Calcium hydroxide-loaded nanoparticles dispersed in thermosensitive gel as a novel intracanal medicament.

AIM: Design, produce and assess the viability of a novel nanotechnological antibacterial thermo-sensible intracanal medicament This involves encapsulating calcium hydroxide (Ca(OH)2) within polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) and dispersing them in a thermosensitive gel (Ca(OH)2-NPs-gel). In addition, perform in vitro and ex vivo assessments to evaluate tissue irritation and penetration capacity into dentinal tubules in comparison to free Ca(OH)2. METHODOLOGY: Reproducibility of Ca(OH)2-NPs was confirmed by obtaining the average size of the NPs, their polydispersity index, zeta potential and entrapment efficiency. Moreover, rheological studies of Ca(OH)2-NPs-gel were carried out with a rheometer, studying the oscillatory stress sweep, the mean viscosity value, frequency and temperature sweeps. Tolerance was assessed using the membrane of an embryonated chicken egg. In vitro Ca(OH)2 release was studied by direct dialysis in an aqueous media monitoring the amount of Ca(OH)2 released. Six extracted human teeth were used to study the depth of penetration of fluorescently labelled Ca(OH)2-NPs-gel into the dentinal tubules and significant differences against free Ca(OH)2 were calculated using one-way anova. RESULTS: Ca(OH)2-NPs-gel demonstrated to be highly reproducible with an average size below 200 nm, a homogeneous NPs population, negative surface charge and high entrapment efficiency. The analysis of the thermosensitive gel allowed us to determine its rheological characteristics, showing that at 10°C gels owned a fluid-like behaviour meanwhile at 37°C they owned an elastic-like behaviour. Ca(OH)2-NPs-gel showed a prolonged drug release and the depth of penetration inside the dentinal tubules increased in the most apical areas. In addition, it was found that this drug did not produce irritation when applied to tissues such as eggs' chorialantoidonic membrane. CONCLUSION: Calcium hydroxide-loaded PLGA NPs dispersed in a thermosensitive gel may constitute a suitable alternative as an intracanal antibacterial medicament.

Out-of-Hospital Cardiac Arrest Following the COVID-19 Pandemic.

Importance: Out-of-hospital cardiac arrest (OHCA) health care provision may be a good indicator of the recovery of the health care system involved in OHCA care following the COVID-19 pandemic. There is a lack of data regarding outcomes capable of verifying this recovery. Objective: To determine whether return to spontaneous circulation, overall survival, and survival with good neurological outcome increased in patients with OHCA since the COVID-19 pandemic was brought under control in 2022 compared with prepandemic and pandemic levels. Design, Setting, and Participants: This observational cohort study was conducted to examine health care response and survival with good neurological outcome at hospital discharge in patients treated following OHCA. A 3-month period, including the first wave of the pandemic (February 1 to April 30, 2020), was compared with 2 periods before (April 1, 2017, to March 31, 2018) and after (January 1 to December 31, 2022) the pandemic. Data analysis was performed in July 2023. Emergency medical services (EMS) serving a population of more than 28 million inhabitants across 10 Spanish regions participated. Patients with OHCA were included if participating EMS initiated resuscitation or continued resuscitation initiated by a first responder. Exposure: The pandemic was considered to be under control following the official declaration that infection with SARS-CoV-2 was to be considered another acute respiratory infection. Main Outcome and Measures: The main outcomes were return of spontaneous circulation, overall survival, and survival at hospital discharge with good neurological outcome, expressed as unimpaired or minimally impaired cerebral performance. Results: A total of 14 732 patients (mean [SD] age, 64.2 [17.2] years; 10 451 [71.2%] male) were included, with 6372 OHCAs occurring during the prepandemic period, 1409 OHCAs during the pandemic period, and 6951 OHCAs during the postpandemic period. There was a higher incidence of OHCAs with a resuscitation attempt in the postpandemic period compared with the pandemic period (rate ratio, 4.93; 95% CI, 4.66-5.22; P < .001), with lower incidence of futile resuscitation for OHCAs (2.1 per 100 000 person-years vs 1.3 per 100 000 person-years; rate ratio, 0.81; 95% CI, 0.71-0.92; P < .001). Recovery of spontaneous circulation at hospital admission increased from 20.5% in the pandemic period to 30.5% in the postpandemic period (relative risk [RR], 1.08; 95% CI, 1.06-1.10; P < .001). In the same way, overall survival at discharge increased from 7.6% to 11.2% (RR, 1.45; 95% CI, 1.21-1.75; P < .001), with 6.6% of patients being discharged with good neurological status (Cerebral Performance Category Scale categories 1-2) in the pandemic period compared with 9.6% of patients in the postpandemic period (RR, 1.07; 95% CI, 1.04-1.10; P < .001). Conclusions and Relevance: In this cohort study, survival with good neurological outcome at hospital discharge following OHCA increased significantly after the COVID-19 pandemic.

