Fine Tuning between Radical versus Nonradical States of Azoheteroarenes on Selective Osmium Platforms.

The article highlights the cooperative impact of azoheteroarenes [abbt: 2,2'-azobis(benzothiazole), L1-L3; bmpd: (E)-1,2-bis(1-methyl-1H-pyrazole-3-yl) diazene, L4] and coligands [bpy: 2,2'-bipyridine; pap: 2-phenylazopyridine] in tuning radical (N-N•-) versus nonradical (N═N0) states of L on selective OsII-platforms in structurally/spectroscopically characterized monomeric [1]ClO4-[6]ClO4 and [1](ClO4)2-[2](ClO4)2/[7](ClO4)2-[8](ClO4)2, respectively. The preferred syn-configuration of L in the complexes prevented obtaining ligand bridged dimeric species. It revealed that {Os(bpy)2} facilitated the stabilization of both nonradical ([1](ClO4)2-[2](ClO4)2) and radical ([1]ClO4-[2]ClO4) states of L1/L2, while it delivered exclusively the radical form for L3 in [3]ClO4. In contrast, {Os(pap)2} generated radical states of L1-L3 in [4]ClO4-[6]ClO4, respectively, without any alteration of the redox state of OsII and azo (N═N0) function of the pap coligand. The neutral state of L4 was, however, ascertained in [7](ClO4)2 or [8](ClO4)2 irrespective of the nature of the metal fragment {Os(bpy)2} or {Os(pap)2}, respectively. Switching between radical and nonradical forms of L in the complexes as a function L and coligand could be addressed based on their relative FMO (frontier molecular orbital) energies. Multiple close redox steps of the complexes extended a competitive electron transfer scenario between the redox active components including metal/L/bpy/pap, leading to delicate electronic forms in each case.

Clinical features, severity and outcome of acute pancreatitis in systemic lupus erythematosus.

Acute pancreatitis (AP) is a rare but life threatening manifestation of Systemic Lupus Erythematosus (SLE). The current study aims to study the clinical characteristics, severity, mortality, and outcome of SLE-related AP in Indian population. We retrospectively reviewed medical records of patients with SLE who had AP in the past. Data from 13 rheumatology centers across India were compiled. All patients satisfied SLICC criteria for SLE and ATLANTA criteria for AP. AP was classified in to mild, moderate and severe using revised Atlanta classification. Patients with known risk factors like gall stone and alcohol were excluded.Sixty-six patients (six, children) were studied. Majority of patients were females (82%). The median age of presentation was 24 (11-63) years and most patients (57.5%) presented within first year of diagnosis of lupus. AP occurred mostly in the setting of active lupus (89%). Active nephritis was seen in 39% while a fourth had CNS disease. Patients with severe AP had lower C3. Ascites and sepsis were most common local and systemic complications, respectively. Mortality was 17%. Hypocalcemia, presence of sepsis and shock predicted mortality. In the multivariate analysis, only presence of shock remained as independent predictor of death (OR 63.0, 95% CI: 5.2-760.3). Pancreatitis is an early manifestation of SLE and is associated with active disease. Significant mortality is seen particularly with severe pancreatitis.

Wheat inositol pyrophosphate kinase TaVIH2-3B modulates cell-wall composition and drought tolerance in Arabidopsis.

