MFP1 defines the subchloroplast location of starch granule initiation.

Starch is one of the major carbohydrate storage compounds in plants. The biogenesis of starch granules starts with the formation of initials, which subsequently expand into granules. Several coiled-coil domain-containing proteins have been previously implicated with the initiation process, but the mechanisms by which they act remain largely elusive. Here, we demonstrate that one of these proteins, the thylakoid-associated MAR-BINDING FILAMENT-LIKE PROTEIN 1 (MFP1), specifically determines the subchloroplast location of initial formation. The expression of MFP1 variants "mis"-targeted to specific locations within chloroplasts in Arabidopsis results in distinctive shifts in not only how many but also where starch granules are formed. Importantly, "re" localizing MFP1 to the stromal face of the chloroplast's inner envelope is sufficient to generate starch granules in this aberrant position. These findings provide compelling evidence that a single protein MFP1 possesses the capacity to direct the initiation and biosynthesis machinery of starch granules.

The PRK/Rubisco shunt strongly influences Arabidopsis seed metabolism and oil accumulation, affecting more than carbon recycling.

The carbon efficiency of storage lipid biosynthesis from imported sucrose in green Brassicaceae seeds is proposed to be enhanced by the PRK/Rubisco shunt, in which ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) acts outside the context of the Calvin-Benson-Bassham cycle to recycle CO2 molecules released during fatty acid synthesis. This pathway utilizes metabolites generated by the nonoxidative steps of the pentose phosphate pathway. Photosynthesis provides energy for reactions such as the phosphorylation of ribulose 5-phosphate by phosphoribulokinase (PRK). Here, we show that loss of PRK in Arabidopsis thaliana (Arabidopsis) blocks photoautotrophic growth and is seedling-lethal. However, seeds containing prk embryos develop normally, allowing us to use genetics to assess the importance of the PRK/Rubisco shunt. Compared with nonmutant siblings, prk embryos produce one-third less lipids-a greater reduction than expected from simply blocking the proposed PRK/Rubisco shunt. However, developing prk seeds are also chlorotic and have elevated starch contents compared with their siblings, indicative of secondary effects. Overexpressing PRK did not increase embryo lipid content, but metabolite profiling suggested that Rubisco activity becomes limiting. Overall, our findings show that the PRK/Rubisco shunt is tightly integrated into the carbon metabolism of green Arabidopsis seeds, and that its manipulation affects seed glycolysis, starch metabolism, and photosynthesis.

Selective Dissolution of Calcium Pyrophosphate Dihydrate Crystals Using a Pyrophosphate Specific Receptor.

Pseudo-gout is caused by the deposition of highly insoluble calcium pyrophosphate dihydrate (CPPD) crystals in the joints of sufferers. This leads to inflammation and ultimately joint damage. The insolubility of CPPD is driven by the strong attraction of di-cationic calcium ions with tetra-anionic pyrophosphate ions. One of the challenges of dissolving CPPD is that a related mineral, hydroxy apatite (HA) is present in larger amounts in the form of bone and also contains strongly interacting calcium and phosphate ions. Our aim in this work was to selectively dissolve CPPD in preference to HA. To accomplish this, we used a known receptor for pyrophosphate that contains two complexed zinc ions that are ideally spaced to interact with the tetra-anion of pyrophosphate. We hypothesized that such a molecule could act as a preorganized tetra-cation that would be able to outcompete the two calcium ions present in the crystal lattice of CPPD. We demonstrate both visually and through analysis of released phosphorous that this molecule is able to preferentially dissolve CPPD over the closely related HA and thus can form the basis for a possible approach for the treatment of pseudo-gout.

Role of bio-flavonols and their derivatives in improving mitochondrial dysfunctions associated with pancreatic tumorigenesis.