Population Pharmacokinetics of Intra-articular and Intravenous Administration of Tranexamic Acid in Patients Undergoing Total Knee Replacement.

BACKGROUND: Tranexamic acid (TXA), an antifibrinolytic drug, is usually administered intravenously; however, intra-articular administration has recently been proven to be as effective as intravenous administration. Limited information regarding the pharmacokinetics (PK) of TXA after intra-articular administration has been reported. AIMS: The aim of this study was to develop a population PK model of TXA administered as a single intra-articular dose and as two intravenous doses, and to study the sources of interindividual variability (IIV) in the PK processes of TXA. The developed model was used to simulate PK profiles of TXA at different dosage regimens and in patients with renal impairment. METHODS: Patients who underwent primary unilateral total knee replacement (TKR) received 1 g/10 mL (concentration of 100 mg/mL) of TXA applied directly to the surgical field before wound closure, or 2 g (two doses of 1 g) of intravenous TXA. A population PK model was developed using a nonlinear mixed-effects approach and sources of IIV, such as sex, age, body weight, height, body mass index (BMI), preoperative haemoglobin, preoperative haematocrit, and creatinine clearance. RESULTS: Twenty-four patients were included, 12 in each group. Twenty patients were female, mean age (standard deviation) was 73.7 years (5.6). The disposition of TXA was best described as a two-compartment model with clearance dependent on creatinine clearance. Bootstrap results indicated that the model was stable and robust. The estimated bioavailability for intra-articular administration was 81%. Simulations indicated that 100% of patients would have plasma concentrations associated with partial fibrinolysis at 8 h post-administration with the dosages and routes of administration used in the present study. Intra-articular administration would produce complete inhibition of fibrinolysis in only 12% of patients compared with 72.5% with intravenous administration. No adverse events were reported. CONCLUSIONS: This population PK model demonstrated that a single dose of high-concentration, low-volume intra-articular TXA can achieve antifibrinolytic plasma concentrations of the drug for 8 h, providing both local and systemic effects in patients undergoing TKR. TXA administration to the surgical field could be an alternative to the intravenous; route for patients undergoing TKR; however, clinical studies are needed to assess the toxic local effects of TXA. TRIAL REGISTRATION: Spanish Clinical Studies Registry Number: 2017-004059-22. Date of registration: 12 April 2018.

Crystallization-Induced Diastereomer Transformation of α-Bromo α'-Sulfinyl Ketones. Diastereodivergent Synthesis of (+)-α-Conhydrine and (-)-ß-Conhydrine.

Crystallization-Induced Diastereomer Transformation (CIDT) of α-bromo-α'-(R)-sulfinylketones is reported. This process provides not readily accessible enantiopure stereolabile α-bromoketones, which after diastereoselective carbonyl group reduction lead to the corresponding highly value-added anti and syn-bromohydrins with excellent diastereoselectivities. As an application, a diastereodivergent synthesis of enantiopure hemlock alkaloid (+)-α-conhydrine and its diastereomer (-)-ß-conhydrine is also described.

Target-templated de novo design of macrocyclic d-/l-peptides: discovery of drug-like inhibitors of PD-1.

Peptides are a rapidly growing class of therapeutics with various advantages over traditional small molecules, especially for targeting difficult protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing bioactive cyclic topologies that go beyond natural l-amino acids. Here, we report a generalizable framework that exploits the computational power of Rosetta, in terms of large-scale backbone sampling, side-chain composition and energy scoring, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we developed two new inhibitors (PD-i3 and PD-i6) of programmed cell death 1 (PD-1), a key immune checkpoint in oncology. A comprehensive biophysical evaluation was performed to assess their binding to PD-1 as well as their blocking effect on the endogenous PD-1/PD-L1 interaction. Finally, NMR elucidation of their in-solution structures confirmed our de novo design approach.