BACKGROUND: Inositol pyrophosphates (PP-InsPs) are high-energy derivatives of inositol, involved in different signalling and regulatory responses of eukaryotic cells. Distinct PP-InsPs species are characterized by the presence of phosphate at a variable number of the 6-carbon inositol ring backbone, and two distinct classes of inositol phosphate kinases responsible for their synthesis have been identified in Arabidopsis, namely ITPKinase (inositol 1,3,4 trisphosphate 5/6 kinase) and PP-IP5Kinase (diphosphoinositol pentakisphosphate kinases). Plant PP-IP5Ks are capable of synthesizing InsP8 and were previously shown to control defense against pathogens and phosphate response signals. However, other potential roles of plant PP-IP5Ks, especially towards abiotic stress, remain poorly understood. RESULTS: Here, we characterized the physiological functions of two Triticum aestivum L. (hexaploid wheat) PPIP5K homologs, TaVIH1 and TaVIH2. We demonstrate that wheat VIH proteins can utilize InsP7 as the substrate to produce InsP8, a process that requires the functional VIH-kinase domains. At the transcriptional level, both TaVIH1 and TaVIH2 are expressed in different wheat tissues, including developing grains, but show selective response to abiotic stresses during drought-mimic experiments. Ectopic overexpression of TaVIH2-3B in Arabidopsis confers tolerance to drought stress and rescues the sensitivity of Atvih2 mutants. RNAseq analysis of TaVIH2-3B-expressing transgenic lines of Arabidopsis shows genome-wide reprogramming with remarkable effects on genes involved in cell-wall biosynthesis, which is supported by the observation of enhanced accumulation of polysaccharides (arabinogalactan, cellulose, and arabinoxylan) in the transgenic plants. CONCLUSIONS: Overall, this work identifies a novel function of VIH proteins, implicating them in modulation of the expression of cell-wall homeostasis genes, and tolerance to water-deficit stress. This work suggests that plant VIH enzymes may be linked to drought tolerance and opens up the possibility of future research into using plant VIH-derived products to generate drought-resistant plants.

Enteral nutrition in circulatory shock: friend or foe?

PURPOSE OF REVIEW: Circulatory shock is associated with reduced splanchnic blood flow and impaired gut epithelial barrier function (EBF). Early enteral nutrition (EN) has been shown in animal models to preserve EBF. There are limited human data informing early EN in circulatory shock and critical care nutrition guidelines provide disparate recommendations regarding the optimal timing and dose. The purpose of this review is to describe the harms and benefits of early EN in circulatory shock by identifying and appraising recent human data. RECENT FINDINGS: The cumulative risk of nonocclusive bowel ischemia and necrosis in patients with circulatory shock is no higher than 0.3% across observational and randomized controlled trial-level data, and whether the risk is increased by EN delivery remains uncertain. Observational data suggest that early EN in circulatory shock is associated with improved clinical outcomes but data from robust randomized controlled trials remain equivocal, so the optimal timing and dose remain unknown. SUMMARY: Based on the best available data, initiating restrictive dose EN into the stomach after initial resuscitation in patients with circulatory shock does not appear to be harmful. In fact, early EN may preserve EBF and improve clinical outcomes.

COVID-19 vaccine hesitancy in patients with systemic autoimmune rheumatic disease: an interview-based survey.

Patients with a systemic autoimmune rheumatic disease (AIRD) are vulnerable to SARS Cov-2 infection. Vaccination against this infection can prevent the patients from developing severe disease. But vaccine hesitancy in this group can emerge as a hurdle. So there is a need to understand the perception regarding vaccination in AIRD patients. The study is an interview-based survey done in AIRD patients and a control group from the general population. The questionnaire included the subject's demographic details, duration, diagnosis, the activity of AIRD, and questions regarding the perception of the vaccination. The survey included 280 patients with AIRD and 102 control subjects. 54% (152/280) of the patients and 67% (68/102) of the controls were willing to get vaccinated (p = 0.03). Patients > 45-years of age were more willing to vaccinate than those with age ≤ 45-years (61.9% vs. 44.8%; p = 0.001). Patients with lower education had more vaccine hesitancy than those with graduation and above (38% vs. 69%; p < 0.001). The common reason for vaccine hesitancy was not-yet-decided, fear related to vaccine side-effects, and disease worsening. 29% (82/280) patients were already vaccinated, out of which 35% (35/82) had mild events (fever/myalgia/headache). AIRD patients had fewer side effects than controls, and disease flare was seen in only one patient. Thus, educating AIRD patients regarding the pros and cons of vaccination, particularly concerning immunological disease, can help us overcome vaccine hesitancy. The message should clearly penetrate that there is a negligible risk of AIRD-flares with the COVID-19 immunization and the side effects are mild and manageable.

Hereditary C1 inhibitor deficiency associated with systemic lupus erythematosus.

