Two in ten patients seeking addiction treatment within São Paulo's Crackland report recent use of Synthetic Cannabinoids.

The profile investigation of crack cocaine dependents seeking addiction treatment within Sao Paulo's open drug use scene known as "Crackland" demonstrated that 20% of them reported consuming variations of Synthetic Cannabinoids. This equated to 1.054 patients in a span of four months (between 08/05/2023 to 08/09/2023). This preliminary finding is well-timed and holds significant value making it suitable for a briefer publication format, such as a letter, that can promptly disseminate this relevant information to the scientific community. Additional and complementary evidence expanding the discussion beyond the medical aspects of SC consumption is also provided. This figure is a clear indication of the shift in the population accessing this drug, now reaching the most vulnerable segment of our nation's population. The letter brings on further insights with a more social perspective, also discussing the intricate interplay between affordability, availability price and how criminal organizations are likely involved now with SC's control and distribution in Brazil.

Landscaping macrocyclic peptides: stapling hDM2-binding peptides for helicity, protein affinity, proteolytic stability and cell uptake.

Cyclic peptides that modulate protein-protein interactions can be valuable therapeutic candidates if they can be delivered intact to their target proteins in cells. Here we systematically compare the effects of different helix-inducing cyclization constraints on the capacity of a macrocyclic peptide component to confer α-helicity, protein-binding affinity, resistance to degradative proteases and cell uptake to a 12-residue peptide fragment of tumor suppressor protein p53. We varied the helix-inducing constraint (hydrocarbon, lactam, aliphatic or aromatic thioether, etc.) and the position of the cyclization linker (i to i + 4 or i to i + 7 bridges) in order to sculpt the macrocyclic size, stabilize its structure, and promote cell uptake. We find that rigidifying the macrocycle leads to higher alpha helicity, target affinity and proteolytic stability to different extents, whereas cell uptake of compounds shown here is mostly driven by hydrophobicity and aromaticity of the macrocycle.

Dynamics and Determinants of SARS-CoV-2 RT-PCR Testing on Symptomatic Individuals Attending Healthcare Centers during 2020 in Bahia, Brazil.

RT-PCR testing data provides opportunities to explore regional and individual determinants of test positivity and surveillance infrastructure. Using Generalized Additive Models, we explored 222,515 tests of a random sample of individuals with COVID-19 compatible symptoms in the Brazilian state of Bahia during 2020. We found that age and male gender were the most significant determinants of test positivity. There was evidence of an unequal impact among socio-demographic strata, with higher positivity among those living in areas with low education levels during the first epidemic wave, followed by those living in areas with higher education levels in the second wave. Our estimated probability of testing positive after symptom onset corroborates previous reports that the probability decreases with time, more than halving by about two weeks and converging to zero by three weeks. Test positivity rates generally followed state-level reported cases, and while a single laboratory performed ~90% of tests covering ~99% of the state's area, test turn-around time generally remained below four days. This testing effort is a testimony to the Bahian surveillance capacity during public health emergencies, as previously witnessed during the recent Zika and Yellow Fever outbreaks.

Tuning Electrostatic and Hydrophobic Surfaces of Aromatic Rings to Enhance Membrane Association and Cell Uptake of Peptides.

Aromatic groups are key mediators of protein-membrane association at cell surfaces, contributing to hydrophobic effects and π-membrane interactions. Here we show electrostatic and hydrophobic influences of aromatic ring substituents on membrane affinity and cell uptake of helical, cyclic and cell penetrating peptides. Hydrophobicity is important, but subtle changes in electrostatic surface potential, dipoles and polarizability also enhance association with phospholipid membranes and cell uptake. A combination of fluorine and sulfur substituents on an aromatic ring induces microdipoles that enhance cell uptake of 12-residue peptide inhibitors of p53-HDM2 interaction and of cell-penetrating cyclic peptides. These aromatic motifs can be readily inserted into peptide sidechains to enhance their cell uptake.

Telemedicine Versus Face-to-Face Care in Ophthalmology: Costs and Utility Measures in a Real-World Setting.