Synthesis and Biological Activities of Cyclodepsipeptides of Aurilide Family from Marine Origin.

Aurilides are a class of depsipeptides occurring mainly in marine cyanobacteria. Members of the aurilide family have shown to exhibit strong cytotoxicity against various cancer cell lines. These compounds bear a pentapeptide, a polyketide, and an α-hydroxy ester subunit in their structure. A large number of remarkable studies on aurilides have emerged since 1996. This comprehensive account summarizes the biological activities and total syntheses of natural compounds of the aurilide family as well as their synthetic analogues.

Evaluation of grip strength in hook of hamate fractures treated with osteosynthesis. Is this surgical treatment necessary?

OBJECTIVE: The aim of this study was to evaluate the outcomes of open reduction and internal fixation (ORIF) in hamate hook fractures and review the literature on this surgical procedure. METHODS: We report the outcomes of ORIF of hamate hook fractures in 13 consecutive patients (12 men and 1 woman; mean age: 32 years (range, 22-48 years)). In eight patients (61%) the fracture was associated with ulnar nerve neuritis in Guyon's canal. We assessed the following clinical data: age, sex, mechanism of injury, side of the injured hand and associated lesions, fracture classification, average time from injury to correct diagnosis, surgical technique, complications, and length of follow-up. All patients underwent radiological imaging, including standard radiographs in two planes (anteroposterior and lateral projections), and a CT study. Functional outcomes evaluated were pain, range of motion, grip strength, Disabilities of the arm, shoulder and hand (DASH) and Mayo wrist score. RESULTS: The mean follow-up was 36 months (range, 12-144 months). All 13 cases were treated with ORIF of the hook of the hamate. Mean VAS pain score was 5 preoperatively (4-9) and 1 (0-2) postoperatively. All patients returned to pre-injury level and only one patient felt pain on activity. Preoperative modified Mayo wrist score was 51 and the postoperative value was 94. All outcomes scores improved significantly from preoperative values. The patients who participated in sports postoperatively were able to do so at or near pre-injury levels. Postoperative average range of wrist motion was 76° in extension, 71° in flexion, 14° in ulnar deviation, and 21° in radial deviation. Mean grip strength in the hand with the hook fracture was 58 kg compared with 53 Kg in the unaffected hand. All patients returned to their pre-injury level of functioning after 10-12 weeks and there were no complications. Analysis of grip strength revealed values comparable with the unaffected hand. CONCLUSION: ORIF of hamate hook fractures is a safe and effective technique to restore normal grip strength and return to pre-injury level. In cases of ulnar nerve neuritis, neurolysis of the deep palmar branch is mandatory. LEVEL OF EVIDENCE: Level IV, Therapeutic study.

Out-of-hospital cardiac arrest (OHCA) attended by mobile emergency teams with a physician on board. Results of the Spanish OHCA Registry (OSHCAR).

Most survival outcomes in out-of-hospital cardiac arrest (OHCA) are provided by emergency medical services (EMS) without a doctor on board. Our objective was to determine such outcomes in a whole country with public physician-led EMS. METHODS: We analyzed data from a nationwide prospective registry of OHCA cases attended by 19 public EMS in Spain, covering the period from 1-October 2013 to 30-October 2014. RESULTS: Advanced life support (ALS) was initiated in 9347 cases (incidence 18.6 cases/105 inhabitants per year). Resuscitation was considered futile in 558 cases (5.9%), and ALS was continued in 8789 cases (94.1%); mean age 63.5±17 years, 72.1% men. Initial rhythm was shockable in 22.1% of cases. Basic life support (BLS) was provided by bystanders in 1602 (24%) cases (635 of them with telephone assistance from the dispatch center). Of 8789 patients receiving ALS, 72.1% men, 2669 (30.4%) patients had return of spontaneous circulation on hospital arrival, 50.6% when the initial rhythm was shockable. Hospital discharge with good neurological status (CPC1-2) was found in 11.1% of the study population and in 27.6% when considering the Utstein comparator group of patients. A total of 216 (2.5%) patients arrived at the hospital with ongoing resuscitation, of whom only one survived with CPC1-2, and 165 (1.9%) patients were included in non-heart-beating donation programs. CONCLUSIONS: In Spain with physician-led EMS, OHCA survival with CPC1-2 reached a reasonable percentage despite only a modest contribution of bystander BLS. Ongoing resuscitation strategy seems to be futile except when considering non-heart beating donation programs.