Mitochondria, a cellular metabolic center, efficiently fulfill cellular energy needs and regulate crucial metabolic processes, including cellular proliferation, differentiation, apoptosis, and generation of reactive oxygen species. Alteration in the mitochondrial functions leads to metabolic imbalances and altered extracellular matrix dynamics in the host, utilized by solid tumors like pancreatic cancer (PC) to get energy benefits for fast-growing cancer cells. PC is highly heterogeneous and remains unidentified for a longer time because of its complex pathophysiology, retroperitoneal position, and lack of efficient diagnostic approaches, which is the foremost reason for accounting for the seventh leading cause of cancer-related deaths worldwide. PC cells often respond poorly to current therapeutics because of dense stromal barriers in the pancreatic tumor microenvironment, which limit the drug delivery and distribution of antitumor immune cell populations. As an alternative approach, various natural compounds like flavonoids are reported to possess potent antioxidant and anticancerous properties and are less toxic than current chemotherapeutic drugs. Therefore, we aim to summarize the current state of knowledge regarding the pharmacological properties of flavonols in PC in this review from the perspective of mitigating mitochondrial dysfunctions associated with cancer cells. Our literature survey indicates that flavonols efficiently regulate cellular metabolism by scavenging reactive oxygen species, mitigating inflammation, and arresting the cell cycle to promote apoptosis in tumor cells via intrinsic mitochondrial pathways. In particular, flavonols proficiently inhibit the cancer-associated proliferation and inflammatory pathways such as EGFR/MAPK, PI3K/Akt, and nuclear factor κB in PC. Overall, this review provides in-depth evidence about the therapeutic potential of flavonols for future anticancer strategies against PC; still, more multidisciplinary human interventional studies are required to dissect their pharmacological effect accurately.

Number of serotonergic neurons in the subthalamic nucleus and globus pallidus internus could influence the effects of deep brain stimulation in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is a standard treatment for Parkinson's disease (PD), with both regions exhibiting similar treatment effectiveness. However, posttreatment neuropsychiatric side effects, such as severe depression, are common, primarily due to the loss of serotonergic cells. Identifying a region with fewer serotonergic neurons could potentially reduce these side effects. This study aimed to quantify the number of serotonergic neurons in the STN and GPi. Both regions were analyzed using hematoxylin and eosin staining and immunohistochemistry. The GPi exhibited a significantly lower number and H-score of serotonergic neurons than the STN. Within the STN, the number and H-score of serotonergic neurons were higher in the medial aspect than in the lateral aspect. Three different types of neurons, large and small, were observed. In STN, large neurons were concentrated in the center and small neurons in the periphery. This distribution was not observed in GPi. In addition, the concentration of the serotonergic neurons is less in GPi. These findings suggest that the GPi may be a safer target region, potentially reducing the incidence of post-DBS depression.

Emerging Colistin Resistance: Experience from an Intensive Care Unit of a Tertiary Care Center in India.

BACKGROUND: Resistance to the currently available classes of antimicrobials has emerged as a major health concern, with a growing number of isolated organisms demonstrating resistance to available antimicrobials. With the escalation of carbapenem resistance, the use of polymyxin B/E (colistin) has increased over the years, which has, in turn, contributed to the worldwide emergence of colistin resistance. The available data on colistin resistance from Southeast Asian nations, including India, is limited, especially in intensive care unit (ICU) settings. The primary objective of our study was to analyze the clinical profile of patients with polymyxin B/E (colistin) resistant positive cultures and to study their outcome in terms of length of ICU stay and outcome at discharge. MATERIALS AND METHODS: This observational, single-center, prospective study was conducted in a 20-bed adult ICU serving both medical and surgical patients at a 1,600-bed tertiary care institute in northern India between Jan 2020 and Dec 2021. In this study, all adult patients, defined as individuals older than 18 years of age, admitted to our ICU with cultures detecting polymyxin B/E (colistin) resistant organisms were included as cases, and all adult ICU patients (age >18 years) with polymyxin B/E (colistin) sensitive cultures were taken as controls. Clinical, laboratory, and demographic parameters, along with ICU variables like severity of illness, length of ICU stay, mechanical ventilation, days of shock, renal replacement therapy (RRT), etc., and outcome at discharge were collected. Identification of resistance to colistin and minimal inhibitory concentration (MIC) of colistin is based on Clinical and Laboratory Standards Institute (CLSI) guidelines. For statistical analysis, Mann-Whitney U test, Fisher's exact test, and binary logistic regression were used. RESULTS: Twenty-eight cases and 55 controls (n = 83) were included for analysis. Abdominal [gastrointestinal (GI)] sepsis was the most common diagnosis (41.8%) at admission to the ICU, and Klebsiella pneumoniae was the most common species isolated in both the cases (96.4%) and the controls (50.9%). The most common site of isolation of Gram-negative bacteria in both cases and controls was blood (71.4 vs 74.5%), followed by deep-seated pus (21.4 vs 23.64%). The most common class of drugs to which the cases were sensitive was tetracyclines in 60.7%, followed by ceftazidime-avibactam. Factors such as prior exposure to colistin, exposure to monobactams in the ICU, and ICU stay in days were identified as independent predictors for colistin resistance. Overall mortality was not statistically different between cases and controls (p -value 0.38). CONCLUSION: Factors like prolonged ICU stay, exposure to monobactams in the ICU, and a history of prior exposure to colistin in the previous 90 days are independent predictors of colistin resistance. The most common organism to develop colistin resistance identified was K. pneumoniae, and the most common site of isolation was blood. There was no difference in mortality between colistin-resistant and colistin-sensitive patients.