OBJECTIVES: Advances in telemedicine offer a unique opportunity to expand access to the health system. Nevertheless, few studies have described the impact of telediagnosis implementation on health and economic outcomes. METHODS: An ophthalmology telediagnosis service (TeleOftalmo) was compared with traditional face-to-face care provided by the Brazilian public health system. For both groups, utility data were collected at 2 time points using the Visual Function Questionnaire-Utility Index instrument from interviews with 536 patients. The cost per patient encounter was analyzed according to the time-driven activity-based costing. Value analyses were conducted to ascertain whether and how telemedicine service has the potential to generate cost savings for the health system. RESULTS: Visual function-related quality of life did not differ significantly between TeleOftalmo and face-to-face care groups. Using the current model, the telemedicine service assisted an average of 1159 patients per month at a median cost per telediagnosis of Int$97 (interquartile range, Int$82-Int$119) versus Int$77 (interquartile range, Int$75-Int$80) for face-to-face care. If the telemedicine service was redesigned, considering the opportunities for improvement identified, it could operate at a cost of Int$53 per telediagnosis (a 31% cost savings) and could serve 3882 patients per month. CONCLUSIONS: This study demonstrates the potential value of a telemedicine service. There was no difference in patient-perceived utility between a telediagnostic ophthalmology service and face-to-face care by an eye specialist. TeleOftalmo has the potential to be a cost-saving strategy for the Brazilian health system and could be a template for implementation of telediagnostic services in other regions.

Teaming-up nurses with ophthalmologists to expand the reach of eye care in a middle-income country: Validation of health data acquisition by nursing staff in a telemedicine strategy.

Telemedicine can be used to conduct ophthalmological assessment of patients, facilitating patient access to specialist care. Since the teleophthalmology models require data collection support from other health professionals, the purpose of our study was to assess agreement between the nursing technician and the ophthalmologist in acquisition of health parameters that can be used for remote analysis as part of a telemedicine strategy. A cross-sectional study was conducted with 140 patients referred to an ophthalmological telediagnosis center by primary healthcare doctors. The health parameters evaluated were visual acuity (VA), objective ophthalmic measures acquired by autorefraction, keratometry, and intraocular pressure (IOP). Bland-Altman plots were used to analyze agreement between the nursing technician and the ophthalmologist. The Bland-Altman analysis showed a mean bias equal to zero for the VA measurements [95%-LoA: -0.25-0.25], 0.01 [95%-LoA: -0.86-0.88] for spherical equivalent (M), -0.08 [95%-LoA: -1.1-0.95] for keratometry (K) and -0.23 [95%-LoA: -4.4-4.00] for IOP. The measures had a high linear correlation (R [95%CI]: 0.87 [0.82-0.91]; 0.97 [0.96-0.98]; 0.96 [0.95-0.97] and 0.88 [0.84-0.91] respectively). The results observed demonstrate that remote ophthalmological data collection by adequately trained health professionals is viable. This confirms the utility and safety of these solutions for scenarios in which access to ophthalmologists is limited.

Effects of extra virgin olive oil and pecans on plasma fatty acids in patients with stable coronary artery disease.

OBJECTIVE: The aim of this study was to determine the effects of a healthy diet supplemented with extra virgin olive oil or pecans on plasma fatty acids (PFAs) in patients with stable coronary artery disease (CAD). METHODS: Patients 40 to 80 y of age were randomized to one of three dietary interventions (allocation ratio 1: 1: 1): healthy diet based on guidelines (control group [CG]), healthy diet supplemented with 30 g/d of pecans (PNG), or a healthy diet supplemented with 30 mL/d of extra virgin olive oil (OOG). PFAs were identified at baseline and at the end of follow-up (12 wk), and correlations between dietary fatty acids intake, PFAs, and clinical biomarkers of the lipid profile were also assessed before and after the interventions. RESULTS: Among 149 participants included in the analysis (43 CG; 51 PNG; and 55 OOG), correlations were observed between food intake, PFAs, and lipid profile before and after interventions independent of statins used, but all were considered weak. At the end of the study, the OOG showed increased concentrations of oleic fatty acid independently of the type of statin in use (1.49%; 95% confidence interval, 0.08-2.89; P = 0.029); however, there were no significant differences between the groups regarding the final mean values of oleic fatty acid or in the other PFAs. CONCLUSIONS: In patients with stable CAD, there were no significant differences in PFAs after 12 wk according to dietary interventions evaluated.

Health-related quality of life associated with diabetic retinopathy in patients at a public primary care service in southern Brazil.

