Palladium-Catalyzed Electrooxidative Double C-H Arylation.

The electrochemical transition metal-catalyzed cross-dehydrogenative reaction has emerged as a promising platform to achieve a sustainable and atom-economic organic synthesis that avoids hazardous oxidants and minimizes undesired byproducts and circuitous functional group operations. However, a poor mechanistic understanding still prevents the widespread adoption of this strategy. In this regard, we herein present an electrochemical palladium-catalyzed oxidative coupling strategy to access biaryls in the absence of a stoichiometric chemical oxidant. The robust palladaelectrocatalysis considerably suppresses the occurrence of homocoupling and oxygenation, being compatible even with electron-deficient arenes. Late-stage functionalization and Boscalid precursor synthesis further highlighted the practical importance of our electrolysis. Remarkably, mechanistic studies including the evaluation of the reaction order of each component by variable time normalization analysis (VTNA) and initial rate analysis, H/D exchange experiment, kinetic isotope effect, and stoichiometric organometallic experiments provided strong support for the involvement of transmetalation between two organopalladium complexes in the turnover limiting step. Therefore, matching the concentrations or lifetimes of two distinct organopalladium intermediates is revealed to be a pivot to the success of electrooxidative catalysis. Moreover, the presence of cationic copper(II) seems to contribute to the stabilization of the palladium(0) catalyst instead of playing a role in the oxidation of the catalyst.

Enantioselective Cobaltaphotoredox-Catalyzed C-H Activation.

The quest for sustainable strategies in molecular synthesis has spurred the emergence of photocatalysis as a particularly powerful technique. In recent years, the application of photocatalysis in this context has greatly promoted the development of asymmetric catalysis. Despite the impressive advances, enantioselective photoinduced strong arene C-H activations by cobalt catalysis remain unexplored. Herein, we report a strategy that merges organic photoredox catalysis and enantioselective cobalt-catalyzed C-H activation, enabling the regio- and stereoselective dual functionalization of indoles in an enantioselective fashion. Thereby, the assembly of various chiral indolo[2,3-c]isoquinolin-5-ones was realized with high enantioselectivities of up to 99%. The robustness of the cobaltaphotoredox catalysis was demonstrated through enantioselective C-H activation and annulations in a continuous flow to provide straightforward access to central and axially chiral molecules.

Homozygosity for a Rare FASTKD2 Variant Resulting in an Adult Onset Autosomal Recessive Mitochondrial Podocytopathy.

Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with sub-nephrotic proteinuria, who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 mutations. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy, which are, instead, pathogenically related to adenosine triphosphate deficiency.

Sleep deprivation increases the regularity of isometric torque fluctuations.

The regularity of the fluctuations present in torque signals represent the adaptability of the motor control. While previous research showed how it is affected by neuromuscular fatigue and ageing, the underlying mechanisms remain unclear. It is currently under debate whether these changes are explained by central or peripheral neuromuscular mechanisms. Here, we experimentally manipulated the sleep of thirteen young adults through a supervised 24 h-sleep deprivation protocol. This study aimed to investigate the effect of sleep deprivation on the regularity of torque fluctuations, and other standard torque-related outcomes (Peak Torque - PT - and Rate of Torque Development - RTD). The participants were asked to perform knee extension maximal voluntary contractions (MVC) and submaximal knee extensions at 40% of MVC for 30 s. PT and RTD were calculated from the MVC and the regularity of the torque fluctuations was determined on the submaximal task through Sample Entropy (SampEn). In addition, rate of perceived effort (RPE) was collected. We found no significant changes in PT and RTD. The regularity of torque fluctuations significantly increased (i.e., a decrease in SampEn) after 24 h-sleep deprivation (PRE = 1.76 ± 0.268, POS24 = 1.71 ± 0.306; p = 0.044). Importantly, we found a negative correlation between RPE and SampEn relative changes after sleep deprivation. This study brings new insights towards the understanding of the underlying mechanisms that explain changes in torque fluctuations, demonstrating that these changes are not limited to neuromuscular processes but are also likely to be affected by other domains, such as psychological profile, which can indirectly affect the neural drive to the muscles.

Assessment of inter- and intraobserver agreement for META score in distinguishing osteoporotic from multiple myeloma vertebral fractures.