Niosomes based formulation containing tenoxicam: A newer solution for the rheumatic diseases.

OBJECTIVE: This investigation aimed to explore the potential of non-ionic surfactant based niosomal vesicles encapsulating tenoxicam (TN; anti-rheumatic drug) for the treatment of rheumatic diseases. MATERIAL AND METHODS: Mechanical dispersion technique with controlled pressure was employed to prepare different niosomal formulations. The effects of different ratios of surfactant (span-60), lipid, and sodium deoxycholate on noisome's physicochemical properties have been examined. Moreover, inhibition of TNF-α in lipopolysaccharide-activated cultured Human leukemia monocytic (THP-1) cells were demonstrated to assess the in vitro inflammation profile. Finally, the optimized niosomal formulation (TN3) was prepared in gel matrix consist of carbopol 934 (termed as TN34) and stability was also tested at 4±2 ÌŠC, 25±2 ÌŠC, 37±2 ÌŠC and 45±2 ÌŠC for 6 months. RESULTS: The optimized niosomal formulation exhibited a small vesicle size (165±14nm) and high drug encapsulation (79.64±1.5%). Niosomal gel formulation TN34 showed pH (6.7), viscosity (6810±3.34 cps), spreadability (19.11±1.87gm.cm/sec) and also displayed sustained release pattern of drug release (98.16±0.07% TN released from gel matrix in 24h) in vitro release study. TN34 exhibited substantial anti-inflammatory response, with ∼75% inhibition of TNF-α in 48h. Stability investigation revealed that refrigerator temperature is most suitable for the storage of niosomal gel. CONCLUSION: Transdermal niosomal formulation displayed promising potential in the treatment of rheumatic diseases.

Development of engineered transferosomal gel containing meloxicam for the treatment of osteoarthritis.

OBJECTIVE: .In this study, we investigated the potential of meloxicam (MLX) developed as transferosomal gel as a novel lipidic drug delivery system to address osteoarthritis (OTA), a degenerative joint disease that causes pain and stiffness. By incorporating meloxicam into a transferosomal gel, our aim was to provide a targeted and efficient delivery system capable of alleviating symptoms and slowing down the progression of OTA. MATERIAL AND METHODS: Classical lipid film hydration technique was utilized to formulate different transferosomal formulations. Different transferosomal formulations were prepared by varying the molar ratio of phospholipon-90H (phosphodylcholine) to DSPE (50:50, 60:40, 70:30, 80:20, and 90:10) and per batch, 80mg of total lipid was used. The quality control parameters such as entrapment efficiency, particle size and morphology, polydispersity and surface electric charge, in vitro drug release, ex vivo permeation and stability were measured. RESULTS: The optimized transferosomal formulations revealed a small vesicle size (121±12nm) and greater MLX entrapment (68.98±2.3%). Transferosomes mediated gel formulation MLX34 displayed pH (6.3±0.2), viscosity (6236±12.3 cps), spreadability (13.77±1.77 gm.cm/sec) and also displayed sustained release pattern of drug release (81.76±7.87% MLX released from Carbopol-934 gel matrix in 24h). MLX34 revealed close to substantial anti-inflammatory response, with ∼81% inhibition of TNF-α in 48h. Physical stability analysis concluded that refrigerator temperature was the preferred temperature to store transferosomal gel. CONCLUSION: MLX loaded transferosomes containing gel improved the skin penetration and therefore resulted into increased inhibition of TNF-α level.