Here, we report a family with two children (the elder son and younger daughter) diagnosed with juvenile-onset systemic lupus erythematosus (SLE) and the father diagnosed with hereditary angioedema. Serum C1 inhibitor (C1-INH) levels were low, and clinical exome next-generation sequencing detected a frameshift mutation in the SERPING-1 gene in all three patients. The mother had neither of the clinical phenotypes. The son had cutaneous symptoms, fever and polyarthralgia, along with lupus nephritis, and thus required rituximab therapy as well as mycophenolate mofetil and low-dose steroids to control disease activity. The daughter had a milder disease, with cutaneous manifestation, fever and polyarthralgia, and which was controlled with mycophenolate mofetil, hydroxychloroquine and low-dose steroids. Both children had never experienced angioedema. The father had a long history of self-limiting, non-life-threatening irregular episodes of subcutaneous angioedema and abdomen pain. He was not on any regular medication for these symptoms. We searched the literature for evidence of hereditary C1-INH deficiency associated with monogenic SLE or SLE-like-phenotype.

Integrative analysis of hexaploid wheat roots identifies signature components during iron starvation.

Iron (Fe) is an essential micronutrient for all organisms. In crop plants, Fe deficiency can decrease crop yield significantly; however, our current understanding of how major crops respond to Fe deficiency remains limited. Herein, the effect of Fe deprivation at both the transcriptomic and metabolic level in hexaploid wheat was investigated. Genome-wide gene expression reprogramming was observed in wheat roots subjected to Fe starvation, with a total of 5854 genes differentially expressed. Homoeologue and subgenome-specific analysis unveiled the induction-biased contribution from the A and B genomes. In general, the predominance of genes coding for nicotianamine synthase, yellow stripe-like transporters, metal transporters, ABC transporters, and zinc-induced facilitator-like protein was noted. Expression of genes related to the Strategy II mode of Fe uptake was also predominant. Our transcriptomic data were in agreement with the GC-MS analysis that showed the enhanced accumulation of various metabolites such as fumarate, malonate, succinate, and xylofuranose, which could be contributing to Fe mobilization. Interestingly, Fe starvation leads to a significant temporal increase of glutathione S-transferase at both the transcriptional level and enzymatic activity level, which indicates the involvement of glutathione in response to Fe stress in wheat roots. Taken together, our result provides new insight into the wheat response to Fe starvation at the molecular level and lays the foundation to design new strategies for the improvement of Fe nutrition in crops.

Clinical and echocardiographic predictors of new-onset atrial fibrillation in patients admitted with blunt trauma.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia after trauma or burn injury; however, its predisposing factors are not well known. Moreover, little is known about its effect on mortality and other short-term clinical outcomes. OBJECTIVES: This study is aimed at identifying risk factors for new-onset AF in patients admitted with blunt trauma or burn injuries at a Level 1 academic trauma center, and to determine its effects on the short-term clinical outcomes. METHODS: This case-control study compared patients with new-onset AF with a cohort of patients without AF during the hospital stay after trauma or burn injury. Patients with prior AF or lack of transthoracic echocardiogram were excluded. Demographic, clinical factors including injury severity score and echocardiographic parameters were compared in both cohorts. Risks of short-term clinical outcomes, namely persistent AF, new stroke, myocardial infarction, or death, were compared. RESULTS: Older age, sepsis, CHADS2-VASC score >1, larger left atrium (LA) size, left ventricular hypertrophy (LVH), and left ventricular diastolic dysfunction imposed a significant risk for new-onset AF on univariate analysis. On multivariate, independent predictors of new-onset AF were LA dilation and LVH. LA enlargement increased odds of new-onset AF by 23-fold (OR 23; CI: 5.7-92, P < 0.0001) and the presence of LVH increased the odds of new-onset AF more than 20-fold (OR 20.8; CI: 5-87, P < 0.0001). CONCLUSIONS: Dilated LA and LVH are independent predictors of new-onset AF in the patients with blunt trauma or burn. New-onset AF did not confer increased risk for in-hospital mortality.