OBJECTIVE: This study aimed to establish the utility values of different health states associated with diabetic retinopathy in a Brazilian sample to provide input to model-based economic evaluations. METHODS: This cross-sectional study was performed in a sample of patients with type 2 diabetes mellitus (T2D) who underwent teleophthalmology screening at a primary care service from 2014 to 2016. Five diabetic retinopathy health states were defined: absent, non-sight-threatening, sight-threatening, and bilateral blindness. Utility values were estimated using the Brazilian EuroQol five dimensions (EQ-5D) tariffs. Descriptive statistics were calculated. Analysis of covariance was performed to adjust the utility values for potential confounders. RESULTS: The study included 206 patients. The mean (± standard deviation [SD]) utility value was 0.765 ± 0.19 (95% confidence interval [CI], 0.740-0.790). The adjusted mean utility value was 0.748 (95% CI, 0.698-0.798) in patients without diabetic retinopathy, 0.752 (95% CI, 0.679-0.825) in those with non-sight-threatening state, 0.628 (95% CI, 0.521-0.736) in those with sight-threatening state, and 0.355 (95% CI, 0.105-0.606) in those with bilateral blindness. A significant utility decrement was found between patients without diabetic retinopathy and those with a sight-threatening health state (0.748 vs. 0.628, respectively, p = 0.04). CONCLUSION: The findings suggest that a later diabetic retinopathy health state is associated with a decrement in utility value compared with the absence of retinopathy in patients with T2D. The results may be useful as preliminary input to model-based economic evaluations. Further research is needed to investigate the impact of diabetic retinopathy on health-related quality of life in a sample more representative of the Brazilian population.

Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc.

c-Myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression in mice with only mild and fully reversible side effects, suggesting this to be a viable therapeutic strategy. Here we reassess the challenges of directly targeting c-Myc, evaluate lessons learned from current inhibitors, and explore how future strategies such as miniaturisation of Omomyc and targeting E-box binding could facilitate translation of c-Myc inhibitors into the clinic.

Late-Stage Hydrocarbon Conjugation and Cyclisation in Synthetic Peptides and Proteins.

The conventional S-alkylation of cysteine relies upon using activated electrophiles. Here we demonstrate high-yielding and selective S-alkylation and S-lipidation of cysteines in unprotected synthetic peptides and proteins by using weak electrophiles and a Zn2+ promoter. Linear or branched iodoalkanes can S-alkylate cysteine in an unprotected 38-residue Myc peptide fragment and in a 91-residue miniprotein Omomyc, thus highlighting selective late-stage synthetic modifications. Metal-assisted cysteine alkylation is also effective for incorporating dehydroalanine into unprotected peptides and for peptide cyclisation via aliphatic thioether crosslinks, including customising macrocycles to stabilise helical peptides for enhanced uptake and delivery to proteins inside cells. Chemoselective and efficient late-stage Zn2+ -promoted cysteine alkylation in unprotected peptides and proteins promises many useful applications.

Ophthalmic image acquired by ophthalmologists and by allied health personnel as part of a telemedicine strategy: a comparative study of image quality.

OBJECTIVES: This study evaluates the quality of ophthalmic images acquired by a nurse technician trained in teleophthalmology as compared with images acquired by an ophthalmologist, in order to provide a better understanding of the workforce necessary to operate remote care programs. METHODS: A cross-sectional study was performed on 2044 images obtained from 118 participants of the TeleOftalmo project, in Brazil. Fundus and slit-lamp photography were performed on site by an ophthalmologist and by a nurse technician under the supervision of a remote ophthalmologist. Image quality was then evaluated by masked ophthalmologists. Proportion of suitable images in each group was compared. RESULTS: The proportion of concordant classification regarding quality was 94.8%, with a corrected kappa agreement of 0.94. When analyzing each type of photo separately, there was no significant difference in the proportion of suitable images between on-site ophthalmologist and nurse technician with remote ophthalmologist assistance for the following: slit-lamp views of the anterior segment and anterior chamber periphery, and fundus photographs centered on the macula and on the optic disc (P = 0.825, P = 0.997, P = 0.194, and P = 0.449, respectively). For slit-lamp views of the lens, the proportion of suitable images was higher among those obtained by an ophthalmologist (99.6%) than by a technician (93.8%, P < 0.01). CONCLUSIONS: Ophthalmic photographs acquired by a trained technician consistently achieved >90% adequacy for remote reading. Compared with ophthalmologist-acquired photos, the proportion of images deemed suitable achieved a high overall agreement. These findings provide favorable evidence of the adequacy of teleophthalmological imaging by nurse technicians.

Fortified Coiled Coils: Enhancing Mechanical Stability with Lactam or Metal Staples.

Coiled coils (CCs) are powerful supramolecular building blocks for biomimetic materials, increasingly used for their mechanical properties. Here, we introduce helix-inducing macrocyclic constraints, so-called staples, to tune thermodynamic and mechanical stability of CCs. We show that thermodynamic stabilization of CCs against helix uncoiling primarily depends on the number of staples, whereas staple positioning controls CC mechanical stability. Inserting a covalent lactam staple at one key force application point significantly increases the barrier to force-induced CC dissociation and reduces structural deformity. A reversible His-Ni2+ -His metal staple also increases CC stability, but ruptures upon mechanical loading to allow helix uncoiling. Staple type, position and number are key design parameters in using helical macrocyclic templates for fine-tuning CC properties in emerging biomaterials.

