Accumulating evidence reveals that sole mutations in hENT3 cause a spectrum of human genetic disorders. Among these include H syndrome, characterized by scleroderma, hyperpigmentation, hypertrichosis, hepatomegaly, cardiac abnormalities and musculoskeletal deformities, pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndrome, characterized by autoantibody-negative diabetes mellitus and skin deformities, familial Rosai-Dorfman disease, characterized by short stature, familial histiocytosis and sinus histiocytosis with massive lymphadenopathy (SHML), characterized by severe tissue infiltration of immune cells and swollen lymph nodes. hENT3 spectrum disorders share a common mutation and share overlapping clinical manifestations that display many intriguing resemblances to mitochondrial and lysosomal disorders. Although earlier studies identify hENT3 as a mitochondrial and a lysosomal nucleoside transporter, the precise connections between hENT3 and the pathophysiology of these disorders remain unresolved. In this study, we performed functional and biochemical characterization of these mutations in hENT3. We report severe reductions/losses of hENT3 nucleoside transport functions of hENT3 syndrome mutants. In addition to transport alterations, we provide evidence for possible loss of hENT3 functions in all H and pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndromes due to either mistrafficking or altered stability of mutant hENT3 proteins.H syndrome and pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) 3 syndrome are recently described autosomal-recessive genetic disorders in humans (1, 2). H syndrome patients display symptoms such as cutaneous hyperpigmentation, hypertrichosis, heart anomalities, hearing loss, hepatomegaly hypogonadism, and etc. The SLC29A3 gene encodes human equilibrative nucleoside transporter 3 (hENT3), a member of a largely conserved group of solute carrier (SLC) transporters called the ENT or SLC29 family (4, 5). These facilitative transporters mediate salvage of hydrophilic nucleosides as well as nucleoside analogs used in the treatment of cancers and viral diseases (4, 5). In comparison with the other human ENT members, hENT3 is unique in that it functions intracellularly with maximal activity at an acidic pH range of 5.5-6.5 (6, 7). Whereas Baldwin et al. (6) reported that hENT3 is localized partially in the late endosomes and lysosomes, our recent studies indicate that hENT3 is also localized in the mitochondria (7). Low pH transport properties and subcellular localization of hENT3 in lysosomes and in mitochondria suggest that hENT3 possibly transports nucleosides from the inside of the lysosomes to the cytoplasm (6) as well as across the inner mitochondrial membrane (7). Although these data indicate that hENT3 is likely to perform physiological functions relating to lysosomes and mitochondria, direct evidence linking hENT3 to these organelle functions has not yet been established.In a study involving 10 families affecte...

Background Clinical pharmacists are established members of the interprofessional patient care team, but limited guidance for the optimal utilization of pharmacy resources is available. Objective measurement of medication regimen complexity offers a novel process for evaluating pharmacist activity. The purpose of this study was to evaluate the relationship between medication regimen complexity, as measured by a novel medication regimen complexity scoring tool (MRC‐ICU), and both pharmacist interventions and drug‐drug interactions (DDIs). Methods This was a multi‐center, prospective, observational study. The electronic medical record was reviewed to collect patient demographics, patient outcomes, and MRC‐ICU and modified MRC‐ICU (mMRC‐ICU) score at 24, 48 hours, and at discharge. Pharmacist interventions were recorded during the patients' intensive care unit (ICU) stay. DDIs were also evaluated at 24, 48 hours, and at discharge. Spearman's rank‐order correlation was used to determine any correlation between the MRC‐ICU score at each time point and the number of pharmacist interventions and DDIs. Results A total of 153 patients were evaluated from both centers. The median MRC‐ICU at 24 hours was 11 (interquartile range [IQR] 7‐15). MRC‐ICU at 24 hours was correlated with interventions at 24 hours (rs .439, P <.001). Furthermore, MRC‐ICU was correlated with total DDIs (rs .4, P < .001). A modified version of the MRC‐ICU was also correlated with number of pharmacist interventions (P < .001) and DDIs (P < .001). Conclusions Medication regimen complexity showed a relationship with number of pharmacist interventions and number of DDIs.

Objective: To evaluate evidence for high-dose daptomycin (doses ≥ 8 mg/kg/d). Data Sources: A PubMed/MEDLINE literature search was performed (January 2000 to December 2020) using the search terms daptomycin, high dose, and dosing. Review article references and society guidelines were reviewed. Study Selection and Data Extraction: Clinical trials, observational studies, retrospective studies, meta-analyses, and systematic reviews reporting on high-dose daptomycin were included. Data Synthesis: Experimentally, daptomycin outperforms other antimicrobials for high inoculum and biofilm-associated infections. Clinically, high-dose daptomycin is supported as salvage and first-line therapy for endocarditis and bacteremia, primarily when caused by methicillin-resistant Staphylococcus aureus (when vancomycin minimum inhibitory concentration is >1 mg/L) and Enterococcus. High-dose daptomycin appears effective for osteomyelitis and central nervous system infections, although comparative studies are lacking. High dosing in renal replacement therapy requires considering clearance modality to achieve exposures like normal renal function. Weight-based dosing in obesity draws concern for elevated exposures, although high doses have not been evaluated kinetically in obesity. Some data show benefits of high doses in overweight populations. Burn patients clear daptomycin more rapidly, and high doses may only achieve drug exposures similar to standard doses (6 mg/kg). Relevance to Patient Care and Clinical Practice: This review analyzes the efficacy and safety of high-dose daptomycin in serious gram-positive infections. Discussion of specific infectious etiologies and patient populations should encourage clinicians to evaluate their daptomycin dosing standards. Conclusions: The efficacy of high-dose daptomycin and limited safety concerns encourage clinicians to consider high-dose daptomycin more liberally in severe gram-positive infections.

A stable doping technique for modifying the conduction behaviour of two-dimensional (2D) nanomaterial-based transistors is imperative for applications based on low-power complementary oxide thin-film transistors. Achieving an ambipolar feature with a controlled threshold voltage in both the p- and n-regimes is crucial for applying MoTe2-based devices as electronic devices because their native doping states are unipolar. In this study, a simple method to tune the threshold voltage of MoTe2 field-effect transistors (FETs) was investigated in order to realise an enhancement-mode MoTe2 thin-film transistor by implementing a facile method to modulate the carrier polarity based on the oxidative properties of MoTe2 FETs. Annealing in air induced a continuous p-doping effect in the devices without significant electrical degradation. Through a precise control of the duration and temperature of the post-annealing process, the tailoring technique induces hole doping, which results in a remarkable shift in transfer characteristics, thus leading to a charge neutrality point of the devices at zero gate bias. This study demonstrates the considerable potential of air heating as a reliable and economical post-processing method for precisely modifying the threshold voltage and further controlling the doping states of MoTe2-based FETs for use in logic inverters with 2D semiconductors.

No abstract