Action-outcome delays modulate the temporal expansion of intended outcomes.

The phenomenon of intentional binding pertains to the perceived connection between a voluntary action and its anticipated result. When an individual intends an outcome, it appears to subjectively extend in time due to a pre-activation of the intended result, particularly evident at shorter action-outcome delays. However, there is a concern that the operationalisation of intention might have led to a mixed interpretation of the outcome expansion attributed to the pre-activation of intention, given the sensitivity of time perception and intentional binding to external cues that could accelerate the realisation of expectations. To investigate the expansion dynamics of an intended outcome, we employed a modified version of the temporal bisection task in two experiments. Experiment 1 considered the action-outcome delay as a within-subject factor, while experiment 2 treated it as a between-subject factor. The results revealed that the temporal expansion of an intended outcome was only evident under the longer action-outcome delay condition. We attribute this observation to working memory demands and attentional allocation due to temporal relevancy and not due to pre-activation. The discrepancy in effects across studies is explained by operationalising different components of the intentional binding effect, guided by the cue integration theory. Moreover, we discussed speculative ideas regarding the involvement of specific intentions based on the proximal intent distal intent (PIDI) theory and whether causality plays a role in temporal binding. Our study contributes to the understanding of how intention influences time perception and sheds light on how various methodological factors, cues, and delays can impact the dynamics of temporal expansion associated with an intended outcome.

A matter of time: how musical training affects time perception.

Musical training has been linked to changes in early attentional and perceptual processing. Thus, such an altered attentional and perceptual processing has enabled musicians to judge the duration differently than non-musicians. Although these claims seem intriguing, there are many questions that are not addressed yet, for example, how would the performance of musically-trained differ from that of untrained on visual and auditory temporal judgments? Is there any advantage to musically-trained person in temporal processing? To understand these questions, we thus conducted a series of Auditory and Visual Temporal Bisection Tasks on 32 musically-trained and 32 musically-untrained participants. We hypothesized that if music training modulates general sensitivity to temporal dimensions, then the temporal judgments of musically-trained participants would differ from those of untrained participants in both visual and auditory tasks. Each participant performed a total of 140 trials (70 visual and 70 auditory) in two different blocks. For each participant, a Point of Subjective Equality (PSE) was obtained for visual and auditory conditions. The findings revealed a significant modality effect on time perception, with auditory stimuli being consistently overestimated compared to visual stimuli. Surprisingly, the musically-trained group exhibited a tendency to underestimate duration relative to the musically-untrained participants. Although these results may appear counterintuitive at first glance, a detailed analysis indicates that the length of musical training plays a significant role in modulating temporal processing within the musically-trained group.

Clinical metabolomics investigation of rheumatoid arthritis patients receiving ayurvedic whole system intervention.

