight into their own BP. However, there were challenges in setting up SMBP services rapidly and embedding them within existing care pathways, particularly around interpreting readings and managing the provision of monitors. CONCLUSIONS: A considerable proportion of maternity units in England commenced a SMBP service for hypertensive or high-risk women from March 2020. There is a need for further research into appropriate care pathways, including guidance around white coat or masked hypertension and the use of SMBP postnatally.

Effect of Self-monitoring of Blood Pressure on Blood Pressure Control in Pregnant Individuals With Chronic or Gestational Hypertension: The BUMP 2 Randomized Clinical Trial.

Importance: Inadequate management of elevated blood pressure is a significant contributing factor to maternal deaths. The role of blood pressure self-monitoring in pregnancy in improving clinical outcomes for the pregnant individual and infant is unclear. Objective: To evaluate the effect of blood pressure self-monitoring, compared with usual care alone, on blood pressure control and other related maternal and infant outcomes, in individuals with pregnancy hypertension. Design, Setting, and Participants: Unblinded, randomized clinical trial that recruited between November 2018 and September 2019 in 15 hospital maternity units in England. Individuals with chronic hypertension (enrolled up to 37 weeks' gestation) or with gestational hypertension (enrolled between 20 and 37 weeks' gestation). Final follow-up was in May 2020. Interventions: Participants were randomized to either blood pressure self-monitoring using a validated monitor and a secure telemonitoring system in addition to usual care (n = 430) or to usual care alone (n = 420). Usual care comprised blood pressure measured by health care professionals at regular antenatal clinics. Main Outcomes and Measures: The primary maternal outcome was the difference in mean systolic blood pressure recorded by health care professionals between randomization and birth. Results: Among 454 participants with chronic hypertension (mean age, 36 years; mean gestation at entry, 20 weeks) and 396 with gestational hypertension (mean age, 34 years; mean gestation at entry, 33 weeks) who were randomized, primary outcome data were available from 444 (97.8%) and 377 (95.2%), respectively. In the chronic hypertension cohort, there was no statistically significant difference in mean systolic blood pressure for the self-monitoring groups vs the usual care group (133.8 mm Hg vs 133.6 mm Hg, respectively; adjusted mean difference, 0.03 mm Hg [95% CI, -1.73 to 1.79]). In the gestational hypertension cohort, there was also no significant difference in mean systolic blood pressure (137.6 mm Hg compared with 137.2 mm Hg; adjusted mean difference, -0.03 mm Hg [95% CI, -2.29 to 2.24]). There were 8 serious adverse events in the self-monitoring group (4 in each cohort) and 3 in the usual care group (2 in the chronic hypertension cohort and 1 in the gestational hypertension cohort). Conclusions and Relevance: Among pregnant individuals with chronic or gestational hypertension, blood pressure self-monitoring with telemonitoring, compared with usual care, did not lead to significantly improved clinic-based blood pressure control. Trial Registration: ClinicalTrials.gov Identifier: NCT03334149.

Effect of Self-monitoring of Blood Pressure on Diagnosis of Hypertension During Higher-Risk Pregnancy: The BUMP 1 Randomized Clinical Trial.

Importance: Inadequate management of elevated blood pressure (BP) is a significant contributing factor to maternal deaths. Self-monitoring of BP in the general population has been shown to improve the diagnosis and management of hypertension; however, little is known about its use in pregnancy. Objective: To determine whether self-monitoring of BP in higher-risk pregnancies leads to earlier detection of pregnancy hypertension. Design, Setting, and Participants: Unblinded, randomized clinical trial that included 2441 pregnant individuals at higher risk of preeclampsia and recruited at a mean of 20 weeks' gestation from 15 hospital maternity units in England between November 2018 and October 2019. Final follow-up was completed in April 2020. Interventions: Participating individuals were randomized to either BP self-monitoring with telemonitoring (n = 1223) plus usual care or usual antenatal care alone (n = 1218) without access to telemonitored BP. Main Outcomes and Measures: The primary outcome was time to first recorded hypertension measured by a health care professional. Results: Among 2441 participants who were randomized (mean [SD] age, 33 [5.6] years; mean gestation, 20 [1.6] weeks), 2346 (96%) completed the trial. The time from randomization to clinic recording of hypertension was not significantly different between individuals in the self-monitoring group (mean [SD], 104.3 [32.6] days) vs in the usual care group (mean [SD], 106.2 [32.0] days) (mean difference, -1.6 days [95% CI, -8.1 to 4.9]; P = .64). Eighteen serious adverse events were reported during the trial with none judged as related to the intervention (12 [1%] in the self-monitoring group vs 6 [0.5%] in the usual care group). Conclusions and Relevance: Among pregnant individuals at higher risk of preeclampsia, blood pressure self-monitoring with telemonitoring, compared with usual care, did not lead to significantly earlier clinic-based detection of hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT03334149.

