Electrophysiological correlates of dentate nucleus deep brain stimulation for post-stroke motor recovery.

While ipsilesional cortical electroencephalography has been associated with post-stroke recovery mechanisms and outcomes, the role of cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that post-stroke motor control relies on increased cortico-cerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting post-stroke motor rehabilitation. We investigated the excitability of ipsilesional cortex, dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, ten human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed 1) significantly improved motor control indexed by computerized motor tasks; 2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and 3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the post-stroke state and its connectivity with ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of cortico-cerebellar-cortical network after stroke and its modulation by DN-DBS.Significance Statement The study aims to understand the brain mechanisms underlying the effects of cerebellar dentate deep brain stimulation (DN-DBS), a novel upcoming therapy for chronic stroke. We provide evidence that functional improvements as a result of DN-DBS therapy were accompanied by significant improvements in task behavior and ipsilesional cortex excitability. More importantly.

Inter-individual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.

OBJECTIVE: We aimed to discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SUBJECTS: A discovery cohort of adult female childhood cancer survivors, from the pan-European PanCareLIFE cohort (n=743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA-based St. Jude Lifetime Cohort (n=391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure. INTERVENTION: No intervention was performed. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0x10-8) and 16 genome-wide suggestive (<5.0x10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0×10-6), and biological relevance, 15 SNPs were selected for replication. None of the SNPs were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated at borderline genome-wide statistical significance (Reference/effect allele: C/T; EAF: 0.04, Beta (SE): -0.484 (0.091), p-value= 9.39×10-8). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity and as well as fertility preservation options for childhood cancer survivors.

Core-shell nanofibers based on microalgae proteins/alginate complexes for enhancing survivability of probiotics.

In this study, a novel one-step coaxial electrospinning process is employed to fabricate shell-core structure fibers choosing Chlorella pyrenoidosa proteins (CP) as the core material. These nanofibers, serving as the wall material for probiotic encapsulation, aimed to enhance the stability and antioxidant activity of probiotics in food processing, storage, and gastrointestinal environments under sensitive conditions. Morphological analysis was used to explore the beads-on-a-string morphology and core-shell structure of the electrospun fibers. Probiotics were successfully encapsulated within the fibers (7.97 log CFU/g), exhibiting a well-oriented structure along the distributed fibers. Compared to free probiotics and uniaxial fibers loaded with probiotics, encapsulation within microalgae proteins/alginate core-shell structure nanofibers significantly enhanced the probiotic cells' tolerance to simulated gastrointestinal conditions (p < 0.05). Thermal analysis indicated that microalgae proteins/alginate core-shell structure nanofibers displayed superior thermal stability compared to uniaxial fibers. The introduction of CP resulted in a 50 % increase in the antioxidant capacity of probiotics-loaded microalgae proteins/alginate nanofibers compared to uniaxial alginate nanofibers, with minimal loss of viability (0.8 log CFU/g) after 28 days of storage at 4 °C. In summary, this dual-layer carrier holds immense potential in probiotic encapsulation and enhancing their resistance to harsh conditions.

Effects of Palm Oil Deodorizer Distillate on the Ruminal Environment of Sheep.

This study aimed to assess the impact of palm oil deodorizer distillate (POD) on the ruminal environment, including (i) microbial community, (ii) ruminal degradability, and (iii) apparent digestibility in sheep. The data used were derived from twenty rumen-cannulated sheep fed five isoproteic and isofiber diets based on elephant grass (Pennisetum purpureum Schum. cv. Roxo) silage supplemented with 0, 25, 50, 75, or 100 g kg-1 POD on a dry matter (DM) basis. Rumen fluid samples were collected three hours after feeding directly from the ventral sac of the rumen via a cannula and then subjected to DNA extraction, which was subsequently used for 16S rDNA amplification, followed by sequencing and diversity analysis. In this study, the microbial diversity was dominated by Bacteroidetes and Firmicutes, followed by Euryarchaetoa, Actinobacteria, and Tenericutes, in the ruminal environment, and was slightly modified when supplemented with the POD up to 100 g/kg (10%), leading to only a slight decrease in the diversity index. The ruminal degradability, ruminal fermentation parameters, and apparent digestibility were slightly compromised by the inclusion of up to 25 g of POD per kg of DM, and larger inclusions interfered with the ruminal degradability of fibrous fractions and the apparent digestibility of dry matter. This lipid supplement showed good results for feeding sheep and is an inexpensive and abundant alternative in the regional market.