PURPOSE: To conduct an independent assessment of inter- and intraobserver agreement for the META score as a tool for differentiating osteoporotic vertebral fractures and multiple myeloma vertebral fractures. METHODS: This is a retrospective observational study. The magnetic resonance imaging analysis was made by two independent spinal surgeons. We designated a Subjective assessment, in which the surgeon should establish a diagnostic classification for each vertebral fracture based on personal experience: secondary to osteoporosis, categorized as a benign vertebral fracture (BVF), or attributed to multiple myeloma, categorized a malign vertebral fracture (MVF). After a 90-day interval, both surgeons repeated the evaluations. For the next step, the observers should establish a diagnosis between BVF and MVF according to the META score system, and both observers repeated the evaluations after a 90-day interval. The intra and interobserver reliability of the Subjective evaluation was studied using the kappa (κ) test. Then, the META evaluations were paralleled using the intraclass correlation coefficient (ICC). RESULTS: A total of 220 patients who had the potential to participate in the study were initially enrolled, but after applying the exclusion criteria, 44 patients were included. Thirty-three patients had BVF, and 12 patients presented MVF. Interobserver agreement for both Subjective evaluations moments (initial and 90-days interval) found a slight agreement for both moments (0.35 and 0.40 respectively). Kappa test for both META evaluations moments (initial and 90-days interval) found a moderate interobserver agreement for both moments (0.54 and 0.48 respectively). It was observed that the ICC calculated for the Initial evaluation using META score was 0.680 and that in the 90-days interval was 0.726, indicating regular to good agreement. Kappa test for intraobserver agreements for the Subjective evaluation presented moderate agreement for both Surgeons. On the other side, Kappa test for intraobserver agreements for the META evaluation presented substantial agreement for both Surgeons. The Intraclass Correlation Coefficient of the META score found presented an almost perfect agreement for both Surgeons. CONCLUSION: Intra and interobserver agreement for both surgeons were unsatisfactory. The lack of consistent reproducibility by the same observer discourages and disfavors the routine use of the META score in clinical decision making, when potentially cases of multiple myeloma may be present.

Ethical regulation of biomedical research in Brazil: a quality improvement initiative.

BACKGROUND: Q-CEP (Qualificação dos Comitês de Ética em Pesquisa que compõem o Sistema CEP/Conep) is a nationwide project resulting from a partnership between the Brazilian National Research Ethics Commission (Conep), the Ministry of Health and Hospital Moinhos de Vento (HMV). It was developed to consolidate policy for ethical review of research with human beings in all members of the CEP/Conep System, Brazil's national system of institutional review boards. The aim of this study was therefore to report on the experience and results of the Q-CEP project. METHODS: An observational, retrospective study includes data from the Q-CEP, obtained from visits to all the institutional research ethics committees (RECs) in the country. The actions implemented by Q-CEP were part of a two-step process: (i) training visits to each REC; (ii) development of distance learning modules on strategic topics pertaining to research ethics evaluation. The data presented herein cover step one (training visits), defined by Q-CEP as the diagnostic stage of the project. For a country with social and economics inequalities such as Brazil, this is a particularly important stage; an accurate picture of reality is needed to inform planning of quality improvement strategies. RESULTS: In 2019-2021, Q-CEP visited 832 RECs and trained 11,197 people. This sample covered almost all active RECs in the country; only 4 (0.5%) were not evaluated. Of the 94 items evaluated, 62% did not reach the target of at least 80% compliance and around 1/4 (26%) were below 50% compliance. The diagnostic stage of the process revealed inadequacies on the part of the RECs in their ethical reviews. The analysis of informed consent forms showed compliance in only 131 RECs (15.74%). The description of pending issues made by RECs in their reports was compliant in 19.33% (n = 161). Administrative and operational aspects were also considered inadequate by more than half of the RECs. CONCLUSIONS: Overall, Brazilian RECs showed poor compliance in several aspects of their operation, both in ethics evaluation and in other processes, which justifies additional training. The Q-CEP project is part of a quality improvement policy promoted by the Brazilian Ministry of Health. The data obtained in the diagnostic step of the project have contributed to the qualification and consolidation of one of the world's largest research ethics evaluation systems.