D-optimal mixture design inspired modified release tablet formulation of lamotrigine for the treatment of seizures: An in-depth characterization.

OBJECTIVE: Lamotrigine (LTG) an anticonvulsant drug with a dissociation constant (pKa: 5.7), suffers from enhanced blood plasma spike after each dose, when administered as fast release tablet. Being BCS class-II candidate and pH dependent solubility, development of release-controlled tablets of LTG is a major challenge. This investigation aims at designing the release-controlled tablet (RCT) formulation of LTG using a solid dispersion (SD) technique via addressing its solubility and release problems. MATERIAL AND METHODS: RCT of LTG was fabricated using SD blend of Eudragit RL and Eudragit RS and PVP K-30 with different polymer blend ratio (1:5 and 1:7). The optimization of RCT of LTG was performed using D-optimal mixture design with three independent variables, three response variables, and one constraint. The dissolution rate was determined and data were then fitted to different mathematical models. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) studies and tableting parameters were analyzed. RESULT: In vitro studies of predicted optimized batches (POBs) have shown that drug release over a period of 12hours was 88.05±3.4% in media I, 86.10±3.7% in media II and 85.84±4.2% in media III. An in vitro kinetic model equating R2-value for all the tested models indicated that the first order and Higuchi release kinetics model were the most appropriate. CONCLUSION: Based on the optimized formulation consisting of SD of LTG with Eudragit RL, Eudragit RS and PVP K-30, the release rate was consistently similar throughout the GI tract, regardless of the pH of the environment.

Inadequate Rectal Pressure and Insufficient Relaxation and Abdominopelvic Coordination in Defecatory Disorders.

BACKGROUND & AIMS: Diagnostic tests for defecatory disorders (DDs) asynchronously measure anorectal pressures and evacuation and show limited agreement; thus, abdominopelvic-rectoanal coordination in normal defecation and DDs is poorly characterized. We aimed to investigate anorectal pressures, anorectal and abdominal motion, and evacuation simultaneously in healthy and constipated women. METHODS: Abdominal wall and anorectal motion, anorectal pressures, and rectal evacuation were measured simultaneously with supine magnetic resonance defecography and anorectal manometry. Evacuators were defined as those who attained at least 25% rectal evacuation. Supervised (logistic regression and random forest algorithm) and unsupervised (k-means cluster) analyses identified abdominal and anorectal variables that predicted evacuation. RESULTS: We evaluated 28 healthy and 26 constipated women (evacuators comprised 19 healthy participants and 8 patients). Defecation was initiated by abdominal wall expansion that was coordinated with anorectal descent, increased rectal and anal pressure, and then anal relaxation and rectal evacuation. Compared with evacuators, nonevacuators had lower anal diameters during simulated defecation, rectal pressure, anorectal junction descent, and abdominopelvic-rectoanal coordination (P < .05). Unsupervised cluster analysis identified 3 clusters that were associated with evacuator status (P < .01), that is, 10 evacuators (83%), 16 evacuators (73%), and 1 evacuator (5%) in clusters 1, 2, and 3, respectively. Each cluster had distinct characteristics (eg, maximum abdominosacral distance, rectal pressure, anorectal junction descent, anal diameter) and correlates that were more (clusters 1-2) or less (cluster 3) conducive to evacuation. Cluster 2 had 16 evacuators (73%) and intermediate characteristics (eg, lower anal resting pressure and relaxation during evacuation; P < .05). CONCLUSIONS: Women with DDs and a modest proportion of healthy women had specific patterns of anorectal dysfunction, including inadequate rectal pressurization, anal relaxation, and abdominopelvic-rectoanal coordination. These observations may guide individualized therapy for DDs in the future.