From Nucleation to Fat Crystal Network: Effects of Stearic-Palmitic Sucrose Ester on Static Crystallization of Palm Oil.

Palm oil (PO), a semi-solid fat at room temperature, is a popular food ingredient. To steer the fat functionality, sucrose esters (SEs) are often used as food additives. Many SEs exist, varying in their hydrophilic-to-lipophilic balance (HLB), making them suitable for various food and non-food applications. In this study, a stearic-palmitic sucrose ester with a moderate HLB (6) was studied. It was found that the SE exhibited a complex thermal behavior consistent with smectic liquid crystals (type A). Small-angle X-ray scattering revealed that the mono- and poly-esters of the SE have different packings, more specifically, double and single chain-length packing. The polymorphism encountered upon crystallization was repeatable during successive heating and cooling cycles. After studying the pure SE, it was added to palm oil, and the crystallization behavior of the mixture was compared to that of pure palm oil. The crystallization conditions were varied by applying cooling at 20 °C/min (fast) and 1 °C/min (slow) to 0 °C, 20 °C or 25 °C. The samples were followed for one hour of isothermal time. Differential scanning calorimetry (DSC) showed that nucleation and polymorphic transitions were accelerated. Wide-angle X-ray scattering (WAXS) unraveled that the α-to-ß' polymorphic transition remained present upon the addition of the SE. SAXS showed that the addition of the SE at 0.5 wt% did not significantly change the double chain-length packing of palm oil, but it decreased the domain size when cooling in a fast manner. Ultra-small-angle X-ray scattering (USAXS) revealed that the addition of the SE created smaller crystal nanoplatelets (CNPs). The microstructure of the fat crystal network was visualized by means of polarized light microscopy (PLM) and cryo-scanning electron microscopy (cryo-SEM). The addition of the SE created a finer and space-filling network without the visibility of separate floc structures.

Coding, Decoding and Retrieving a Message Using DNA: An Experience from a Brazilian Center Research on DNA Data Storage.

DNA data storage based on synthetic oligonucleotides is a major attraction due to the possibility of storage over long periods. Nowadays, the quantity of data generated has been growing exponentially, and the storage capacity needs to keep pace with the growth caused by new technologies and globalization. Since DNA can hold a large amount of information with a high density and remains stable for hundreds of years, this technology offers a solution for current long-term data centers by reducing energy consumption and physical storage space. Currently, research institutes, technology companies, and universities are making significant efforts to meet the growing need for data storage. DNA data storage is a promising field, especially with the advancement of sequencing techniques and equipment, which now make it possible to read genomes (i.e., to retrieve the information) and process this data easily. To overcome the challenges associated with developing new technologies for DNA data storage, a message encoding and decoding exercise was conducted at a Brazilian research center. The exercise performed consisted of synthesizing oligonucleotides by the phosphoramidite route. An encoded message, using a coding scheme that adheres to DNA sequence constraints, was synthesized. After synthesis, the oligonucleotide was sequenced and decoded, and the information was fully recovered.

Exploring the antileishmanial activity of dicentrine from Ocotea puberula (Lauraceae) using biomembrane models.

