Total Synthesis of Anti-MRSA Active Diorcinols and Analogues.

Diorcinols and related prenylated diaryl ethers were reported to exhibit activity against methicillin-resistant clinical isolates of Staphylococcus aureus (MRSA). Within these lines, we report the first total synthesis of diorcinol D, I, J, the proposed structure of verticilatin and recently isolated antibacterial diaryl ether by using an efficient and highly divergent synthetic strategy. These total syntheses furnish the diaryl ethers in only five to seven steps employing a Pd-catalyzed diaryl ether coupling as the key step. The total synthesis led to the structural revision of the natural product verticilatin, which has been isolated from a plant pathogenic fungus. Furthermore, these structures were tested in order to determine their antibacterial activities against different MRSA strains as well as further Gram-positive and -negative bacteria.

Maintaining endotracheal tube cuff pressure at 20 mmHg during anterior cervical spine surgery to prevent dysphagia: a double-blind randomized controlled trial.

PURPOSE: Anterior cervical spine surgery is associated with postoperative dysphagia, sore throat and dysphonia. It is unclear, whether this is caused by increased endotracheal tube (ETT) cuff pressure after retractor placement. This study aims to assess the effect of ETT cuff pressure adjustment on postoperative dysphagia, sore throat and dysphonia. METHODS: In this, single-centre, observer and patient-blinded randomized controlled trial patients treated with anterior cervical spine surgery were randomized to adjustment of the ETT cuff pressure to 20 mmHg after placement of the retractor versus no adjustment. Primary outcome was the incidence and severity of postoperative dysphagia. Secondary outcomes were sore throat and dysphonia. Outcomes were evaluated on day one and 2 months after the operation. RESULTS: Of 177 enrolled patients, 162 patients (92.5%) could be evaluated. The incidence of dysphagia was 75.9% on day one and 34.6% 2 months after surgery. Dysphagia in the intervention and control group was present in 77.8% versus 74.1% of patients on day one (odds ratio (OR) 1.2, 95% confidence interval (CI) (0.6-2.5)) and 28.4% versus 40.7% of patients after 2 months (OR 0.6, 95% CI 0.3-1.1), respectively. Severity of dysphagia, sore throat and dysphonia was similar in both groups. CONCLUSIONS: Anterior cervical spine surgery is accompanied by a high incidence of postoperative dysphagia, lasting until at least 2 months after surgery in over a third of our patients. Adjusting ETT cuff pressure to 20 mmHg after retractor placement, as compared to controls, did not lower the risk for both short- and long-term dysphagia. Netherlands National Trial Registry Number: NTR 3542. These slides can be retrieved under electronic supplementary material.

Maintaining endotracheal tube cuff pressure at 20 mm Hg to prevent dysphagia after anterior cervical spine surgery; protocol of a double-blind randomised controlled trial.

BACKGROUND: In anterior cervical spine surgery a retractor is obligatory to approach the spine. Previous studies showed an increase of endotracheal tube cuff pressure after placement of a retractor. It is known that high endotracheal tube cuff pressure increases the incidence of postoperative dysphagia, hoarseness, and sore throat. However, until now no evidence supports the fact whether adjusting the endotracheal tube cuff pressure during anterior cervical spine surgery will prevent this comorbidity. We present the design of a randomized controlled trial to determine whether adjusting endotracheal tube cuff pressure after placement of a retractor during anterior cervical spine surgery will prevent postoperative dysphagia. METHODS/DESIGN: 177 patients (aged 18-90 years) scheduled for anterior cervical spine surgery on 1 or more levels will be included. After intubation, endotracheal tube cuff pressure is manually inflated to 20 mm Hg in all patients. Patients will be randomized into two groups. In the control group endotracheal tube cuff pressure is not adjusted after retractor placement. In the intervention group endotracheal tube cuff pressure after retractor placement is maintained at 20 mm Hg and air is withdrawn when cuff pressure exceeds 20 mm Hg. Endotracheal tube cuff pressure is measured after intubation, before and after placement and removal of the retractor. Again air is inflated if cuff pressure sets below 20 mmHg after removal of the retractor. The primary outcome measure is postoperative dysphagia. Other outcome measures are postoperative hoarseness, postoperative sore throat, degree of dysphagia, length of hospital stay, and pneumonia. The study is a single centre double blind randomized trial in which patients and research nurses will be kept blinded for the allocated treatment during the follow-up period of 2 months. DISCUSSION: Postoperative dysphagia occurs frequently after anterior cervical spine surgery. This may be related to high endotracheal tube cuff pressure. Whether adaptation and maintaining the pressure after placement of the retractor will decrease the incidence of dysphagia, has to be determined by this trial. TRIAL REGISTRATION: Netherlands Trial Register (NTR) 3542: http://www.trialregister.nl.