BACKGROUND: Arthritis is a common clinical condition seen in Ayurveda clinics. Clinical trials have reported Ayurvedic interventions to be of benefits in many arthritic conditions including Rheumatoid Arthritis (RA). No mechanistic details however are available about how such interventions on their own or as a combination of whole system Ayurveda might be working. OBJECTIVE: The study aims to evaluate simultaneously the clinical outcome of Ayurveda whole system (AWS) intervention in RA patients and identifying the serum metabolic signatures which could be useful for diagnosing the disease and monitoring treatment response. MATERIAL AND METHODS: RA patients (n = 37) simultaneously diagnosed as Amavata fulfilling the specific inclusion and exclusion criteria were recruited in the study and were given Ayurveda whole system (AWS) intervention comprised of oral medicines, local therapy and dietary recommendation for 3 months. The clinical and serum metabolic changes were investigated for pre-treatment RA patients (baseline RA group, n = 37) and post-treatment RA patients (following treatment of 6-weeks (RA_F, n = 26) and three months (RA_T, n = 36). For comparative serum metabolomics analysis, 57 normal healthy control (HC) subjects were also involved and the serum metabolic profiles were measured at high-field 800 MHz NMR spectrometer. The serum metabolic profiles were compared using multivariate statistical analysis and discriminatory metabolic features were evaluated for diagnostic potential using receiver operating characteristic (ROC) curve analysis. RESULTS: A significant reduction in DAS-28 ESR, AAM Score, total swollen joints, total tender joints were observed following AWS intervention. The clinical outcomes were concordant with changes in metabolic profiles of RA patients as these were also shifting towards the normal levels following the intervention. Compared to healthy control (HC) subjects, the sera of baseline RA patients were characterised by increased circulatory level of succinate, lysine, mannose, creatine, and 3-Hydroxybutyrate (3-HB) and decreased levels of alanine. The present study also evaluated the serum metabolic ratios for their discriminatory and diagnostic potential and notably, six metabolic ratios (KHR, KThR, KVR, GHR, PTR and SHR) were found significantly altered (elevated) in baseline RA patients. However, in RA patients receiving AWS treatment, these metabolic changes showed marked convergence towards the metabolic signatures of healthy controls. CONCLUSION: This first of its kind study clearly shows the clinical efficacy of Ayurvedic Whole System (AWS) intervention in the management of Rheumatoid Arthritis (RA), as demonstrated by significant improvements in key clinical parameters. The intervention not only alleviated symptoms but also induced a profound metabolic shifting towards normalization; thus, underscoring the potential of AWS intervention to modulate cellular metabolism in a manner that facilitates a return to homeostasis in RA patients. However, future studies are imperative to confirm these preliminary observations and delineate the underlying mechanisms of action of intervention in cases of RA.

Evaluation of the Effectiveness of Telemedicine in Postoperative Follow-Up Care After Dental Implant Surgery. A Pilot Study.

Aim: Telemedicine has emerged as a potential solution to enhance postoperative follow-up care after dental implant surgery, offering the convenience of remote monitoring and reduced need for in-person visits. Materials and Methods: Participants were randomly assigned to either the telemedicine group (n = 15) or the in-person group (n = 15). In the telemedicine group, patients received remote follow-up care through virtual consultations, during which they could communicate their concerns and share images of the surgical site. The in-person group received standard in-person follow-up visits. Patient satisfaction was measured using a standardized survey, with responses collected on a Likert scale. Results: Telemedicine group exhibited comparable levels of patient satisfaction (mean satisfaction score ± standard deviation: 4.6 ± 0.3) to the in-person group (4.7 ± 0.2). Moreover, clinical outcomes, including wound healing assessment, were similar between the two groups. No significant differences were observed in the incidence of postoperative complications or the need for additional interventions. Conclusion: In conclusion, this pilot study demonstrates that telemedicine is an effective alternative to traditional in-person follow-up care for postoperative dental implant surgery patients. It offers comparable patient satisfaction and clinical outcomes while proving to be more cost-effective.

Assessment of Patient Satisfaction and Treatment Outcomes in Digital Smile Design vs. Conventional Smile Design: A Randomized Controlled Trial.

Background: The esthetics of a smile holds significant importance in an individual's self-esteem and overall quality of life. In the realm of cosmetic dentistry, smile design has traditionally relied on conventional methods, but recent advances in technology have introduced digital smile design (DSD) as a promising alternative. Materials and Methods: In this randomized controlled trial, 150 adult patients seeking smile enhancement procedures were enrolled and randomly assigned to one of two groups: the DSD group or the conventional smile design group. The DSD group underwent smile design using digital technology, including intraoral scans, computer-aided design, and 3D simulations. Meanwhile, the conventional smile design group received smile design through traditional methods, involving manual impressions, stone models, and manual wax-ups. Patient satisfaction was measured using a visual analog scale (VAS) ranging from 0 to 100 immediately after the procedure, while treatment outcomes were assessed three months post-procedure by dental professionals using a standardized assessment scale. Results: In terms of patient satisfaction, the DSD group demonstrated a mean score of 85.4 (SD ± 6.2), while the conventional smile design group had a mean score of 79.8 (SD ± 7.1). This suggests that patients in the DSD group reported higher levels of satisfaction with their smile enhancements. Regarding treatment outcomes, 92% of patients in the DSD group exhibited excellent restoration fit, occlusion, and esthetics, whereas 78% of patients in the conventional smile design group achieved the same level of excellence. These findings collectively indicate that digital smile design (DSD) may yield superior patient satisfaction and improved treatment outcomes when compared to conventional smile design methods, particularly with regard to esthetic results and overall patient contentment. Conclusion: In conclusion, the results of this randomized controlled trial emphasize the potential advantages of integrating digital technology into smile design procedures.