Short term creatine loading improves strength endurance even without changing maximal strength, RPE, fatigue index, blood lactate, and mode state.

Creatine is consumed by athletes to increase strength and gain muscle. The aim of this study was to evaluate the effects of creatine supplementation on maximal strength and strength endurance. Twelve strength-trained men (25.2 ± 3.4 years) supplemented with 20 g Creatina + 10g maltodextrin or placebo (20g starch + 10g maltodextrin) for five days in randomized order. Maximal strength and strength endurance (4 sets 70% 1RM until concentric failure) were determined in the bench press. In addition, blood lactate, rate of perceived effort, fatigue index, and mood state were evaluated. All measurements were performed before and after the supplementation period. There were no significant changing in maximal strength, blood lactate, RPE, fatigue index, and mood state in either treatment. However, the creatine group performed more repetitions after the supplementation (Cr: Δ = +3.4 reps, p = 0.036, g = 0.53; PLA: Δ = +0.3reps, p = 0.414, g = 0.06), and higher total work (Cr: Δ = +199.5au, p = 0.038, g = 0.52; PLA: Δ = +26.7au, p = 0.402, g = 0.07). Creatine loading for five days allowed the subjects to perform more repetitions, resulting in greater total work, but failed to change the maximum strength.

The modified Nice knot has improved mechanical performance compared to the cinch stitch for meniscal root repair.

PURPOSE: According to previous biomechanical studies, the success of meniscus root repair depends on the suture-meniscus interface and optimisation of this procedure seems to be critical. A progressive, reliable and adjustable knot has numerous advantages in meniscal repair since the surgeon can adapt and meticulously tune the final strength of the fixation. We hypothesised that a single passage of one tape at two different points of the posterior meniscal root with a modified Nice knot configuration may allow similar or superior fixation for root repair compared to the cinch stitch suture technique. METHODS: Posterior root repair of medial and lateral meniscus was performed on 26 porcine knees. In group (A), two simple cinch stitches were applied, and in group (B), a modified Nice knot was used in a crossmatch configuration. For both groups, two passages through the meniscus with a 2-mm braided tape were used, and a single transosseous tibial tunnel technique was performed and tested in pull-out conditions. RESULTS: The modified Nice knot showed an improved biomechanical performance considering the maximum failure load for both the medial (600.7 ± 77.5 N) and lateral (686.1 ± 83.5 N) (p = 0.006) posterior root fixation when compared to a double cinch stitch (558.0 ± 123.9 N) and (629.0 ± 110.2 N) (p = 0.178) for medial and lateral fixation, respectively. The maximum stiffness was also higher for the modified Nice knot configuration for both medial (17.1 ± 1.5 vs. 13.3 ± 1.6 N/mm) and lateral meniscus (20.0 ± 2.6 vs. 13.8 ± 2.3 N/mm), being this difference statistically significative (p = 0.001). CONCLUSIONS: The modified Nice knot allowed better adaptation in the pull-out tests and presented higher fixation strength, stiffness and reproducibility, with lower standard deviation, being at the same time economically advantageous, since only one tape is needed. LEVEL OF EVIDENCE: Level III.

Effects of interprofessional practice on nursing workload in hospitals: A systematic review.

OBJECTIVE: To synthesise scientific evidence on interprofessional practice in hospital care and the effects on nursing workload. METHODS: Systematic mixed method review, registered in PROSPERO (CRD42021225627) and conducted in the following databases: CINAHL, Medline, Web of Science and Scopus, with no restrictions on the publication period of the studies. Primary studies were recruited on nurses' interprofessional practice (actions and interactions with other professional categories) in hospitals and the effects on one or more dimensions of nursing workload (quantitative, qualitative, physical, cognitive, emotional, time and variation). Scientific articles available in open access, in English, Spanish or Portuguese, were included. The searches were carried out in January 2021. The studies were evaluated by pairs of independent researchers to verify methodological quality, through the Mixed Method Appraisal Tool, and data extraction. To summarise the studies, thematic analysis was adopted. RESULTS: A total of 1774 publications were assessed for eligibility and 17 studies were included. Of these, two were mixed methods, four were qualitative, and 11 were quantitative, published between 2011 and 2020. The main scenarios investigated were Intensive Care Units and/or Inpatient Units. During data analysis, three thematic categories emerged: Interprofessional practice in coping with emotional overload; Time dedicated by nurses to professional communication; and Working conditions and patient care. The third category consisted of three subthemes: Conflict and flexibility in the context of practice; Working conditions and interprofessional practice; and Effects on patient care. CONCLUSIONS: The evidence points to the emotional overload of nurses in the face of uncooperative practices. Interprofessional actions, especially communicative ones, demand nurses' time and impact the care provided. The results contribute to political decisions and health work management.