This study aimed to assess the antiprotozoal efficacy of dicentrine, an aporphine alkaloid isolated from Ocotea puberula, against amastigote forms of Leishmania (L.) infantum. Our findings reveal that dicentrine demonstrated a notable EC50 value of 10.3 µM, comparable to the positive control miltefosine (EC50 of 10.4 µM), while maintaining moderate toxicity to macrophages (CC50 of 51.9 µM). Utilizing an in silico methodology, dicentrine exhibited commendable adherence to various parameters, encompassing lipophilicity, water solubility, molecule size, polarity, and flexibility. Subsequently, we conducted additional investigations to unravel the mechanism of action, employing Langmuir monolayers as models for protozoan cell membranes. Tensiometry analyses unveiled that dicentrine disrupts the thermodynamic and mechanical properties of the monolayer by expanding it to higher areas and increasing the fluidity of the film. The molecular disorder was further corroborated through dilatational rheology and infrared spectroscopy. These results contribute insights into the role of dicentrine as a potential antiprotozoal drug in its interactions with cellular membranes. Beyond elucidating the mechanism of action at the plasma membrane's external surface, our study sheds light on drug-lipid interface interactions, offering implications for drug delivery and other pharmaceutical applications.

Intestinal-specific oral delivery of lactoferrin with alginate-based composite and hybrid CaCO3-hydrogel beads.

Sodium alginate hydrogel beads and sodium alginate/gellan gum composite hydrogel beads crosslinked by calcium chloride were prepared with different alginate concentrations (3-20 mg·mL-1). Additionally, a simple method for growing CaCO3in situ on the hydrogel to create novel inorganic-organic hybrid hydrogel beads was presented. FT-IR analysis revealed the involvement of hydrogen bonding and electrostatic interactions in bead formation. Swelling behavior in acidic conditions showed a maximum of 13 g/g for composite hydrogels and CaCO3-incorporated hybrid hydrogels. Lactoferrin encapsulation efficiency within these hydrogels ranged from 44.9 to 56.6%. In vitro release experiments demonstrated that these hydrogel beads withstand harsh gastric environments with <16% cumulative release of lactoferrin, achieving controlled release in intestinal surroundings. While composite sodium alginate/gellan gum beads exhibited slower gastrointestinal lactoferrin digestion, facile synthesis and pH responsiveness of CaCO3-incorporated hybrid hydrogel also provide new possibilities for future studies to construct a novel inorganic-organic synergetic system for intestinal-specific oral delivery.

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer.

Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental. Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis. Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm. Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%. Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental.

Hypoxia-inducible factor-driven glycolytic adaptations in host-microbe interactions.

Mammalian cells utilize glucose as a primary carbon source to produce energy for most cellular functions. However, the bioenergetic homeostasis of cells can be perturbed by environmental alterations, such as changes in oxygen levels which can be associated with bacterial infection. Reduction in oxygen availability leads to a state of hypoxia, inducing numerous cellular responses that aim to combat this stress. Importantly, hypoxia strongly augments cellular glycolysis in most cell types to compensate for the loss of aerobic respiration. Understanding how this host cell metabolic adaptation to hypoxia impacts the course of bacterial infection will identify new anti-microbial targets. This review will highlight developments in our understanding of glycolytic substrate channeling and spatiotemporal enzymatic organization in response to hypoxia, shedding light on the integral role of the hypoxia-inducible factor (HIF) during host-pathogen interactions. Furthermore, the ability of intracellular and extracellular bacteria (pathogens and commensals alike) to modulate host cellular glucose metabolism will be discussed.

Synthesis and Evaluation of (Bis)benzyltetrahydroisoquinoline Alkaloids as Antiparasitic Agents.

Visceral leishmaniasis and Chagas disease are neglected tropical diseases (NTDs) that severely impact the developing world. With current therapies suffering from poor efficacy and safety profiles as well as emerging resistance, new drug leads are direly needed. In this work, 26 alkaloids (9 natural and 17 synthetic) belonging to the benzyltetrahydroisoquinoline (BI) family were evaluated against both the pro/trypomastigote and amastigote forms of the parasites Leishmania infantum and Trypanosoma cruzi, the causative agents of these diseases. These alkaloids were synthesized via an efficient and modular enantioselective approach based on Bischler-Napieralski cyclization/Noyori asymmetric transfer hydrogenation to build the tetrahydroisoquinoline core. The bis-benzyltetrahydroisoquinoline (BBI) alkaloids were prepared using an Ullmann coupling of two BI units to form the biaryl ether linkage, which enabled a comprehensive survey of the influence of BI stereochemistry on bioactivity. Preliminary studies into the mechanism of action against Leishmania mexicana demonstrate that these compounds interfere with the cell cycle, potentially through inhibition of kinetoplast division, which may offer opportunities to identify a new target/mechanism of action. Three of the synthesized alkaloids showed promising druglike potential, meeting the Drugs for Neglected Disease initiative (DNDi) criteria for a hit against Chagas disease.