Cross-sectional diagnostic accuracy study of self-testing for proteinuria during hypertensive pregnancies: The UDIP study.

OBJECTIVE: To determine the accuracy of self-testing for proteinuria during pregnancy. DESIGN: Diagnostic accuracy study. SETTING: Antenatal clinics, maternity assessment units and inpatient wards at three hospital sites. POPULATION OR SAMPLE: 345 pregnant women. METHODS: Pregnant women self-tested in-clinic for urinary protein using visually read dipsticks with samples then sent for laboratory estimation of the spot protein-creatinine ratio (PCR) (primary reference test). Secondary index tests included testing by antenatal healthcare professionals and an automated colorimetric reader. MAIN OUTCOME MEASURES: Sensitivity, specificity, negative predictive value, positive predictive value and likelihood ratios were calculated for self-testing (primary index test) along with healthcare professional and colorimetric testing compared to the primary reference test (PCR). RESULTS: 335/345 (97%) had sufficient data to be included in the analysis. Self-testing had a sensitivity of 0.71 (95% confidence interval [CI] 0.62-0.79) and a specificity of 0.89 (95% CI 0.84-0.92) compared to PCR. Sensitivity and specificity of testing by healthcare professionals and the colorimetric reader were similar: sensitivity 0.73 (95% CI 0.64-0.80) and 0.78 (95% CI 0.69-0.85), respectively; specificity 0.88 (95% CI 0.82-0.92) and 0.83 (95% CI 0.78-0.88), respectively. CONCLUSION: Pregnant women can visually read a dipstick for urinary protein with similar accuracy to antenatal healthcare professionals. Automated colorimetric testing was not significantly different, in contrast to some previous studies. Self-testing has the potential to form part of a self-monitoring regime in pregnancy.

Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells.

Class I histone deacetylase (HDAC) enzymes 1, 2, and 3 organize chromatin as the catalytic subunits within seven distinct multiprotein corepressor complexes and are established drug targets. We report optimization studies of benzamide-based Von Hippel-Lindau (VHL) E3-ligase proteolysis targeting chimeras (PROTACs) and for the first time describe transcriptome perturbations resulting from these degraders. By modifying the linker and VHL ligand, we identified PROTACs 7, 9, and 22 with submicromolar DC50 values for HDAC1 and/or HDAC3 in HCT116 cells. A hook effect was observed for HDAC3 that could be negated by modifying the position of attachment of the VHL ligand to the linker. The more potent HDAC1/2 degraders correlated with greater total differentially expressed genes and enhanced apoptosis in HCT116 cells. We demonstrate that HDAC1/2 degradation by PROTACs correlates with enhanced global gene expression and apoptosis, important for the development of more efficacious HDAC therapeutics with reduced side effects.

Current prevalence of self-monitoring of blood pressure during pregnancy: the BUMP Survey.