The meaning in loss protocol: A clinical trial of online grief therapy.

For a minority of the bereaved, the loss of a significant other can trigger an overwhelming emotional reaction and impaired functioning across life domains, known as prolonged grief disorder (PGD). Hence, ongoing efforts have been made to refine existing treatments to increase their efficacy and to accommodate the idiosyncrasies of grief reactions. This study presents the results of an open clinical trial of the feasibility and effectiveness of the Meaning in Loss (MIL) protocol in an online format. The brief intervention of 12 to 16 sessions combines constructivist and narrative strategies to explore and work through impediments to meaning reconstruction in loss. The sample included 25 participants diagnosed with PGD who were treated by six therapists. Baseline and post-therapy comparisons showed a significant improvement in all clinical measures (grief symptomatology, depression and general distress) and an increase of meaning making regarding the loss. Meaning making was found to be a prospective mediator of symptomatic improvement in grief across the course of therapy. These findings suggest the effectiveness of the MIL protocol in decreasing grief specific and associated symptomatology and argue for the relevance of further controlled evaluations of its efficacy. Moreover, results confirm previous findings that meaning making is a relevant factor in the evolution of grief reactions, including in the context of psychotherapy.

Chagas Disease: A Silent Threat for Dogs and Humans.

Chagas disease (CD) is a vector-borne Neglected Zoonotic Disease (NZD) caused by a flagellate protozoan, Trypanosoma cruzi, that affects various mammalian species across America, including humans and domestic animals. However, due to an increase in population movements and new routes of transmission, T. cruzi infection is presently considered a worldwide health concern, no longer restricted to endemic countries. Dogs play a major role in the domestic cycle by acting very efficiently as reservoirs and allowing the perpetuation of parasite transmission in endemic areas. Despite the significant progress made in recent years, still there is no vaccine against human and animal disease, there are few drugs available for the treatment of human CD, and there is no standard protocol for the treatment of canine CD. In this review, we highlight human and canine Chagas Disease in its different dimensions and interconnections. Dogs, which are considered to be the most important peridomestic reservoir and sentinel for the transmission of T. cruzi infection in a community, develop CD that is clinically similar to human CD. Therefore, an integrative approach, based on the One Health concept, bringing together the advances in genomics, immunology, and epidemiology can lead to the effective development of vaccines, new treatments, and innovative control strategies to tackle CD.

Spirulina (Arthrospira platensis) supplementation: Impact on growth, metabolism, and antioxidant status in zebrafish.

Zebrafish (Danio rerio) is a valuable model for biomedical research because of its mammalian genetic similarities, rapid reproduction, and low maintenance costs. However, further investigation is required regarding their nutritional requirements and standardized laboratory diets. This study evaluated the metabolic and growth responses of zebrafish juveniles fed on diets supplemented with spirulina, Arthrospira platensis (SP) at different levels for 77 days. Six diets with SP inclusion levels of 0%, 2%, 4%, 6%, 8%, and 10% (SP0-SP10) were formulated. A total of 300 zebrafish juveniles with an average initial weight of 0.113 ± 0.10 g (mean ± SD) were randomly distributed across six groups, with five replicates per group, each containing 10 animals. After 77 days, the SP6 group demonstrated significantly enhanced growth performance compared with the other supplementation levels. The condition factor was markedly higher in the SP6 and SP8 groups than in the SP0 group. No significant effects on total cholesterol levels were observed, but the SP4, SP6, and SP10 diets decreased triglyceride levels. Lipase activity was higher in the SP6 and SP8 groups than in the control group, whereas amylase activity showed no significant differences between treatments. Catalase and superoxide dismutase activities were significantly higher in the SP8 and SP10 groups than in the SP0 and SP2 groups. Glutathione S-transferase activity was higher in the SP6, SP8, and SP10 groups than in the SP0 group. In addition, SP inclusion in zebrafish diets improved female gonadal development. In conclusion, this study indicates that SP supplementation has substantial potential as a growth promoter, positively influencing lipid metabolism and antioxidant enzyme activity without affecting zebrafish survival.

Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction.

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required for skeletal indole editing. In contrast, we herein show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) and proved robust on scale, while tolerating a variety of valuable functional groups.

Doxycycline protects against sepsis-induced endothelial glycocalyx shedding.

Endothelial glycocalyx (eGC) covers the inner surface of the vessels and plays a role in vascular homeostasis. Syndecan is considered the "backbone" of this structure. Several studies have shown eGC shedding in sepsis and its involvement in organ dysfunction. Matrix metalloproteinases (MMP) contribute to eGC shedding through their ability for syndecan-1 cleavage. This study aimed to investigate if doxycycline, a potent MMP inhibitor, could protect against eGC shedding in lipopolysaccharide (LPS)-induced sepsis and if it could interrupt the vascular hyperpermeability, neutrophil transmigration, and microvascular impairment. Rats that received pretreatment with doxycycline before LPS displayed ultrastructural preservation of the eGC observed using transmission electronic microscopy of the lung and heart. In addition, these animals exhibited lower serum syndecan-1 levels, a biomarker of eGC injury, and lower perfused boundary region (PBR) in the mesenteric video capillaroscopy, which is inversely related to the eGC thickness compared with rats that only received LPS. Furthermore, this study revealed that doxycycline decreased sepsis-related vascular hyperpermeability in the lung and heart, reduced neutrophil transmigration in the peritoneal lavage and inside the lungs, and improved some microvascular parameters. These findings suggest that doxycycline protects against LPS-induced eGC shedding, and it could reduce vascular hyperpermeability, neutrophils transmigration, and microvascular impairment.

Exploring the Biological Overlapping Between Brain Calcifications and Tumorgenesis.

This article discusses a rare case of coexistent meningiomas and Primary familial brain calcification (PFBC). PFBC is a neurodegenerative disease characterized by brain calcifications and a variety of neuropsychiatric symptoms and signs, with pathogenic variants in specific genes. The study explores the potential link between PFBC and meningiomas, highlighting shared features like intralesional calcifications and common genes such as MEA6. The article also revisits PFBC patients developing other brain tumors, particularly gliomas, emphasizing the intersection of oncogenes like PDGFB and PDGFRB in both calcifications and tumor progression. In recent investigations, attention has extended beyond brain tumors to breast cancer metastasis, unveiling a noteworthy connection. These findings suggest a broader connection between brain calcifications and tumors, encouraging a reevaluation of therapeutic approaches for PFBC.

The Importance of Early Diagnosis and Treatment in Septic Arthritis of the Temporomandibular Joint: A Case Report.

Septic arthritis of the temporomandibular joint (SATMJ), primarily caused by bacterial infections, is a rare condition with a diverse etiology that is inadequately documented in the literature, resulting in the absence of standardized treatment protocols. Its nonspecific clinical presentation often leads to misdiagnosis as other temporomandibular disorders, delaying diagnosis and treatment and potentially causing severe complications in the absence of established therapeutic guidelines. The main objective of this article is to report a case of a 61-year-old female with diabetes who was undergoing prolonged corticosteroid therapy and presented with pain, swelling in the right pre-auricular area, and progressive limitation in mouth opening, with no history of facial trauma, where the early diagnosis and isolation of Staphylococcus aureus after a single-port arthrocentesis prompted the timely adjustment of the treatment regimen, significantly influencing the outcome by mitigating the risk of complications. Additionally, this report includes a comprehensive literature review, highlighting the crucial importance of this prompt intervention to achieve a favorable clinical outcome.

Electrochemical Enantioselective C-H Annulation by Achiral Rhodium(III)/Chiral Brønsted Base Domino Catalysis.