Advances in Nanoarchitectonics: A Review of "Static" and "Dynamic" Particle Assembly Methods.

Particle assembly is a promising technique to create functional materials and devices from nanoscale building blocks. However, the control of particle arrangement and orientation is challenging and requires careful design of the assembly methods and conditions. In this study, the static and dynamic methods of particle assembly are reviewed, focusing on their applications in biomaterial sciences. Static methods rely on the equilibrium interactions between particles and substrates, such as electrostatic, magnetic, or capillary forces. Dynamic methods can be associated with the application of external stimuli, such as electric fields, magnetic fields, light, or sound, to manipulate the particles in a non-equilibrium state. This study discusses the advantages and limitations of such methods as well as nanoarchitectonic principles that guide the formation of desired structures and functions. It also highlights some examples of biomaterials and devices that have been fabricated by particle assembly, such as biosensors, drug delivery systems, tissue engineering scaffolds, and artificial organs. It concludes by outlining the future challenges and opportunities of particle assembly for biomaterial sciences. This review stands as a crucial guide for scholars and professionals in the field, fostering further investigation and innovation. It also highlights the necessity for continuous research to refine these methodologies and devise more efficient techniques for nanomaterial synthesis. The potential ramifications on healthcare and technology are substantial, with implications for drug delivery systems, diagnostic tools, disease treatments, energy storage, environmental science, and electronics.

Highly selective alkylcoumarates and diterpenoids isolated from leaves of Baccharis quitensis: a search for new hit compounds against Trypanosoma cruzi.

In the present work, the hexane extract of aerial parts of Baccharis quitensis Kunth. was subjected to chromatographic fractionation to afford two alkyl phenylpropanoids: n-docosyl (E)-p-coumarate (1) and n-tetracosyl (E)-p-coumarate (2) as well as five diterpenes: ent-kaurenoic acid (3), grandifloric acid (4), 15ß-senecioyl-oxy-ent-kaur-16-en-19-oic acid (5), and 15-oxo-ent-kaurenoic acid (6). Using an ex-vivo assay with macrophages infected with Trypanosoma cruzi, compounds 1 and 2 demonstrated high potency against intracellular amastigotes, with EC50 values of 7.5 and 6.9 µM, respectively. Compound 6 revealed a moderate potency against T. cruzi, with an EC50 of 25.6 µM, and compounds 3-5 showed no effectiveness. Additionally, compounds 1-6 compounds presented no toxicity for mammalian cells to the highest tested concentration of 200 µM. Based on potency and the selectivity indexes of 1, 2 and 6, these compounds could be future candidates for optimisation studies for the design of prototypes against Chagas disease.

Bone health index in the assessment of bone health: The Generation R Study.

Bone Health Index (BHI) has been proposed as a useful instrument for assessing bone health in children. However, its relationship with fracture risk remains unknown. We aimed to investigate whether BHI is associated with bone mineral density (BMD) and prevalent fracture odds in children from the Generation R Study. We also implemented genome-wide association study (GWAS) and polygenic score (PGS) approaches to improve our understanding of BHI and its potential. In total, 4150 children (49.4 % boys; aged 9.8 years) with genotyped data and bone assessments were included in this study. BMD was measured across the total body (less head following ISCD guidelines) using a GE-Lunar iDXA densitometer; and BHI was determined from the hand DXA scans using BoneXpert®. Fractures were self-reported collected with home questionnaires. The association of BHI with BMD and fractures was evaluated using linear models corrected for age, sex, ethnicity, height, and weight. We observed a positive correlation between BHI and BMD (ρ = 0.32, p-value<0.0001). Further, every SD decrease in BHI was associated with an 11 % increased risk of prevalent fractures (OR:1.11, 95 % CI 1.00-1.24, p-value = 0.05). Our BHI GWAS identified variants (lead SNP rs1404264-A, p-value = 2.61 × 10-14) mapping to the ING3/CPED1/WNT16 locus. Children in the extreme tails of the BMD PGS presented a difference in BHI values of -0.10 standard deviations (95% CI -0.14 to -0.07; p-value<0.0001). On top of the demonstrated epidemiological association of BHI with both BMD and fracture risk, our results reveal a partially shared biological background between BHI and BMD. These findings highlight the potential value of using BHI to screen children at risk of fracture.