Investigating the Long-Term Success and Complication Rates of Zirconia Dental Implants: A Prospective Clinical Study.

This study addresses the durability and complications of zirconia dental implants through a prospective clinical investigation. Zirconia implants are increasingly utilized in dental implantation, and a comprehensive understanding of their long-term performance is essential. Background: Zirconia dental implants have gained attention due to their biocompatibility and aesthetics. However, research on their extended success and complication rates is limited. Materials and Methods: A prospective clinical study involved the placement of 30 zirconia dental implants in patients requiring tooth replacement. The implants were followed up for five years. Success was defined as the implant remaining stable and functional. Complications, including peri-implant mucositis and peri-implantitis, were monitored. Statistical analysis included descriptive statistics, Chi-square test, and P-values were set at P < 0.05. Results: The long-term success rate of zirconia dental implants was found to be 93.3%. Among the 30 implants, only 2 exhibited failure. The most common complication was peri-implant mucositis, occurring in 16.7% of implants. Notably, the incidence of peri-implantitis was limited, observed in 6.7% of implants. Statistical analysis showed significant associations between implant failure and smoking (P = 0.021). Conclusion: Zirconia dental implants demonstrated a high long-term success rate of 93.3% over five years. Peri-implant mucositis was the predominant complication, with a relatively low occurrence of peri-implantitis. The findings underscore the potential of zirconia implants for reliable dental implantation. Addressing modifiable risk factors, such as smoking, could further enhance implant success. Continued research is recommended to validate and expand upon these outcomes.

Influence of Zirconia/Glass Veneer Thickness and Implant Abutment Material on the Final Shade of Implant Restorations.

Background: Achieving an optimal shade match for these restorations is crucial for aesthetic outcomes. The thickness of zirconia/glass veneer and the choice of implant abutment material play vital roles in determining the final shade of implant restorations. Materials and Methods: This study investigated the influence of zirconia/glass veneer thickness (0.5 mm and 1.0 mm) and implant abutment material (zirconia and titanium) on the final shade of implant restorations. A total of 60 identical implant restorations were fabricated and divided into four groups based on the combinations of veneer thickness and abutment material. The shade of each restoration was assessed using a shade guide, and color differences (ΔE) were measured with a spectrophotometer. Data were analyzed using statistical tests (e.g., ANOVA). Results: The results indicated that the veneer thickness significantly influenced the final shade of implant restorations. Restorations with 0.5 mm veneer thickness exhibited a lower ΔE value (indicating a closer shade match) compared to those with 1.0 mm veneer thickness. Additionally, the choice of implant abutment material had a minor but statistically significant effect on shade. Zirconia abutments yielded slightly better shade-matching results compared to titanium abutments. Conclusion: In implant restorations, the thickness of the zirconia/glass veneer plays a critical role in achieving a desirable shade match. A veneer thickness of 0.5 mm is recommended for optimal aesthetic outcomes.

Analysis of modified palatal surface for better speech in edentulous patients: A clinico-analytical study.