Rhodium(III)-catalyzed enantioselective C-H activation has emerged as a powerful tool for assembling enabling chiral molecules. However, this approach is significantly hampered by the cumbersome synthetic routes for preparing chiral rhodium catalysts. In sharp contrast, we herein report on an electrochemical domino catalysis system that exploits an achiral Cp*-rhodium catalyst along with an easily accessible chiral Brønsted base for an enantioselective C-H activation/annulation reaction of alkenes by benzoic acids. Our strategy offers an environmentally benign and most user-friendly approach for assembling synthetically useful chiral phthalides in good enantioselectivity, employing electricity as the sustainable oxidant.

A Standard-Cell-Based Neuro-Inspired Integrate-and-Fire Analog-to-Time Converter for Biological and Low-Frequency Signals - Comparison With Analog Version.

Continuous-time asynchronous data converters namely, analog-to-digital converters and analog-to-time converters, can be beneficial for certain types of applications, such as, processing of biological signals with sparse information. A particular case of these converters is the integrate-and-fire converter (IFC) that is inspired by the neural system. If it is possible to develop a standard-cell-based (SCB) IFC circuit to perform well in advanced technology nodes, it will benefit from the simplicity of SCB circuit designs and can be implemented in widely available field-programmable gate arrays (FPGAs). This way, this paper proposes two IFC circuits designed and prototyped in a 130 nm CMOS standard process. The first is a novel SCB open-loop dynamic IFC. The latter, is a closed-loop analog IFC with conventional blocks. This paper presents a through comparison between the two IFC circuits. They have a power dissipation of 59 µW and 53 µW, and an energy per pulse of 18 pJ and 1060 pJ, SCB and analog IFC, respectively. The SCB IFC has one of the lowest energy per pulse consumption reported for IFC circuits. The analog IFC, being fully differential, is to our knowledge the first of its kind. Moreover, they do not require an external clock. They can convert signals with a peak-to-peak amplitude from 1.6 mV to 28 mV and 0.6 mV to 2.4 mV, and a frequency range of 2 Hz to 42 kHz and 10 Hz to 4 kHz, SCB and analog IFC, respectively. Presenting low normalized RMS conversion plus reconstruction errors, below 5.2%. The maximum pulse density (average firing-rate) is 3300 kHz, for the SCB and 50 kHz, for the analog IFC.

Cerebral Tuberculosis After Therapy With Adalimumab for Hidradenitis Suppurativa: A Rare Case.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited therapeutic options. Adalimumab, an anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibody, was the first biological agent approved for the treatment of moderate to severe HS. Tuberculosis (TB) is a highly prevalent global public health problem, affecting individuals worldwide. Continuous immunosuppression from TNF-α treatment increases the risk of TB development. Isolated neurotuberculosis, in the absence of other symptoms, emerges as a rarely observed infection pattern in such patients. We present a case of a 23-year-old woman with severe HS undergoing treatment with adalimumab. After two years, she developed a pronounced occipital tension headache, constant nausea, and persistent fever. The patient's latent TB status was unknown without annual screening. Subsequent magnetic resonance imaging revealed a lesion in the cerebellar vermis. Immunosuppressive therapy was suspended and an etiological study was conducted; the only positive result was the interferon-gamma release assay. Empirically, antituberculosis treatment and prednisolone were initiated, leading to clinical and neurological improvement. After one year of treatment, symptoms resolved without neurological sequelae. This case highlights the importance of vigilant monitoring before, during, and after immunosuppressive treatment. Early recognition, discontinuation of anti-tumor necrosis factor medications, and appropriate management of TB are crucial to prevent complications.

Clinical guidelines for posterior restorations based on Coverage, Adhesion, Resistance, Esthetics, and Subgingival management. The CARES concept: Part III ­ subgingival margins, "ferrule" design, and posts in severely compromised teeth

Despite the clear advances regarding the restoration of posterior teeth, especially with the minimally invasive approach, there are still several topics where the available scientific evidence does not provide clear answers in terms of clinical decisions. The indications, differences, and clinical protocols for partial adhesive restorations (onlays, overlays, and endocrowns) and resistance form restorations (full-contour resistive crowns) were presented in Parts I and II of the present article series based on Coverage of susceptible cusps, Adhesion advantages and limitations, Resistance forms to be implemented, Esthetic concerns, and Subgingival management - the CARES concept. Now, in Part III, the focus is on different approaches of managing subgingival areas, gaining "ferrule" design, and the role of posts on the restorability strategies of severely compromised teeth.