Study protocol: Effects of active versus passive recharge burst spinal cord stimulation on pain experience in persistent spinal pain syndrome type 2: a multicentre randomized trial (BURST-RAP study).

BACKGROUND: Spinal cord stimulation (SCS) has shown to be an effective treatment for patients with persistent spinal pain syndrome type 2 (PSPS Type 2). The method used to deliver electrical charge in SCS is important. One such method is burst stimulation. Within burst stimulation, a recharge pattern is used to prevent buildup of charge in stimulated tissues. Two variations of burst waveforms are currently in use: one that employs active recharge and one that uses passive recharge. It has been suggested that differences exist between active and passive recharge paradigms related to both efficacy of pain relief and their underlying mechanism of action. Active recharge has been shown to activate both the medial spinal pathway, engaging cortical sensorimotor areas involved in location and intensity of pain, and lateral pathway, reaching brain areas involved with cognitive-emotional aspects of pain. Passive recharge has been suggested to act via modulation of thalamic neurons, which fire in a similar electrical pattern, and thereby modulate activity in various cortical areas including those related to motivational and emotional aspects of pain. The objective of this randomized clinical trial is to assess and compare the effect of active versus passive recharge Burst SCS on a wide spectrum of pain in PSPS Type 2 patients. METHODS: This multicentre randomized clinical trial will take place in 6 Dutch hospitals. PSPS Type 2 patients (n=94) will be randomized into a group receiving either active or passive recharge burst. Following a successful trial period, patients are permanently implanted. Patients complete the Pain Catastrophizing Scale (PCS) (primary outcome at 6 months), Numeric Pain Rating Scale (NRS), Patient Vigilance and Awareness Questionnaire (PVAQ), Hospital Anxiety and Depression Scale (HADS), Quality of Life (EQ-5D), Oswestery Disability Index (ODI), Patient Global Impression of Change (PGIC) and painDETECT questionnaires (secondary outcomes) at baseline, after trial, 1, 3, 6 and 12 months following implantation. DISCUSSION: The BURST-RAP trial protocol will shed light on possible clinical differences and effectivity of pain relief, including emotional-motivational aspects between active and passive burst SCS in PSPS Type 2 patients. TRIAL REGISTRATION: ClinicalTrials.gov registration:  NCT05421273 . Registered on 16 June 2022. Netherlands Trial Register NL9194. Registered on 23 January 2021.

Molecular Insight into Gene Response of Diorcinol- and Rubrolide-Treated Biofilms of the Emerging Pathogen Stenotrophomonas maltophilia.

Stenotrophomonas maltophilia is a multidrug-resistant human opportunistic pathogen. S. maltophilia contributes to disease progression in cystic fibrosis patients and is found in wounds and infected tissues and on catheter surfaces. Due to its well-known multidrug resistance, it is difficult to treat S. maltophilia infections. Strain-specific susceptibility to antimicrobials has also been reported in several studies. Recently, three fungal diorcinols and 14 rubrolides were shown to reduce S. maltophilia K279a biofilm formation. Based on these initial findings, we were interested to extend this approach by testing a larger number of diorcinols and rubrolides and to understand the molecular mechanisms behind the observed antibiofilm effects. Of 52 tested compounds, 30 were able to significantly reduce the biofilm thickness by up to 85% ± 15% and had strong effects on mature biofilms. All compounds with antibiofilm activity also significantly affected the biofilm architecture. Additional RNA-sequencing data of diorcinol- and rubrolide-treated biofilm cells of two clinical isolates (454 and K279) identified a small set of shared genes that were affected by these potent antibiofilm compounds. Among these, genes for iron transport, general metabolism, and membrane biosynthesis were most strongly and differentially regulated. A further hierarchical clustering and detailed structural inspection of the diorcinols and rubrolides implied that a prenyl group as side chain of one of the phenyl groups of the diorcinols and an increasing degree of bromination of chlorinated rubrolides were possibly the cause of the strong antibiofilm effects. This study gives a deep insight into the effects of rubrolides and diorcinols on biofilms formed by the important global pathogen S. maltophilia. IMPORTANCE Combating Stenotrophomonas maltophilia biofilms in clinical and industrial settings has proven to be challenging. S. maltophilia is multidrug resistant, and occurrence of resistance to commonly used drugs as well as to antibiotic combinations, such as trimethoprim-sulfamethoxazole, is now frequently reported. It is therefore now necessary to look beyond conventional and already existing antimicrobial drugs when battling S. maltophilia biofilms. Our study contains comprehensive and detailed data sets for diorcinol and rubrolide-treated S. maltophilia biofilms. The study defines genes and pathways affected by treatment with these different compounds. These results, together with the identified structural elements that may be crucial for their antibiofilm activity, build a strong backbone for further research on diorcinols and rubrolides as novel and potent antibiofilm compounds.

Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The aim of this paper was undertake a systematic review and meta-analysis of the use of spinal cord stimulation (SCS) in the management of refractory angina. METHODS: We searched a number of electronic databases including Medline, Embase and Cochrane Library up to February 2008 to identify randomised controlled trials (RCTs) reporting exercise capacity, ischemic burden, functional class, quality of life, usage of anti-anginal medication, costs and adverse events including mortality. Results were reported both descriptively for each study and using random effects meta-analysis. Given the variety in outcomes reported, some outcome results were pooled as standardised mean differences (SMD) and reported in standard deviation units. RESULTS: Seven RCTs were identified in a total of 270 refractory angina patients. The outcomes of SCS were found to be similar when directly compared to coronary artery bypass grafting (CABG) and percutaneous myocardial laser revascularisation (PMR). Compared to a 'no stimulation' control, there was some evidence of improvement in all outcomes following SCS implantation with significant gains observed in pooled exercise capacity (SMD: 0.76, 0.07 to 1.46, p = 0.03) and health-related quality of life (SMD: 0.83, 95% CI: 0.32 to 1.34, p = 0.001). Trials were small and were judged to range considerably in their quality. The healthcare costs of SCS appeared to be lower than CABG at 2-years follow up. CONCLUSION: SCS appears to be an effective and safe treatment option in the management of refractory angina patients and of similar efficacy and safety to PMR, a potential alternative treatment. Further high quality RCT and cost effectiveness evidence is needed before SCS can be accepted as a routine treatment for refractory angina.

The sustained benefits of long-term neurostimulation in patients with refractory chest pain and normal coronary arteries.

OBJECTIVES: To assess the long-term efficacy of neurostimulation for treating refractory angina pectoris-like chest pain, we followed patients, treated with either transcutaneous electrical nerve stimulation (TENS) or spinal cord stimulation (SCS). METHODS: Neurostimulation was judged successful and subsequently continued when initial pain was reduced at least 50%. All patients started with TENS, but if skin irritation occurred during TENS, a SCS system was implanted. The quality of life was measured at baseline and follow-up with the Seattle Angina Questionnaire. Additional information was gathered concerning anti-anginal medication, complaints, and physical condition. RESULTS: Of 36 patients treated successfully with neurostimulation, we identified 24 patients after a mean (SD) follow-up period of 5.08 (3.86) years; 12 patients dropped out of the study. In 13 of the remaining 24 patients, TENS induced skin irritation. Eight of these 13 patients received successful SCS, while five refused implantation. In the 24 patients, a mean pain reduction of 57% was achieved in conjunction with an increased exercise capacity of 30% and walking distance increased from 0.73 (0.83) to 1.62 (1.62) (p=0.018). Within the Seattle Angina Questionnaire the domain 'disease perception' improved from 38.89 (16.61) to 49.31 (21.83) (p=0.004), the domain 'physical limitation' improved from 29.89 (15.10) to 40.97 (22.63) (p=0.001) and 'anginal frequency' improved from 41.67 (24.08) to 55.00 (23.03) (p=0.005). In addition, nitroglycerin consumption was reduced from 7.85 (8.49) to 1.98 (2.19) (p=0.001). CONCLUSION: Neurostimulation techniques should thus be of widespread value for treating angina pectoris-like chest pain in patients who are refractory to medication.

The effect of electrical neurostimulation on collateral perfusion during acute coronary occlusion.