Nanomedicine to aid immunogenic cell death (ICD)-based anticancer therapy.

Immunogenic cell death (ICD) is emerging as a key component of antitumor therapy that harnesses the immune system of the patient to combat cancer. In recent years, several efforts were made to improve the ICD-based therapies. Here, we discuss how nanomaterial-based strategies increase the efficacy of ICD and highlight their benefits and challenges.

The role of dorsolateral striatum in the effects of deep cerebellar stimulation-mediated motor recovery following ischemic stroke in rodents.

Despite great advances in acute care and rehabilitation, stroke remains the leading cause of motor impairment in the industrialized world. We have developed a deep brain stimulation (DBS)-based approach for post-stroke rehabilitation that has shown reproducible effects in rodent models and has been recently translated to humans. Mechanisms underlying the rehabilitative effects of this novel therapy have been largely focused on the ipsilesional cortex, including cortical reorganization, synaptogenesis, neurogenesis and greater expression of markers of long-term potentiation. The role of subcortical structures on its therapeutic benefits, particularly the striatum, remain unclear. In this study, we compared the motor rehabilitative effects of deep cerebellar stimulation in two rodent models of cerebral ischemia: a) cortical ischemia; and b) combined striatal and cortical ischemia. All animals underwent the same procedures, including implantation of the electrodes and tethered connections for stimulation. Both experimental groups received four weeks of continuous lateral cerebellar nucleus (LCN) DBS and each was paired with a no stimulation, sham, group. Fine motor function was indexed using the pasta matrix task. Brain tissue was harvested for histology and immunohistochemical analyses. In the cortical-only ischemia, the average pasta matrix performance of both sham and stimulated groups reduced from 19 to 24 pieces to 7-8 pieces following the stroke induction. At the end of the four-week treatment, the performance of stimulated group was significantly greater than that of sham group (14 pieces vs 7 pieces, p < 0.0001). Similarly, in the combined cortical and striatal ischemia, the performance of both sham and stimulated groups reduced from 29 to 30 pieces to 7-11 pieces following the stroke induction. However, at the end of the four-week treatment, the performance of stimulated group was not significantly greater than that of sham group (15 pieces vs 11 pieces, p = 0.452). In the post-mortem analysis, the number of cells expressing CaMKIIα at the perilesional cortical and striatum of the LCN DBS treated animals receiving cortical-only stroke elevated but not those receiving cortical+striatal stroke. The current findings suggested that the observed, LCN DBS-enhanced motor recovery and perilesional plasticity may involve striatal mechanisms.

Lignans Isolated from Piper truncatum Act as New Potent Antitrypanosomal Compounds.

The hexane extract from twigs of Piper truncatum Vell (Piperaceae) displayed activity against Trypanosoma cruzi and was subjected to chromatographic steps to afford six dibenzylbutyrolactolic lignans, being four knowns: cubebin (1), (-)-9α-O-methylcubebin (2), (+)-9ß-O-methylcubebinin (3) and 3,4-dimethoxy-3,4-demethylenedioxycubebin (4) as well as two new, named truncatin A (5) and B (6). Initially, in vitro activity against trypomastigotes was evaluated and compounds 1, 4 and 6 exhibited EC50 values of 41.6, 21.0 and 39.6 µM, respectively. However, when tested against amastigotes, the relevant clinical form in the chronic phase of Chagas disease, compounds 1-6 displayed activities with EC50 values ranging from 1.6 to 13.7 µM. In addition, the mammalian cytotoxicity of compounds 1-6 was evaluated against murine fibroblasts (NCTC). Compounds 2, 3 and 4 exhibited reduced toxicity against NCTC cells (CC50>200 µM), resulting in SI values of>21.9,>14.5 and>121.9, respectively. Compound 4 showed the highest potency with an SI value twice superior to that determined by the standard drug benznidazole (SI>54.6) against the intracellular amastigotes. These data suggest that lignan 4 can be considered a possible scaffold for designing a new drug candidate for Chagas disease.