OBJECTIVE: To understand the current prevalence of, and attitudes to, self-monitoring of blood pressure (BP) during pregnancy. METHODS: Five thousand, five hundred and fifty-five pregnant women from antenatal clinics in 16 hospitals in England were invited to complete a survey. MAIN OUTCOME MEASURES: The primary outcome was the proportion of women currently BP self-monitoring. Secondary outcomes included self-monitoring schedules and women's interactions with clinicians regarding self-monitoring. Population characteristics including risk factors for preeclampsia, ethnicity and deprivation level were considered. RESULTS: Completed surveys were received and analysed from 5181 pregnant women (93% response rate). Comparison to hospital demographic data suggests that respondents were representative of the UK population. Nine hundred and eighty-three of 5181 (19%) women were currently self-monitoring their BP, constituting 189 of 389 (49%) hypertensive women and 794 of 4792 (17%) normotensive women. However, only 482 of 983 (49%) reported ever sharing this information with antenatal care teams. Of those who self-monitored, 68% (668/983) were able to provide a previous BP reading, compared with 1% (67/5181) of those who did not self-monitor. CONCLUSION: Many women are now choosing to self-monitor their BP during pregnancy and clinicians should enquire about this proactively and consider providing better information on BP monitoring. Those who self-monitor appear to have better knowledge about their blood pressure. If these findings were replicated nationwide, around 125 000 pregnant women would be currently self-monitoring BP in the UK, yet only half of these women may communicate their readings to their antenatal care teams, suggesting a missed opportunity for enhanced care. Current trials will make the place of self-monitoring in pregnancy clearer.

Exploring the potential for introducing home monitoring of blood pressure during pregnancy into maternity care: current views and experiences of staff-a qualitative study.

OBJECTIVE: One in 20 women are affected by pre-eclampsia, a major cause of maternal and perinatal morbidity, death and premature birth worldwide. Diagnosis is made from monitoring blood pressure (BP) and urine and symptoms at antenatal visits after 20 weeks of pregnancy. There are no randomised data from contemporary trials to guide the efficacy of self-monitoring of BP (SMBP) in pregnancy. We explored the perspectives of maternity staff to understand the context and health system challenges to introducing and implementing SMBP in maternity care, ahead of undertaking a trial. DESIGN: Exploratory study using a qualitative approach. SETTING: Eight hospitals, English National Health Service. PARTICIPANTS: Obstetricians, community and hospital midwives, pharmacists, trainee doctors (n=147). METHODS: Semi-structured interviews with site research team members and clinicians, interviews and focus group discussions. Rapid content and thematic analysis undertaken. RESULTS: The main themes to emerge around SMBP include (1) different BP changes in pregnancy, (2) reliability and accuracy of BP monitoring, (3) anticipated impact of SMBP on women, (4) anticipated impact of SMBP on the antenatal care system, (5) caution, uncertainty and evidence, (6) concerns over action/inaction and patient safety. CONCLUSIONS: The potential impact of SMBP on maternity services is profound although nuanced. While introducing SMBP does not reduce the responsibility clinicians have for women's health, it may enhance the responsibilities and agency of pregnant women, and introduces a new set of relationships into maternity care. This is a new space for reconfiguration of roles, mutual expectations and the relationships between and responsibilities of healthcare providers and women. TRIAL REGISTRATION NUMBER: NCT03334149.

HDAC3 deacetylates the DNA mismatch repair factor MutSß to stimulate triplet repeat expansions.

Trinucleotide repeat (TNR) expansions cause nearly 20 severe human neurological diseases which are currently untreatable. For some of these diseases, ongoing somatic expansions accelerate disease progression and may influence age of onset. This new knowledge emphasizes the importance of understanding the protein factors that drive expansions. Recent genetic evidence indicates that the mismatch repair factor MutSß (Msh2-Msh3 complex) and the histone deacetylase HDAC3 function in the same pathway to drive triplet repeat expansions. Here we tested the hypothesis that HDAC3 deacetylates MutSß and thereby activates it to drive expansions. The HDAC3-selective inhibitor RGFP966 was used to examine its biological and biochemical consequences in human tissue culture cells. HDAC3 inhibition efficiently suppresses repeat expansion without impeding canonical mismatch repair activity. Five key lysine residues in Msh3 are direct targets of HDAC3 deacetylation. In cells expressing Msh3 in which these lysine residues are mutated to arginine, the inhibitory effect of RGFP966 on expansions is largely bypassed, consistent with the direct deacetylation hypothesis. RGFP966 treatment does not alter MutSß subunit abundance or complex formation but does partially control its subcellular localization. Deacetylation sites in Msh3 overlap a nuclear localization signal, and we show that localization of MutSß is partially dependent on HDAC3 activity. Together, these results indicate that MutSß is a key target of HDAC3 deacetylation and provide insights into an innovative regulatory mechanism for triplet repeat expansions. The results suggest expansion activity may be druggable and support HDAC3-selective inhibition as an attractive therapy in some triplet repeat expansion diseases.

Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics-single molecules comprising a HDAC inhibitor conjugated to another specificity targeting moiety. This review summarises the recent advancements in novel types of dual-targeting HDAC modulators, including proteolysis-targeting chimeras (PROTACs), with a focus on HDAC isoform and complex selectivity, and the future potential of such bifunctional molecules in achieving enhanced drug efficacy and therapeutic benefits in treating disease.

Accuracy of blood-pressure monitors owned by patients with hypertension (ACCU-RATE study): a cross-sectional, observational study in central England.

BACKGROUND: Home blood-pressure (BP) monitoring is recommended in guidelines and is increasingly popular with patients and health professionals, but the accuracy of patients' own monitors in real-world use is not known. AIM: To assess the accuracy of home BP monitors used by people with hypertension, and to investigate factors affecting accuracy. DESIGN AND SETTING: Cross-sectional, observational study in urban and suburban settings in central England. METHOD: Patients (n = 6891) on the hypertension register at seven practices in the West Midlands, England, were surveyed to ascertain whether they owned a BP monitor and wanted it tested. Monitor accuracy was compared with a calibrated reference device at 50 mmHg intervals between 0-280/300 mmHg (static pressure test); a difference from the reference monitor of +/-3 mmHg at any interval was considered a failure. Cuff performance was also assessed. Results were analysed by frequency of use, length of time in service, make and model, monitor validation status, purchase price, and any previous testing. RESULTS: In total, 251 (76%, 95% confidence interval [95% CI] = 71 to 80%) of 331 tested devices passed all tests (monitors and cuffs), and 86% (CI] = 82 to 90%) passed the static pressure test; deficiencies were, primarily, because of monitors overestimating BP. A total of 40% of testable monitors were not validated. The pass rate on the static pressure test was greater in validated monitors (96%, 95% CI = 94 to 98%) versus unvalidated monitors (64%, 95% CI = 58 to 69%), those retailing for >£10 (90%, 95% CI = 86 to 94%), those retailing for ≤£10 (66%, 95% CI = 51 to 80%), those in use for ≤4 years (95%, 95% CI = 91 to 98%), and those in use for >4 years (74%, 95% CI = 67 to 82%). All in all, 12% of cuffs failed. CONCLUSION: Patients' own BP monitor failure rate was similar to that demonstrated in studies performed in professional settings, although cuff failure was more frequent. Clinicians can be confident of the accuracy of patients' own BP monitors if the devices are validated and ≤4 years old.

PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes.

We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell viability, establishing a degradation strategy as an alternative to class I HDAC inhibition.

Blood pressure monitoring in high-risk pregnancy to improve the detection and monitoring of hypertension (the BUMP 1 and 2 trials): protocol for two linked randomised controlled trials.