Morpho-functional characterization of the submucosal glands at the nasopharyngeal end of the auditory tube in humans.

BACKGROUND: The auditory tube (AT), an osteocartilaginous channel, connects the nasopharynx to the middle ear cavity. At the nasopharyngeal opening of the AT, there are dense collections of submucosal glands. In a recent article, Valstar et al. proposed these nasopharyngeal tubal glands conglomerate as salivary glands, which starkly contrasts with their previously known anatomy for being a component of the respiratory tract. This study examines the contesting views regarding the taxonomical categorization of the nasopharyngeal tubal glands. MATERIALS AND METHODS: The AT glands in context were examined in human cadavers grossly, and microscopically using routine and special (Hematoxylin and Eosin [H&E] and Periodic acid-Schiff [PAS] respectively), as well as immunohistochemical (for alpha-SMA and salivary amylase) staining methods and compared with the major and minor salivary glands and the submucosal glands in the trachea. Further, a biochemical analysis was performed to detect the presence of salivary amylase in the oral and nasopharyngeal secretions of the four living human subjects, representing major salivary glands and tubal glands, respectively. RESULTS: The submucosal seromucous glands with a surface lining of respiratory epithelium were observed at the nasopharyngeal end of AT. The cells in the tubal glands showed cytoplasmic positivity for alpha-SMA, which indicated the presence of the myoepithelial cells; however, this expression was significantly lower than in the seromucous submucosal glands within the trachea. Salivary alpha-amylase was undetectable in the cadaveric tissue samples. Moreover, the amylase level in the nasopharyngeal swabs was negligible compared to the oral swabs. CONCLUSION: The anatomical location along the respiratory tract, the presence of respiratory epithelium in the overlying mucosa, their morpho-functional resemblance to the seromucous glands in the trachea, and the absence of salivary amylase strongly indicate that the tubal glands are taxonomically different from the salivary glands. Given the available evidence, their existing recognition as a part of the respiratory tract and an integral component of the AT seems more appropriate.

STARCH SYNTHASE5, a Noncanonical Starch Synthase-Like Protein, Promotes Starch Granule Initiation in Arabidopsis.

What determines the number of starch granules in plastids is an enigmatic aspect of starch metabolism. Several structurally and functionally diverse proteins have been implicated in the granule initiation process in Arabidopsis (Arabidopsis thaliana), with each protein exerting a varying degree of influence. Here, we show that a conserved starch synthase-like protein, STARCH SYNTHASE5 (SS5), regulates the number of starch granules that form in Arabidopsis chloroplasts. Among the starch synthases, SS5 is most closely related to SS4, a major determinant of granule initiation and morphology. However, unlike SS4 and the other starch synthases, SS5 is a noncanonical isoform that lacks catalytic glycosyltransferase activity. Nevertheless, loss of SS5 reduces starch granule numbers that form per chloroplast in Arabidopsis, and ss5 mutant starch granules are larger than wild-type granules. Like SS4, SS5 has a conserved putative surface binding site for glucans and also interacts with MYOSIN-RESEMBLING CHLOROPLAST PROTEIN, a proposed structural protein influential in starch granule initiation. Phenotypic analysis of a suite of double mutants lacking both SS5 and other proteins implicated in starch granule initiation allows us to propose how SS5 may act in this process.

An efficient one-pot synthesis and docking studies of bioactive new antiproliferative dispiro[oxindole/acenaphthylenone‒benzofuranone] pyrrolidine scaffolds.

A new and efficient method has been developed to synthesize dispiro[oxindole/acenaphthylenone-benzofuranone]pyrrolidine compounds. This is done by triggering the 1,3-dipolar cycloaddition reaction of azomethine ylides by reacting isatin/acenaphthoquinone with L-picolinic acid/L-proline/sarcosine/L-thioproline/tetrahydroisoquinolines, in a highly regioselective manner in an ionic liquid [DBU][Ac] with 4'-chloro-auron[2-(4-chlorobenzylidene)benzofuran-3(2H)-one]. Single-crystal X-ray diffraction data support the proposed structures of the new compounds. The heterocycles derived from amino acids such as L-picolinic acid, L-proline, and L-thioproline showed significant inhibitory effects against six human solid tumors, including lung, breast, cervix, colon, and others. These new structures were also tested in the active sites of the MDM2 receptor to further study their antiproliferative effects.