Limosilactobacillus reuteri as an Adjuvant in the Treatment of Peri-implant Mucositis in Total Rehabilitation: An Exploratory Study.

OBJECTIVES: Mechanical debridement is the traditional method for the treatment of peri-implant mucositis (P-im) and its success depends on the patient's correct oral hygiene. It is believed that probiotics may help by their ability to modulate the oral biofilm, resulting in anti-inflammatory and antibacterial plaque action. The aim of this study was to evaluate the adjuvant effect of the probiotic Limosilactobacillus reuteri (LR) in the mechanical treatment of P-im. MATERIALS AND METHODS: This exploratory study included 29 subjects with implant-supported total rehabilitation and P-im, divided into test (TG) and control (CG) groups, equally subjected to professional mechanical debridement, with the administration of a daily GUM PerioBalance lozenge for 30 days added to the TG. The modified Plaque Index (mPlI) modified Sulcus Bleeding Index (mBI) and pocket depth (PD) were evaluated before the intervention (baseline) and 6 and 10 weeks later. STATISTICAL ANALYSIS: Parametric and nonparametric tests with 5% significance level were used in the statistical analysis, using IBM SPSS Statistics 27.0 software. RESULTS: Both treatments resulted in reduced mPlI, mBI, and PD at 6 weeks; while from 6 to 10 weeks there was an increase in mPlI and mBI and maintenance of PD. Compared with baseline, differences were close to statistical significance in the reduction in PD at 10 weeks in the CG (p = 0.018), after Bonferroni correction, and statistically significant in the mPlI at 6 weeks in the CG (p = 0.004) and in the TG (p = 0.002) as well as at 10 weeks in the TG (p = 0.016). Comparing the groups in the postintervention assessments, no statistically significant differences were found. CONCLUSION: LR adjuvant mechanical treatment of P-im does not show a clear benefit compared with mechanical treatment alone, with both interventions achieving similar clinical results. Further prospective and long-term studies are needed.

Loss of Efficacy in Ventral Intermediate Nucleus Stimulation for Essential Tremor.

OBJECTIVE: The primary aim of this study is to report long-term outcomes associated with deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) performed at our institution. We further aimed to elicit the factors associated with loss of efficacy and to discuss the need for exploring and establishing reliable rescue targets. METHODS: To study long-term outcomes, we performed a retrospective chart review and extracted tremor scores of 43 patients who underwent VIM DBS lead implantation for essential tremor at our center. We further evaluated factors that could influence outcomes over time, including demographics, body mass index, duration of follow-up, degree of parenchymal atrophy indexed by the global cortical atrophy scale, and third ventricular width. RESULTS: In this cohort, tremor scores on the latest follow-up (median 52.7 months) were noted to be worse than initial postoperative scores in 56% of DBS leads. Furthermore, 14% of leads were associated with clinically significant loss of benefit. Factors including the length of time since the lead implantation, age at the time of surgery, sex, body mass index, preoperative atrophy, and third ventricular width were not predictive of long-term outcomes. CONCLUSIONS: Our study identified a substantial subgroup of VIM-DBS patient who experienced a gradual decline in treatment efficacy over time. We propose that this phenomenon can be attributed primarily to habituation and disease progression. Furthermore, we discuss the need to establish reliable and effective rescue targets for this subpopulation of patients, with ventral-oralis complex and dentate nucleus emerging as potential candidates.