New Structural insights into Kir channel gating from molecular simulations, HDX-MS and functional studies.

Inward rectifier potassium (Kir) channels play diverse and important roles in shaping action potentials in biological membranes. An increasing number of diseases are now known to be directly associated with abnormal Kir function. However, the gating of Kir still remains unknown. To increase our understanding of its gating mechanism, a dynamical view of the entire channel is essential. Here the gating activation was studied using a recent developped in silico method, MDeNM, which combines normal mode analysis and molecular dynamics simulations that showed for the very first time the importance of interrelated collective and localized conformational movements. In particular, we highlighted the role played by concerted movements of the different regions throughout the entire protein, such as the cytoplasmic and transmembrane domains and the slide helices. In addition, the HDX-MS analysis achieved in these studies provided a comprehensive and detailed view of the dynamics associated with open/closed transition of the Kir channel in coherence with the theoretical results. MDeNM gives access to the probability of the different opening states that are in agreement with our electrophysiological experiments. The investigations presented in this article are important to remedy dysfunctional channels and are of interest for designing new pharmacological compounds.

The use of telemedicine to support Brazilian primary care physicians in managing eye conditions: The TeleOftalmo Project.

PURPOSE: To determine whether teleophthalmology can help physicians in assessing and managing eye conditions and to ascertain which clinical conditions can be addressed by teleophthalmology in primary care setting. METHODS: We evaluated the resolution capacity of TeleOftalmo, strategy implemented in the public health system of southern Brazil. Resolution capacity was defined as the ability to fully address patients' eye complaints in primary care with remote assistance from ophthalmologists. Data from tele-eye reports were collected over 14 months. Resolution capacity was compared across different age groups and different ocular conditions. RESULTS: Overall, 8,142 patients had a tele-eye report issued in the study period. Resolution capacity was achieved in 5,748 (70.6%) patients. When stratified into age groups, the lowest capacity was 43.1% among subjects aged ≥65 years, while the highest was 89.7% among subjects aged 13-17 years (p<0.001). Refractive error (70.3%) and presbyopia (56.3%) were the most prevalent conditions followed by cataract (12.4%) and suspected glaucoma (7.6%). Resolution capacity was higher in cases of refractive error, presbyopia, spasm of accommodation and lid disorders than in patients diagnosed with other condition (p<0.001). CONCLUSIONS: With telemedicine support, primary care physicians solved over two-thirds of patients' eye or vision complaints. Refractive errors had high case resolution rates, thus having a great impact on reducing the number of referrals to specialty care. Teleophthalmology adoption in primary-care settings as part of the workup of patients with eye or vision complaints promotes a more effective use of specialty centers and will hopefully reduce waiting times for specialty referral.

Cost-utility Analysis of Opportunistic and Systematic Diabetic Retinopathy Screening Strategies from the Perspective of the Brazilian Public Healthcare System.

OBJECTIVE: To perform a cost-utility analysis of diabetic retinopathy (DR) screening strategies from the perspective of the Brazilian Public Healthcare System. METHODS: A model-based economic evaluation was performed to estimate the incremental costs per quality-adjusted life-year (QALY) gained between three DR screening strategies: (1) the opportunistic ophthalmology referral-based (usual practice), (2) the systematic ophthalmology referral-based, and (3) the systematic teleophthalmology-based. The target population included individuals with type 2 diabetes (T2D) aged 40 years, without retinopathy, followed over a 40-year time horizon. A Markov model was developed with five health states and a 1-year cycle. Model parameters were based on literature and country databases. One-way and probabilistic sensitivity analyses were performed to assess model parameters' uncertainty. WHO willingness-to-pay (WHO-WTP) thresholds were used as reference (i.e. one and three times the Brazilian per capita Gross Domestic Product of R$32747 in 2018). RESULTS: Compared to usual practice, the systematic teleophthalmology-based screening was associated with an incremental cost of R$21445/QALY gained ($9792/QALY gained). The systematic ophthalmology referral-based screening was more expensive (incremental costs = R$4) and less effective (incremental QALY = -0.012) compared to the systematic teleophthalmology-based screening. The probability of systematic teleophthalmology-based screening being cost-effective compared to usual practice was 0.46 and 0.67 at the minimum and the maximum WHO-WTP thresholds, respectively. CONCLUSION: Systematic teleophthalmology-based DR screening for the Brazilian population with T2D would be considered very cost effective compared to the opportunistic ophthalmology referral-based screening according to the WHO-WTP threshold. However, there is still a considerable amount of uncertainty around the results.