Lewis Acid Induced Switch of Torquoselectivity in the Nazarov Cyclization of Activated Dienones Bearing a Chiral Sulfoxide.

A Nazarov cyclization of activated dienones bearing a dihydropyran as an electron-donating group (EDG) and a chiral sulfoxide group as an electron-withdrawing group (EWG) and chiral inductor is described. The direction of the torquoselectivity depends highly on the nature of the Lewis acid promoter. This diastereodivergent strategy furnishes both trans stereoisomers from a common precursor. The potential of the Nazarov cyclization products was highlighted by further synthetic elaboration.

New Insights into the Synthesis and Biological Activity of the Pamamycin Macrodiolides.

After a brief account of the biological properties of pamamycins, this review highlights the latest developments on the total synthesis and the biosynthesis of these macrodiolides.

Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials.

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.

Results achieved by emergency physicians in teaching basic cardiopulmonary resuscitation to secondary school students.

OBJECTIVE: We investigated the results obtained with a basic cardiopulmonary resuscitation (b-CPR) program (PROCES) specifically designed for secondary school students (14-16 years old) and taught by emergency physicians. METHODS: We used a multiple-choice test with 20 questions (10 on theory and 10 on skills) answered before and immediately after and 1 year after receiving the b-CPR course. Satisfactory learning was considered when at least 8 out of 10 skill questions were correctly answered. We investigated student variables associated with better immediate and deferred (1 year after) PROCES performance. We compared the results with those obtained using a more standardized program to teach b-CPR to police cadets. RESULTS: We enrolled 600 high school students. PROCES achieved significant improvement in overall, theory and skill marks immediately after the course (P<0.001), with a significant decay in all of them 1 year after the course (P<0.001). Satisfactory learning was achieved by 57% of school students immediately after PROCES and by 37% when assessed 1 year later. Students without pending study subjects (P=0.001) and those from private schools (P<0.01) achieved significantly better performance immediately after PROCES and only female students achieved greater performance 1 year after the course (P<0.05). With respect to police cadets instructed through a standardized course, immediate satisfactory learning of school students was lower (79 vs. 57%, respectively; P<0.001), whereas deferred satisfactory learning was higher (23 vs. 37%, respectively; P<0.05). CONCLUSION: Emergency physicians can satisfactorily instruct secondary school students in b-CPR using PROCES, and this specific program achieves a reasonable amount of satisfactory learning.

[Stroke. Diagnosis and therapeutic management of cerebrovascular disease]. / Ictus. Diagnóstico y tratamiento de las enfermedades cerebrovasculares.

Stroke is the second cause of death and the first cause of disability with an important economical cost. Thrombolysis and stroke units are the major contribution to stroke treatment of the last years changing a nihilist therapeutic attitude towards an active attitude, stroke is a medical emergency. Treatment with rtPA has shown to be effective in the first 3 hours following stroke and the FDA and the European Medical Agency (EMEA) have approved its use. A protocolised management of the acute phase to treat physiological complications is the mainstone of stroke units showing a reduction in mortality and disability. Multiple strategies are under development in order to treat more patients, drugs with a longer therapeutic window, intravenous thrombolysis followed by intrarterial thrombolysis, selection of patients with mismatch with new neuroimaging techniques and neuroprotective therapies. Preventive treatment has also experienced a change due to a better knowledge of the ethiopathogeny, the role of vascular risk factors and the development of new preventive drugs. Knowledge of cerebrovascular diseases is today's clue for the best treatment of our patients.

Teaching basic life support to 12-16 year olds in Barcelona schools: views of head teachers.