INTRODUCTION: Self-monitoring of blood pressure (BP) in pregnancy could improve the detection and management of pregnancy hypertension, while also empowering and engaging women in their own care. Two linked trials aim to evaluate whether BP self-monitoring in pregnancy improves the detection of raised BP during higher risk pregnancies (BUMP 1) and whether self-monitoring reduces systolic BP during hypertensive pregnancy (BUMP 2). METHODS AND ANALYSES: Both are multicentre, non-masked, parallel group, randomised controlled trials. Participants will be randomised to self-monitoring with telemonitoring or usual care. BUMP 1 will recruit a minimum of 2262 pregnant women at higher risk of pregnancy hypertension and BUMP 2 will recruit a minimum of 512 pregnant women with either gestational or chronic hypertension. The BUMP 1 primary outcome is the time to the first recording of raised BP by a healthcare professional. The BUMP 2 primary outcome is mean systolic BP between baseline and delivery recorded by healthcare professionals. Other outcomes will include maternal and perinatal outcomes, quality of life and adverse events. An economic evaluation of BP self-monitoring in addition to usual care compared with usual care alone will be assessed across both study populations within trial and with modelling to estimate long-term cost-effectiveness. A linked process evaluation will combine quantitative and qualitative data to examine how BP self-monitoring in pregnancy is implemented and accepted in both daily life and routine clinical practice. ETHICS AND DISSEMINATION: The trials have been approved by a Research Ethics Committee (17/WM/0241) and relevant research authorities. They will be published in peer-reviewed journals and presented at national and international conferences. If shown to be effective, BP self-monitoring would be applicable to a large population of pregnant women. TRIAL REGISTRATION NUMBER: NCT03334149.

Quality evaluation of community pharmacy blood pressure (BP) screening services: an English cross-sectional survey with geospatial analysis.

OBJECTIVES: The primary objective was to assess the accuracy (calibration and validation status) of digital blood pressure (BP) monitors used within community pharmacy in England and the secondary objectives were to assess the overall quality of the BP service by assessing service prevalence, service utilisation and other in-service considerations. DESIGN: A cross-sectional survey. SETTING: Primary-care retail-pharmacies. PARTICIPANTS: 500 pharmacies that contribute to government dispensing-data were invited by post to complete the survey. Private contractors were excluded. INTERVENTIONS: We conducted a questionnaire survey with a follow-up (September 2018 to December 2018). RESULTS: 109 responses were received. 61% (n=66) of responding pharmacies provided a free BP check to their patients. 40 (61%) pharmacies used recommended validated clinical metres, 6 (9%) had failed validation and 20 (30%) provided too little information to enable us to determine their monitor's status. CONCLUSIONS: Responding pharmacies were able to provide useful BP monitoring services to their patients, though quality enhancements need to be implemented. Majority of pharmacies use validated BP monitors, however, there was a lack of range of cuff sizes, variation in replacement and calibration of monitors and apparent absence of such practice in a minority of pharmacies alongside variation in training standards. We noted higher frequency of BP screening in the most deprived postcodes.We recommend in-service redesign and delivery improvements, and suggest professional bodies and researchers work together to create clearer frameworks for front-line practitioners, creating appropriate incentives to facilitate this service redesign.Funders and policy setters should consider the value added to the National Health Service and other healthcare agencies of such screening by pharmacy providers both nationally and internationally. It has the potential to reduce complications of undiagnosed hypertension and the medicines burden that it creates. Future work should examine the impact of pharmacist-led BP screening on patients.

Siderophore-Antibiotic Conjugate Design: New Drugs for Bad Bugs?

Antibiotic resistance is a global health concern and a current threat to modern medicine and society. New strategies for antibiotic drug design and delivery offer a glimmer of hope in a currently limited pipeline of new antibiotics. One strategy involves conjugating iron-chelating microbial siderophores to an antibiotic or antimicrobial agent to enhance uptake and antibacterial potency. Cefiderocol (S-649266) is a promising cephalosporin-catechol conjugate currently in phase III clinical trials that utilizes iron-mediated active transport and demonstrates enhanced potency against multi-drug resistant (MDR) Gram-negative pathogens. Such molecules demonstrate that siderophore-antibiotic conjugates could be important future medicines to add to our antibiotic arsenal. This review is written in the context of the chemical design of siderophore-antibiotic conjugates focusing on the differing siderophore, linker, and antibiotic components that make up conjugates. We selected chemically distinct siderophore-antibiotic conjugates as exemplary conjugates, rather than multiple analogues, to highlight findings to date. The review should offer a general guide to the uninitiated in the molecular design of siderophore-antibiotic conjugates.