BACKGROUND: Phonetics with mechanics and aesthetics are considered cardinal factors contributing to the success of complete dentures. OBJECTIVE: The aim of the current study was to evaluate the changes in speech in complete denture patients with and without palatal surface changes. METHODS: The data collected for the study involved completely edentulous Patients (n= 80). Patients were divided into two groups. Group A: Up to 50 years (n= 40); Group B: Above 50 years (n= 40) (including male and female). Each group was further divided into four subgroups for speech analysis-without dentures (A1/B1); with conventional dentures (A2/B2); dentures with a palatogram (A3/B3) and dentures with palate sandblasted (A4/B4). The speech sounds of all patients were evaluated for pitch and intensity using a spectrophotogram (Praat software) and Likert scale. The data so obtained from the quantitative and qualitative analysis were statistically analysed through one-way ANOVA, unpaired student's t-test, and Pearson correlation coefficient. Qualitative analysis was done with the Mann-Whitney U test. RESULTS: The maximum mean value of the pitch and intensity in Groups A and B was subgroup A3 (Palatogram) 190.37 ± 21.50 and 77.07 ± 7.58, B3 (Palatogram) 190.87 ± 24.36 and 75.33 ± 8.12. When comparing Groups A [A1, A2, A3, A4] and B [B1, B2, B3, B4] on the basis of pitch and intensity, a statistically insignificant value was found. No changes in speech sounds (pitch and intensity) were observed in terms of age. Both quantitative and qualitative analysis results showed that speech sounds in the patients with palatogram, had the highest pitch and intensity and were most clear to the listener and there were statistically significant differences from other groups. CONCLUSION: Speech was better in palatogram-based dentures in comparison to a sandblasted denture, conventional denture and without denture in terms of qualitative and quantitative analysis. The physiologic nature of the palatogram fabrication technique produces the palatal part of the denture more compatible with the tongue, thus producing better speech.

Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8.

Phosphate (Pi) serves countless metabolic pathways and is involved in macromolecule synthesis, energy storage, cellular signaling, and bone maintenance. Herein, we describe the coordination of Pi uptake and efflux pathways to maintain mammalian cell Pi homeostasis. We discover that XPR1, the presumed Pi efflux transporter, separately supervises rates of Pi uptake. This direct, regulatory interplay arises from XPR1 being a binding partner for the Pi uptake transporter PiT1, involving a predicted transmembrane helix/extramembrane loop in XPR1, and its hitherto unknown localization in a subset of intracellular LAMP1-positive puncta (named "XLPVs"). A pharmacological mimic of Pi homeostatic challenge is sensed by the inositol pyrophosphate IP8, which functionalizes XPR1 to respond in a temporally hierarchal manner, initially adjusting the rate of Pi efflux, followed subsequently by independent modulation of PiT1 turnover to reset the rate of Pi uptake. These observations generate a unifying model of mammalian cellular Pi homeostasis, expanding opportunities for therapeutic intervention.

Observational longitudinal study to assess the outcome of patients with idiopathic inflammatory myositis using validated tools.

INTRODUCTION: There have been major changes in the classification and treatment of patients with idiopathic inflammatory myositis (IIM) in the last 2 decades. A major challenge is to identify the parameters that can affect the outcome and prognosis of these patients. Here, we have longitudinally followed a well-characterized cohort of IIM patients in a rheumatology center and reported the outcome using the validated tools. METHOD: Patients with a clinical diagnosis of IIM and a follow-up duration of greater than 2 years were prospectively included in the study. The duration of the study was 6 years: July 2016-July 2022. Clinical details and follow-up were recorded using pro-formas and outcomes were noted using validated tools. Ethics approval and written informed consent were taken. RESULTS: Forty patients had a clinical diagnosis of IIM. Mean follow-up duration was 43.8 (15) months. Out of 40 patients, 32 (80%) achieved remission (8 patients each were off corticosteroid and off treatment for >6 months), 5 (12%) expired and 3 (8%) had active disease. Disease course was non-relapsing in 22/35 (73%) patients. Mean manual muscle testing-8 score (n = 29) and myositis disease activity assessment tool score (n = 35) at the final visit were 75.6 (6.8) and 0.048 (0.07) respectively. Thirteen patients had damage (37%). Patients with disease duration >1 year at the time of presentation were more likely to develop chronic-continuous disease course (P = .023, odds ratio [OR] = 7.6), more frequently required second-line or third-line immunosuppression (P = .001, OR = 24) with higher myositis damage index score (p = .0002, OR = 47). CONCLUSIONS: IIM patients had good outcomes with the majority achieving remission and near-complete muscle recovery. However, the patients presenting late to the rheumatologists were more likely to have smoldering disease, more immunosuppressive medicines, and greater accumulated damage.