Research on Antimicrobial Resistance in the Last 15 Years, India: A Bibliometric Analysis.

SUMMARY: Effective antimicrobials play an important element in modern medicine's success in treating infections, without which the patients would be put at risk. Along with the naturally occurring process of antibiotic resistance, the misuse/overuse of these antibiotics also leads to them losing their effectiveness. It limits the treatment options as the microbe that had previously been sensitive becomes resistant. This bibliometric study was performed by searching the Scopus database according to a specific search strategy. A total of 4200 articles were retrieved from the search, and after applying inclusion and exclusion criteria, 1355 articles were included in the study. All of the bibliometric variables examined in this study revealed significant growth in this research field, especially during COVID-19, in terms of increasing scientific output and research collaboration. The study findings indicate an adequate quality and amount of antimicrobial resistance (AMR) research on microbiology and pharmacodynamics in India, whereas more research needs to be conducted on measures to tackle AMR, its public health, and policy aspects.

Mapping of Palliative Care Services and Challenges in Implementation of National Program for Palliative Care in Puducherry.

Objectives: The purpose of this study was to map ongoing palliative care services and describe the characteristics of providers, recipients, level of care, and approach. Second, it seeks to investigate the difficulties encountered in implementing NPPC in the Puducherry district of UT Puducherry. This study aims to review the challenges in its implementation. Material and Methods: The study using both quantitative and qualitative design, including geospatial mapping of organisations, describing service delivery characteristics and exploring challenges faced in implementing NPPC, was conducted from July 2021 to January 2022. In-depth interviews were conducted with seven healthcare providers, four patients and three caregivers, as well as key informant interviews with six doctors in administration. Results: Thirteen organisations providing palliative care to population of Puducherry district of union territory Puducherry and neighbouring districts of Tamil Nadu were identified. Mapped organisations were primarily concentrated in urban areas. Morphine was available only at three medical colleges, providing outpatient palliative care services. Non-governmental organisations provided only home-based palliative care services and the hospices provided both in-patient and home-based services. Key barriers perceived by the health system were difficulty in procuring morphine, inadequate personnel and inadequate funding. Few barriers perceived by patients/family were stigma faced in community, psychological challenges and poor quality of care. Conclusions: Palliative care services are mainly available in urban areas and through private hospices. There is a need to implement palliative care program through the public health system to improve the accessibility in the rural areas.

Abdomino-anal Dyscoordination in Defecatory Disorders.

BACKGROUND & AIMS: The contribution of the abdominal muscles to normal defecation and disturbances thereof in defecatory disorders (DDs) are unknown. METHODS: In 30 healthy and 60 constipated women with normal rectal balloon expulsion time (BET) (n = 26) or prolonged BET (ie, DD; n = 34), seated anorectal pressures (manometry) and thickness (ultrasound) of the external and internal oblique and transversus abdominis muscles were measured simultaneously at rest, during hollowing, squeeze, evacuation, and a Valsalva maneuver. RESULTS: Compared with healthy women with a normal BET, DD women had a lower rectal and greater anal pressure increase during evacuation (P ≤ .05), and more activation of the internal oblique and the transversus abdominis muscles during squeeze (P < .05). The change in transversus abdominis thickness during a Valsalva maneuver vs hollowing (rho = 0.5; P = .002) and separately vs evacuation (rho = 0.7; P < .0001) were correlated in DD but not in healthy women with a normal BET. A principal component (PC) analysis of anorectal pressures and muscle thicknesses during evacuation uncovered a PC (PC3) that was associated with a prolonged BET. Higher PC3 scores were associated with low rectal and high anal pressures at rest and during evacuation, thinner external oblique muscle, and thicker internal oblique muscle during evacuation. A greater PC3 score was associated with increased odds for DD vs health (odds ratio, 1.84; 95% CI, 1.05-3.23), and separately vs constipation with a normal BET (odds ratio, 3.64; 95% CI, 1.73-7.69). CONCLUSIONS: Taken together, these findings show 3, possibly inter-related, disturbances suggestive of dyscoordination in DD: aberrant activation of abdominal muscles during squeeze in DD, dyscoordination of the abdominal muscles during various tasks in constipated women, and abdomino-anal dyscoordination.