AIM: To determine the opinion of head teachers on the educational and logistical characteristics required for a basic cardiopulmonary resuscitation (b-CPR) programme for secondary school teenagers to succeed. MATERIAL AND METHODS: The study was carried out in Barcelona which has 227 public and private secondary schools. Secondary school is started at 12 years old, and finished around 16 once teenagers pass grade 4. A hypothetical b-CPR program split into two parts (concepts and training) was introduced to all Barcelona secondary school head teachers, and a 23 question survey on the programme characteristics was mailed to them three times. RESULTS: One hundred out of 227 (44%) surveys were sent back: 63% from private and 37% from public secondary schools with 85% of head teachers being interested in incorporating a b-CPR programme in the school curriculum. Interested head teachers did not differ in age, sex, or kind of degree compared to their non-interested counterparts. Neither were differences found in secondary school characteristics (ownership, religious orientation, size, and neighborhood average income) of both groups of head teachers. Overall, it was considered that the programme could increase the students' self-esteem (86%), and be useful for saving lives (72%). It was also felt that both theoretical (77%) and practical classes (97%) should be given by healthcare providers. However, up to 69% thought that school teachers would be willing to give theoretical classes if trained previously. The school was identified as the best setting to perform the programme (83%), which should be given to grades 3 or 4 (97%), should last less than 5 h (83%), and should be completed within a time frame of less than 1 week (86%). The greatest programme barrier would be its cost if this was over 5-10 euro per student (55%). CONCLUSIONS: In Barcelona, most secondary schools surveyed were highly interested in a b-CPR programme for their teenagers in grades 3 or 4. Teachers would prefer healthcare providers to give the programme but would be willing to teach b-CPR theory if trained previously.

Conformational analysis of a potent SSTR3-selective somatostatin analogue by NMR in water solution.

The three-dimensional structure of a potent SSTR3-selective analogue of somatostatin, cyclo(3-14)H-Cys(3)-Phe(6)-Tyr(7)-D-Agl(8)(N(beta) Me, 2-naphthoyl)-Lys(9)-Thr(10)-Phe(11)-Cys(14)-OH (des-AA(1, 2, 4, 5, 12, 13)[Tyr(7), D-Agl(8)(N(beta) Me, 2-naphthoyl)]-SRIF) (peptide 1) has been determined by (1)H NMR in water and molecular dynamics (MD) simulations. The peptide exists in two conformational isomers differing mainly by the cis/trans isomerization of the side chain in residue 8. The structure of 1 is compared with the consensus structural motifs of other somatostatin analogues that bind predominantly to SSTR1, SSTR2/SSTR5 and SSTR4 receptors, and to the 3D structure of a non-selective SRIF analogue, cyclo(3-14)H-Cys(3)-Phe(6)-Tyr(7)-D-2Nal(8)-Lys(9)-Thr(10)-Phe(11)-Cys(14)-OH (des-AA(1, 2, 4, 5, 12, 13)[Tyr(7), D-2Nal(8)]-SRIF) (peptide 2). The structural determinant factors that could explain selectivity of peptide 1 for SSTR3 receptors are discussed.

Mono- and bis-thiazolium salts have potent antimalarial activity.

Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC(50) values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED(50)

Dual molecules as new antimalarials.

A new antimalarial pharmacological approach based on inhibition of the plasmodial phospholipid metabolism has been developed. The drugs mimic choline structure and inhibit de novo phosphatidylcholine biosynthesis. Three generations of compounds were rationally designed. Bisquaternary ammonium salts showed powerful antimalarial activity, with IC(50) in the nanomolar range. To remedy their low per os absorption, bioisosteric analogues (bis-amidines) were designed and exhibited similar powerful activities. Finally, the third generation compounds are bis-thiazolium salts and their non-ionic precursors: prodrugs, which in vivo can lead to thiazolium drugs after enzymatic transformation. The compounds are equally effective against multiresistant Plasmodium falciparum malaria. These molecules exert a very rapid cytotoxic effect against malarial parasites in the very low nanomolar range and are active in vivo against P. vinckei-infected mice, with ED(50) lower than 0.2 mg/kg. They are able to cure highly infected mice and, retain full activity after a single injection. They also retain full activity against P. falciparum and P. cynomolgi in primate models with no recrudescence and at lower doses. Compounds are accumulated in P.falciparum-infected erythrocyte, which ensures their potency and specificity. Recently, we discovered that compounds also interact with malarial pigment enhancing the antimalarial effect. It is quite likely that they are dual molecules, exerting their antimalarial activity via two simultaneous toxic effects on the intracellular intraerythrocytic parasites. The current leader compounds are accessible in few steps from commercial products. These crystalline molecules present a remarkable biological activity and low toxicity which is promising for the development of a new antimalarial drug.