BACKGROUND: Electrical neurostimulation can be used to treat patients with refractory angina, it reduces angina and ischemia. Previous data have suggested that electrical neurostimulation may alleviate myocardial ischaemia through increased collateral perfusion. We investigated the effect of electrical neurostimulation on functional collateral perfusion, assessed by distal coronary pressure measurement during acute coronary occlusion. We sought to study the effect of electrical neurostimulation on collateral perfusion. METHODS: Sixty patients with stable angina and significant coronary artery disease planned for elective percutaneous coronary intervention were split in two groups. In all patients two balloon inflations of 60 seconds were performed, the first for balloon dilatation of the lesion (first episode), the second for stent delivery (second episode). The Pw/Pa ratio (wedge pressure/aortic pressure) was measured during both ischaemic episodes. Group 1 received 5 minutes of active neurostimulation before plus 1 minute during the first episode, group 2 received 5 minutes of active neurostimulation before plus 1 minute during the second episode. RESULTS: In group 1 the Pw/Pa ratio decreased by 10 +/- 22% from 0.20 +/- 0.09 to 0.19 +/- 0.09 (p = 0.004) when electrical neurostimulation was deactivated. In group 2 the Pw/Pa ratio increased by 9 +/- 15% from 0.22 +/- 0.09 to 0.24 +/- 0.10 (p = 0.001) when electrical neurostimulation was activated. CONCLUSION: Electrical neurostimulation induces a significant improvement in the Pw/Pa ratio during acute coronary occlusion.

Impact of electrical neurostimulation on persistent ST elevation after successful reperfusion by primary percutaneous coronary intervention.

AIMS: To study the effect of electrical neurostimulation on the ST segment shift in patients with ST elevation myocardial infarction (STEMI) with residual ST elevation after primary percutaneous coronary intervention (PCI). METHODS: After primary PCI, 38 patients with STEMI were divided into 2 groups. Group 1 received 15 minutes of active neurostimulation after the baseline electrocardiogram (ECG); group 2 received 15 minutes of active neurostimulation after 15 minutes of nonactive neurostimulation. RESULTS: In group 1, ST elevation decreased with neurostimulation from 0.65 +/- 0.56 to 0.55 +/- 0.51 (P = .02) and to 0.50 +/- 0.52 (P = .01) without electrical neurostimulation. In group 2, ST elevation changed without neurostimulation from 0.37 +/- 0.32 to 0.33 +/- 0.30 (P = NS) and to 0.28 +/- 0.27 (P = .01) with electrical neurostimulation. In a posthoc analysis, 17 responders had higher ST elevation at the ECG before active electrical neurostimulation than 21 nonresponders (P = .001). CONCLUSION: Electrical neurostimulation may result in significant additional reduction of ST elevation in STEMI after reperfusion treatment, in particular in patients with marked ST elevation on the first ECG after successful primary PCI.

Utilizing the "Plan, Do, Study, Act" Framework to Explore the Process of Curricular Assessment and Redesign in a Physical Therapy Education Program in Suriname.

PURPOSE: To describe how a multinational team worked together to transition a physical therapy (PT) educational program in Paramaribo, Suriname, from a Bachelor level to a Master of Science in Physical Therapy (MSPT) level. The team was made up of PT faculty from Anton De Kom Universiteit van Suriname (AdeKUS), the Flemish Interuniversity Council University Development Cooperation (VLIR-UOS) leadership, and Health Volunteers Overseas volunteers. In this case study, the process for curricular assessment, redesign, and upgrade is described retrospectively using a Plan, Do, Study, Act (PDSA) framework. METHOD: PT educational programs in developing countries are eager for upgrade to meet international expectations and to better meet community health-care needs. An ongoing process which included baseline assessment of all aspects of the existing bachelor's program in PT, development of a plan for a MSPT, implementation of the master's program, and evaluation following implementation is described. CONCLUSION: Curricular assessment and upgrade in resource-limited countries requires the implementation of process-oriented methods. The PDSA process is a useful tool to explore curricular development. The international collaboration described in this paper provides an example of the diligence, consistency, and dedication required to see a project through and achieve success while providing adequate support to the host site. This project might provide valuable insights for those involved in curricular redesign in similar settings.

Myocardial perfusion quantification in patients suspected of cardiac syndrome X with positive and negative exercise testing: a [13N]ammonia positron emission tomography study.

BACKGROUND: The combination of angina pectoris, angiographically normal coronary arteries, and a positive exercise stress test (EST) is referred to as cardiac syndrome X. However, a large group of patients suspected of syndrome X reveals a normal exercise stress test and weakens the diagnosis of syndrome X. Previous studies demonstrated an impaired coronary flow reserve on ammonia positron emission tomography (PET) in patients with syndrome X. AIM: To evaluate the coronary flow reserve in patients suspected of syndrome X with positive and negative EST findings, using [(13)N]ammonia PET as the diagnostic aid. METHODS: Forty-two patients with chest pain and a normal coronary angiography, were analysed by exercise stress testing (EST) and the dypyridamole stress test (DST) on [(13)N]ammonia PET. Two subgroups were predefined, based on outcome of EST: an EST positive and negative group. A normal control group was used as the reference method. RESULTS: A total of 24 (57%) out of 42 patients had significant ST-T changes (EST positive). [(13)N]ammonia PET showed a significantly lower rest flow in the EST positive and EST negative group compared to controls (P<0.001 and P=0.0028, respectively). DST [(13)N]ammonia PET perfusion was significantly reduced in flow in both the EST positive and EST negative groups (P<0.001 both), as was the DST/rest [(13)N]ammonia perfusion reserve (P<0.001 for both), compared to normal controls. CONCLUSION: PET demonstrates a reduced coronary flow reserve in patients suspected of syndrome X, irrespective of the EST findings.