A Novel Long-Range n to π* Interaction Secures the Smallest known α-Helix in Water.

The introduction of an amide bond linking side chains of the first and fifth amino acids forms a cyclic pentapeptide that optimally stabilizes the smallest known α-helix in water. The origin of the stabilization is unclear. The observed dependence of α-helicity on the solvent and cyclization linker led us to discover a novel long-range n to π* interaction between a main-chain amide oxygen and a uniquely positioned carbonyl group in the linker of cyclic pentapeptides. CD and NMR spectra, NMR and X-ray structures, modelling, and MD simulations reveal that this first example of a synthetically incorporated long-range n to π* CO⋅⋅⋅Cγ =Ο interaction uniquely enforces an almost perfect and remarkably stable peptide α-helix in water but not in DMSO. This unusual interaction with a covalent amide bond outside the helical backbone suggests new approaches to synthetically stabilize peptide structures in water.

The Effects of Phonation Into Glass, Plastic, and LaxVox Tubes in Singers: A Systematic Review.

The present study aimed to perform a systematic literature review to assess the effects of phonation therapy on voice quality and function in singers. The systematic search was performed in February and updated in October 2017. No restriction of year, language, or publication status was applied. The primary electronic databases searched were LILACS, SciELO, PubMed, and Cochrane. Kappa coefficient was used to assess the agreement between examiners in judging article eligibility. The eligible articles were analyzed based on their risk of bias using the tools proposed by the Joanna Briggs Institute. Mendeley Desktop 1.13.3 software package (Mendeley Ltd, London, UK) was used to standardize the references of identified articles. The general sample consisted of 1965 articles screened out of the electronic databases. Two examiners analyzed the sample in the search for eligible articles. The agreement between examiners reached excellent outcomes (kappa coefficient = 0.88). After the selection, phase 6 articles remained eligible. Together, the eligible studies accounted 141 subjects (65 men and 76 women) aged between 18 and 72 years old. Electroglottography was considered as the most common method (83.33%) of assessment of the effects of phonation therapy in singers. The most prevalent exercises within the therapies were phonation into straws and phonation into glass tubes. The phonation into glass tubes immersed in water, straws, and LaxVox tubes promoted positive effects on the voice quality in singers, such as more comfortable phonation, better voice projection, and economy in voice emission.

Evaluation of Chemical Strategies for Improving the Stability and Oral Toxicity of Insecticidal Peptides.

Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency of the potent insecticidal spider-venom peptide ω-HXTX-Hv1a (Hv1a). Selective chemical replacement of disulfide bridges with diselenide bonds and N- to C-terminal cyclization were anticipated to improve Hv1a resistance to proteolytic digestion, and thereby its activity when delivered orally. We found that native Hv1a is orally active in blowflies, but 91-fold less potent than when administered by injection. Introduction of a single diselenide bond had no effect on the susceptibility to scrambling or the oral activity of Hv1a. N- to C-terminal cyclization of the peptide backbone did not significantly improve the potency of Hv1a when injected into blowflies and it led to a significant decrease in oral activity. We show that this is likely due to a dramatically reduced rate of translocation of cyclic Hv1a across the insect midgut, highlighting the importance of testing bioavailability in addition to toxin stability.

Bicyclic Helical Peptides as Dual Inhibitors Selective for Bcl2A1 and Mcl-1 Proteins.

A 26-residue peptide BimBH3 binds indiscriminately to multiple oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific inhibition of the BimBH3-Bcl2A1 protein-protein interaction was obtained in vitro and in cancer cells by shortening the peptide to 14 residues, inserting two cyclization constraints to stabilize a water-stable α-helix, and incorporating an N-terminal acrylamide electrophile for selective covalent bonding to Bcl2A1. Mass spectrometry of trypsin-digested bands on electrophoresis gels established covalent bonding of an electrophilic helix to just one of the three cysteines in Bcl2A1, the one (Cys55) at the BimBH3-Bcl2A1 protein-protein interaction interface. Optimizing the helix-inducing constraints and the sequence subsequently enabled electrophile removal without loss of inhibitor potency. The bicyclic helical peptides were potent, cell permeable, plasma-stable, dual inhibitors of Bcl2A1 and Mcl-1 with high selectivity over other Bcl2 proteins. One bicyclic peptide was shown to inhibit the interaction between a pro-apoptotic protein (Bim) and either endogenous Bcl2A1 or Mcl-1, to induce apoptosis of SKMel28 human melanoma cells, and to sensitize them for enhanced cell death by the anticancer drug etoposide. These approaches look promising for chemically silencing intracellular proteins.