Publications by authors named "Rahul Sharma"

488 Publications

The Influence of Hospital Volume on the Outcomes of Nasopharyngeal, Sinonasal, and Skull-Base Tumors: A Systematic Review of the Literature.

J Neurol Surg B Skull Base 2022 Jun 19;83(3):270-280. Epub 2021 Jan 19.

Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States.

 The center of excellence model of health care hypothesizes that increased volume in a specialized center will lead to better and more affordable care. We sought to characterize the volume-outcome data for surgically treated sinonasal and skull base tumors and (chemo) radiation-treated nasopharyngeal malignancy.   Systematic review of the literature.  This review included national database and multi-institutional studies published between 1990 and 2019.  PubMed was interrogated for keywords "hospital volume," "facility volume," and outcomes for "Nasopharyngeal carcinoma," "Sinonasal carcinomas," "Pituitary Tumors," "Acoustic Neuromas," "Chordomas," and "Skull Base Tumors" to identify studies. Single-institution studies and self-reported surveys were excluded.  The main outcome of interest in malignant pathologies was survival; and in benign pathologies it was treatment-related complications.  A total of 20 studies met inclusion criteria. The average number of patients per study was 4,052, and ranged from 394 to 9,950 patients. Six of seven studies on malignant pathology demonstrated improved survival with treatment in high volume centers and one showed no association with survival. Ten of thirteen studies on benign disease showed reduced risk of complications, while one study demonstrated both an increased and decreased association of complications. Two studies showed no volume-outcome associations.  This systematic review demonstrates that a positive volume-outcome relationship exists for most pathologies of the skull base, with some exceptions. The relative dearth of literature supports further research to understand the effect of centralization of care on treatment outcomes.
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http://dx.doi.org/10.1055/s-0040-1721823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9236728PMC
June 2022

COVID-19 infection, and reinfection, and vaccine effectiveness against symptomatic infection among health care workers in the setting of omicron variant transmission in New Delhi, India.

Lancet Reg Health Southeast Asia 2022 Jun 6:100023. Epub 2022 Jun 6.

Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, India.

Background: Surge of SARS CoV-2 infections ascribed to omicron variant began in December 2021 in New Delhi. We determined the infection and reinfection density in a cohort of health care workers (HCWs) along with vaccine effectiveness (VE) against symptomatic infection within omicron transmission period (considered from December 01, 2021 to February 25, 2022.

Methods: This is an observational study from the All India Institute of Medical Sciences, New Delhi. Data were collected telephonically. Person-time at risk was counted from November 30, 2021 till date of infection/ reinfection, or date of interview. Comparison of clinical features and severity was done with previous pandemic periods. VE was estimated using test-negative case-control design [matched pairs (for age and sex)]. Vaccination status was compared and adjusted odds ratios (OR) were computed by conditional logistic regression. VE was estimated as (1-adjusted OR)X100-.

Findings: 11474 HCWs participated in this study. The mean age was 36⋅2 (±10⋅7) years. Complete vaccination with two doses were reported by 9522 (83%) HCWs [8394 (88%) Covaxin and 1072 Covishield (11%)]. The incidence density of all infections and reinfection during the omicron transmission period was 34⋅8 [95% Confidence Interval (CI): 33⋅5-36⋅2] and 45⋅6 [95% CI: 42⋅9-48⋅5] per 10000 person days respectively. The infection was milder as compared to previous periods. VE was 52⋅5% (95% CI: 3⋅9-76⋅5,  = 0⋅036) for those who were tested within 14-60 days of receiving second dose and beyond this period (61-180 days), modest effect was observed.

Interpretation: Almost one-fifth of HCWs were infected with SARS CoV-2 during omicron transmission period, with predominant mild spectrum of COVID-19 disease. Waning effects of vaccine protection were noted with increase in time intervals since vaccination.

Funding: None.
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http://dx.doi.org/10.1016/j.lansea.2022.100023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167830PMC
June 2022

Exposure to the Dioxin-like Pollutant PCB 126 Afflicts Coronary Endothelial Cells via Increasing 4-Hydroxy-2 Nonenal: A Role for Aldehyde Dehydrogenase 2.