Long-term effects of electrical neurostimulation in patients with unstable angina: refractory to conventional therapies.

Background. Patients with unstable angina pectoris may become refractory to conventional therapies. Electrical neurostimulation with transcutaneous electrical stimulation and/or spinal cord stimulation has been shown to be effective for patients with refractory unstable angina pectoris in hospital settings. Our aim was to investigate the effects of electrical neurostimulation on outcomes of unstable angina after hospital discharge, in terms of hospital re-admission rates and long-term survival analysis. Method. Twenty-seven consecutive patients with unstable angina pectoris, refractory to conventional therapies, received electrical neurostimulation in a tertiary referral hospital. We studied the number of hospital admissions in the year before when compared to the first year after electrical neurostimulation and performed survival analysis of the group. Results. Twenty-six patients had beneficial effects of electrical neurostimulation during their admission to the hospital. During a mean follow-up of 6.6 ± 4.1 years, electrical neurostimulation was still effective in 21 out of 26. In 11 patients with previous hospital admissions, the number of hospital admissions decreased significantly after electrical neurostimulation (p = 0.007). The combined mortality and (re)infarction rate after one-year follow-up was 14%. Conclusion. The results of this observational study show long-term beneficial effects of electrical neurostimulation in a population of patients with unstable refractory angina. Therefore, electrical neurostimulation should be considered as a beneficial treatment for patients with unstable angina pectoris, refractory to conventional therapies.

Incidence and angiographic predictors of collateral function in patients with stable coronary artery disease scheduled for percutaneous coronary intervention.

OBJECTIVES: To investigate the incidence and angiographic predictors of functional collateral perfusion in patients with stable coronary artery disease, scheduled for elective PCI. BACKGROUND: Functional collateral perfusion is defined as a Pw/Pa ratio>or=0.24. Since this can only be measured intracoronary, it is important to investigate baseline clinical and angiographic predictors for functional collateral perfusion. METHODS: Collateral perfusion was measured during balloon inflation, with the use of a pressure-monitoring guide wire. Baseline clinical and angiographic characteristics were analyzed and collateral grading was done according to Rentrop's classification for coronary angiograms. RESULTS: Functional collateral perfusion was found in 40 of the 89 patients (45%). Angiographic signs of collaterals (Rentrop>or=1) were present in 15 of the 89 patients. Of the 40 patients with the functional collateral perfusion 11 patients (28%) had Rentrop>or=1; of the 49 patients without functional collaterals there were 4 patients with Rentrop>or=1 (8%) (P=0.02). There were no significant differences in baseline clinical characteristics or in other angiographic characteristics. CONCLUSIONS: In patients with stable coronary artery disease scheduled for elective PCI, 45% have functional collaterals. Rentrop's angiographic classification can be used to predict the presence or absence of functional collaterals, however with a rather modest positive and negative predictive value.

Personality: predictor of neurostimulation outcomes in patients with chest pain and normal coronary arteries.

Objectives. To study the impact of personality traits on the effect of neurostimulation in patients with chest pain and normal coronary arteries. Materials and Methods. Using the Dutch personality questionnaire, we retrospectively studied the personality traits in 33 patients treated with neurostimulation, either transcutaneous electrical nerve stimulation or spinal cord stimulation after 5 years. Neurostimulation was successful in 21 patients. Baseline characteristics and medication also were assessed for possible interactions with personality traits and neurostimulation outcome. Results. Patients with beneficial neurostimulation scored lower on the "social inadequacy" scale than patients with neurostimulation failure (p = 0.032). In univariate analyses, low scores at the "social inadequacy" scale and the use of calcium antagonists were associated with beneficial outcome of neurostimulation. In multivariate analysis low scores at the "social inadequacy" scale remained an independent predictor for beneficial neurostimulation outcome, when adjusted for other variables. Conclusion. Personality traits are a determining factor in the evaluation of neurostimulation for patients with chest pain and normal coronary arteries.