Duodenal Mucosal Barrier in Functional Dyspepsia.

BACKGROUND & AIMS: In addition to gastric sensorimotor dysfunctions, functional dyspepsia (FD) is also variably associated with duodenal micro-inflammation and epithelial barrier dysfunction, the pathogenesis and clinical significance of which are unknown. Our hypothesis was that miRNAs and/or inflammation degrade epithelial barrier proteins, resulting in increased duodenal mucosal permeability in FD. METHODS: We compared the duodenal mucosal gene expression and miRNAs, in vivo permeability (lactulose-mannitol excretion between 0 and 60 and 60 and 120 minutes after saccharide ingestion), ex vivo assessments (transmucosal resistance, fluorescein isothiocyanate [FITC]-dextran flux, and basal ion transport), and duodenal histology (light and electron microscopy) in 40 patients with FD and 24 controls. RESULTS: Compared with controls, the mRNA expression of several barrier proteins (zonula occludens-1, occludin, claudin-12, and E-cadherin) was modestly reduced (ie, a fold change of 0.8-0.85) in FD with increased expression of several miRNAs (eg, miR-142-3p and miR-144-3-p), which suppress these genes. The urinary lactulose excretion and the lactulose:mannitol ratio between 60 and 120 minutes were greater in FD than in controls (P < .05). The FITC-dextran flux, which reflects paracellular permeability, was inversely correlated (r = -0.32, P = .03) with transmucosal resistance and directly correlated (r = 0.4, P = .02) with lactulose:mannitol ratio. Other parameters (mucosal eosinophils, intraepithelial lymphocytes, and mast cells, transmucosal resistance, FITC-dextran flux, average intercellular distance, and proportion of dilated junctions) were not significantly different between groups. CONCLUSIONS: In FD, there is a modest reduction in the expression of several duodenal epithelial barrier proteins, which may be secondary to up-regulation of regulatory miRNAs, and increased small intestinal permeability measured in vivo.

Effectiveness of anti-obesity medications approved for long-term use in a multidisciplinary weight management program: a multi-center clinical experience.

BACKGROUND AND AIMS: Randomized clinical trials have proven the efficacy and safety of Food and Drug Administration (FDA) approved anti-obesity medications (AOMs) for long-term use. It is unclear whether these outcomes can be replicated in real-world clinical practice where clinical complexities arise. The aim of this study was to evaluate the effectiveness and side effects of these medications in real-world multidisciplinary clinical practice settings. METHODS: We reviewed the electronic medical records (EMR) of patients with obesity who were prescribed an FDA-approved AOM for long-term use in academic and community multidisciplinary weight loss programs between January 2016 and January 2020. INTERVENTION: We assessed percentage total body weight loss (%TBWL), metabolic outcomes, and side effect profile up to 24 months after AOM initiation. RESULTS: The full cohort consisted of 304 patients (76% women, 95.2% White, median age of 50 years old [IQR, 39-58]). The median follow-up time was 9.1 months [IQR, 4.2-14.1] with a median number of 3 visits [IQR, 2-4]. The most prescribed medication was phentermine/topiramate extended-release (ER) (51%), followed by liraglutide (26.3%), bupropion/naltrexone sustained-release (SR) (16.5%), and lorcaserin (6.2%). %TBWL was 5.0%, 6.8%, 9.3%, 10.3%, and 10.5% at 3, 6, 12, 18, and 24 months. 60.2% of the entire cohort achieved at least 5% TBWL. Overall, phentermine/topiramate-ER had the most robust weight loss response during follow-up, with the highest %TBWL at 12 months of 12.0%. Adverse events were reported in 22.4% of patients. Only 9% of patients discontinued the medication due to side effects. CONCLUSIONS: AOMs resulted in significant long-term weight loss, that was comparable to outcomes previously reported in clinical trials.