Toxics 2022 Jun 16;10(6). Epub 2022 Jun 16.

Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA.

Exposure to environmental pollutants, including dioxin-like polychlorinated biphenyls (PCBs), play an important role in vascular inflammation and cardiometabolic diseases (CMDs) by inducing oxidative stress. Earlier, we demonstrated that oxidative stress-mediated lipid peroxidation derived 4-hydroxy-2-nonenal (4HNE) contributes to CMDs by decreasing the angiogenesis of coronary endothelial cells (CECs). By detoxifying 4HNE, aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, enhances CEC angiogenesis. Therefore, we hypothesize that ALDH2 activation attenuates a PCB 126-mediated 4HNE-induced decrease in CEC angiogenesis. To test our hypothesis, we treated cultured mouse CECs with 4.4 µM PCB 126 and performed spheroid and aortic ring sprouting assays, the ALDH2 activity assay, and Western blotting for the 4HNE adduct levels and real-time qPCR to determine the expression levels of and oxidative stress-related genes. PCB 126 increased the gene expression and 4HNE adduct levels, whereas it decreased the ALDH2 activity and angiogenesis significantly in MCECs. However, pretreatment with 2.5 µM disulfiram (DSF), an ALDH2 inhibitor, or 10 µM Alda 1, an ALDH2 activator, before the PCB 126 challenge exacerbated and rescued the PCB 126-mediated decrease in coronary angiogenesis by modulating the 4HNE adduct levels respectively. Finally, we conclude that ALDH2 can be a therapeutic target to alleviate environmental pollutant-induced CMDs.
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http://dx.doi.org/10.3390/toxics10060328DOI Listing
June 2022

Formulation Optimization and Evaluation of Nanocochleate Gel of Famciclovir for the Treatment of Herpes Zoster.

Recent Pat Nanotechnol 2022 Jun 22. Epub 2022 Jun 22.

Department of Pharmaceutics, SVKM NMIMS School of Pharmacy and Technology Management, Shirpur, Dhule, India.

Background: Herpes zoster is a viral infection triggered due to the reactivation of the varicella-zoster virus in the posterior dorsal root ganglion. Herpes zoster infections occur mostly in the facial, cervical and thoracic region of the body beginning with pain and resulted in the vesicular eruption. Recently, this infection is observed during the Covid-19 pandemic and also after the induction of mRNA-based vaccine for coronavirus at an extended level. Nanocochleates are cylindrical (cigar-shape) microstructure lipid-based versatile carriers for the drug delivery systems. Famciclovir is an antiviral agent employed for the treatment of Herpes zoster infections.

Objective: The current research aimed at the development of a novel nanocochleate gel of Famciclovir for the treatment of herpes zoster infections with higher efficacy.

Methods: The interaction studies using FTIR were carried out and indicated no such interactions among the drug and lipids. The nanocochleates were developed using hydrogel, trapping, liposome before cochleate dialysis, direct calcium dialysis and binary aqueous-aqueous emulsion methods respectively. The 32 Box-Behnken design was applied by considering the concentration of lipids (phosphatidylcholine and cholesterol) and speed of rotation as independent factors, whereas a particle size and entrapment efficiency as dependable factors.

Results: The developed nanocochleates were estimated for the particle size (276.3 nm), zeta potential (-16.7 mV), polydispersity index (0.241), entrapment efficiency (73.87±0.19 %) and in-vitro diffusion release (>98.8 % in 10 h). The optimized batch was further converted into the topical gel using carbopol 940 as a gelling agent. The prepared gel was smooth, rapidly spreadable with a viscosity (5998.72 cp), drug content (95.3 %) and remain stable during stability studies.

Conclusion: A novel nanocochleate gel of Famciclovir was successfully developed for the treatment of infections associated with Herpes Zoster with sustained release action.
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http://dx.doi.org/10.2174/1872210516666220622115553DOI Listing
June 2022

Virtual Clinical Shadowing for Pre-Clinical Medical Students in an Emergency Medicine-Based Leadership Course.