Association of hypothyroidism with outcomes in hospitalized adults with COVID-19: Results from the International SCCM Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS): COVID-19 Registry.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is associated with high rates of morbidity and mortality. Primary hypothyroidism is a common comorbid condition, but little is known about its association with COVID-19 severity and outcomes. This study aims to identify the frequency of hypothyroidism in hospitalized patients with COVID-19 as well as describe the differences in outcomes between patients with and without pre-existing hypothyroidism using an observational, multinational registry. METHODS: In an observational cohort study we enrolled patients 18 years or older, with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between March 2020 and February 2021. The primary outcomes were (1) the disease severity defined as per the World Health Organization Scale for Clinical Improvement, which is an ordinal outcome corresponding with the highest severity level recorded during a patient's index COVID-19 hospitalization, (2) in-hospital mortality and (3) hospital-free days. Secondary outcomes were the rate of intensive care unit (ICU) admission and ICU mortality. RESULTS: Among the 20,366 adult patients included in the study, pre-existing hypothyroidism was identified in 1616 (7.9%). The median age for the Hypothyroidism group was 70 (interquartile range: 59-80) years, and 65% were female and 67% were White. The most common comorbidities were hypertension (68%), diabetes (42%), dyslipidemia (37%) and obesity (28%). After adjusting for age, body mass index, sex, admission date in the quarter year since March 2020, race, smoking history and other comorbid conditions (coronary artery disease, hypertension, diabetes and dyslipidemia), pre-existing hypothyroidism was not associated with higher odds of severe disease using the World Health Organization disease severity index (odds ratio [OR]: 1.02; 95% confidence interval [CI]: 0.92, 1.13; p = .69), in-hospital mortality (OR: 1.03; 95% CI: 0.92, 1.15; p = .58) or differences in hospital-free days (estimated difference 0.01 days; 95% CI: -0.45, 0.47; p = .97). Pre-existing hypothyroidism was not associated with ICU admission or ICU mortality in unadjusted as well as in adjusted analysis. CONCLUSIONS: In an international registry, hypothyroidism was identified in around 1 of every 12 adult hospitalized patients with COVID-19. Pre-existing hypothyroidism in hospitalized patients with COVID-19 was not associated with higher disease severity or increased risk of mortality or ICU admissions. However, more research on the possible effects of COVID-19 on the thyroid gland and its function is needed in the future.

SARS-CoV-2 infection increases risk of acute kidney injury in a bimodal age distribution.

BACKGROUND: Hospitalized patients with SARS-CoV2 develop acute kidney injury (AKI) frequently, yet gaps remain in understanding why adults seem to have higher rates compared to children. Our objectives were to evaluate the epidemiology of SARS-CoV2-related AKI across the age spectrum and determine if known risk factors such as illness severity contribute to its pattern. METHODS: Secondary analysis of ongoing prospective international cohort registry. AKI was defined by KDIGO-creatinine only criteria. Log-linear, logistic and generalized estimating equations assessed odds ratios (OR), risk differences (RD), and 95% confidence intervals (CIs) for AKI and mortality adjusting for sex, pre-existing comorbidities, race/ethnicity, illness severity, and clustering within centers. Sensitivity analyses assessed different baseline creatinine estimators. RESULTS: Overall, among 6874 hospitalized patients, 39.6% (n = 2719) developed AKI. There was a bimodal distribution of AKI by age with peaks in older age (≥60 years) and middle childhood (5-15 years), which persisted despite controlling for illness severity, pre-existing comorbidities, or different baseline creatinine estimators. For example, the adjusted OR of developing AKI among hospitalized patients with SARS-CoV2 was 2.74 (95% CI 1.66-4.56) for 10-15-year-olds compared to 30-35-year-olds and similarly was 2.31 (95% CI 1.71-3.12) for 70-75-year-olds, while adjusted OR dropped to 1.39 (95% CI 0.97-2.00) for 40-45-year-olds compared to 30-35-year-olds. CONCLUSIONS: SARS-CoV2-related AKI is common with a bimodal age distribution that is not fully explained by known risk factors or confounders. As the pandemic turns to disproportionately impacting younger individuals, this deserves further investigation as the presence of AKI and SARS-CoV2 infection increases hospital mortality risk.