Telemed Rep 2021 27;2(1):233-238. Epub 2021 Oct 27.

Department of Emergency Medicine, New York-Presbyterian Hospital/Weill Cornell Medicine, New York City, New York, USA.

The COVID-19 pandemic limited pre-clinical medical students from participating in traditional clinical in-person shadowing. Rather than eliminating clinical shadowing from an established leadership course, we describe the experience of six pre-clinical medical students shadowing physician preceptors remotely through virtual platforms. Six pre-clinical medical students enrolled in 2020's Weill Cornell Medicine's Healthcare Leadership and Management Scholars Program were prepared with training materials for on-camera patient care. Students shadowed emergency medicine (EM) physicians providing clinical care in one of our New York Presbyterian emergency departments (EDs) and through telemedicine. Pre- and postsurveys were provided to these students. From three different U.S. time zones, students were safely able to shadow EM physicians. The educational fidelity was maintained in physician-student relationships, but revealed opportunities for improvement in students' clinical learning, in ED clinical care, and in telemedicine visits. Virtual clinical shadowing is a viable option for pre-clinical students, when in-person options are not available. With logistical adjustments, this medium may be a long-term educational option especially for telemedicine.
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http://dx.doi.org/10.1089/tmr.2021.0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9049813PMC
October 2021

A More Atherogenic Lipoprotein Status Is Present in Adults With Than Without Type 2 Diabetes Mellitus With Equivalent Degrees of Hypertriglyceridemia.

Can J Diabetes 2022 Feb 9. Epub 2022 Feb 9.

Division of Endocrinology and Metabolism, Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Electronic address:

Objectives: The impact of type 2 diabetes (T2DM) on biomarkers denoting lipoprotein compositional status was studied in mild and moderate hypertriglyceridemia (HTG). Diabetic dyslipidemia pathophysiology could contribute to differences in lipoprotein compositional status, which could be reflected in the preferred cardiovascular disease risk prediction markers in HTG: non-high-density lipoprotein cholesterol (non-HDLC) and apolipoprotein B (apoB).

Methods: 2,775 fasting lipid profiles from a tertiary-care lipid clinic were analyzed as 2 subgroups (with and without T2DM), stratified by triglyceride (TG) levels: normotriglyceridemia (TG 0.01 to 1.7 mmol/L), mild HTG (TG 1.71 to 5 mmol/L) and moderate HTG (TG 5.01 to 10 mmol/L). The mean non-HDLC:apoB ratio in each TG stratum and subgroup was analyzed. We also used linear regression to assess the correlation between non-HDLC and apoB.

Results: The mean non-HDLC:apoB ratio was increased in both subgroups in patients with mild and moderate HTG, compared to those with normotriglyceridemia. In moderate HTG, the mean non-HDLC:apoB ratio in the subgroup with T2DM was significantly lower than the subgroup without T2DM. In mild and moderate HTG, the subgroup with T2DM had a stronger correlation between non-HDLC and apoB than did the subgroup without T2DM.

Discussion And Conclusions: In mild and moderate HTG, adults with T2DM exhibit lipid profiles that represent a different and more atherogenic lipoprotein compositional status, when compared with adults without T2DM. For the same severity of HTG, the lipoprotein compositional status in diabetic dyslipidemia suggests that there is increased abundance of smaller non-HDL particles and their remnants, which are highly atherogenic.
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http://dx.doi.org/10.1016/j.jcjd.2022.02.001DOI Listing
February 2022

CXCR4+ Treg cells control serum IgM levels and natural IgM autoantibody production by B-1 cells in the bone marrow.

J Exp Med 2022 Jul 7;219(7). Epub 2022 Jun 7.

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY.

Regulatory T (Treg) cells represent a specialized lineage of suppressive CD4+ T cells whose functionality is critically dependent on their ability to migrate to and dwell in the proximity of cells they control. Here we show that continuous expression of the chemokine receptor CXCR4 in Treg cells is required for their ability to accumulate in the bone marrow (BM). Induced CXCR4 ablation in Treg cells led to their rapid depletion and consequent increase in mature B cells, foremost the B-1 subset, observed exclusively in the BM without detectable changes in plasma cells or hematopoietic stem cells or any signs of systemic or local immune activation elsewhere. Dysregulation of BM B-1 B cells was associated with a highly specific increase in IgM autoantibodies and total serum IgM levels. Thus, Treg cells control autoreactive B-1 B cells in a CXCR4-dependent manner. These findings have significant implications for understanding the regulation of B cell autoreactivity and malignancies.
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http://dx.doi.org/10.1084/jem.20220047DOI Listing
July 2022

Tracheostomy Outcomes in Patients With COVID-19 at a New York City Hospital.

OTO Open 2022 Apr-Jun;6(2):2473974X221101025. Epub 2022 May 30.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Irving Medical Center, NewYork-Presbyterian Hospital, New York, New York, USA.

Objective: Tracheostomies have been performed in patients with prolonged intubation due to COVID-19. Understanding outcomes in different populations is crucial to tackle future epidemics.

Study Design: Prospective cohort study.

Setting: Tertiary academic medical center in New York City.

Methods: A prospectively collected database of patients with COVID-19 undergoing open tracheostomy between March 2020 and April 2020 was reviewed. Primary endpoints were weaning from the ventilator and from sedation and time to decannulation.

Results: Sixty-six patients underwent tracheostomy. There were 42 males (64%) with an average age of 62 years (range, 23-91). Patients were intubated for a median time of 26 days prior to tracheostomy (interquartile range [IQR], 23-30). The median time to weaning from ventilatory support after tracheostomy was 18 days (IQR, 10-29). Of those sedated at the time of tracheostomy, the median time to discontinuation of sedation was 5 days (IQR, 3-9). Of patients who survived, 39 (69%) were decannulated. Of those decannulated before discharge (n = 39), the median time to decannulation was 36 days (IQR, 27-49) following tracheostomy. The median time from ventilator liberation to decannulation was 14 days (IQR, 8-22). Thirteen patients (20.0%) had minor bleeding requiring packing. Two patients (3%) had bleeding requiring neck exploration. The all-cause mortality rate was 10.6%. No patients died of procedural causes, and no surgeons acquired COVID-19.

Conclusion: Open tracheostomies were successfully and safely performed at our institution in the peak of the COVID-19 pandemic. The majority of patients were successfully weaned from the ventilator and sedation. Approximately 60% of patients were decannulated prior to hospital discharge.
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http://dx.doi.org/10.1177/2473974X221101025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160903PMC
May 2022

Exciton decay mechanism in DNA single strands: back-electron transfer and ultrafast base motions.

Chem Sci 2022 May 19;13(18):5230-5242. Epub 2022 Apr 19.

Laboratory of Ultrafast Spectroscopy (LSU), Lausanne Centre for Ultrafast Science (LACUS), École Polytechnique Fédérale de Lausanne, ISIC-FSB CH-1015 Lausanne Switzerland

The photochemistry of DNA systems is characterized by the ultraviolet (UV) absorption of π-stacked nucleobases, resulting in exciton states delocalized over several bases. As their relaxation sensitively depends on local stacking conformations, disentangling the ensuing electronic and structural dynamics has remained an experimental challenge, despite their fundamental role in protecting the genome from potentially harmful UV radiation. Here we use transient absorption and transient absorption anisotropy spectroscopy with broadband femtosecond deep-UV pulses (250-360 nm) to resolve the exciton dynamics of UV-excited adenosine single strands under physiological conditions. Due to the exceptional deep-UV bandwidth and polarization sensitivity of our experimental approach, we simultaneously resolve the population dynamics, charge-transfer (CT) character and conformational changes encoded in the UV transition dipoles of the π-stacked nucleotides. Whilst UV excitation forms fully charge-separated CT excitons in less than 0.3 ps, we find that most decay back to the ground state a back-electron transfer. Based on the anisotropy measurements, we propose that this mechanism is accompanied by a structural relaxation of the photoexcited base-stack, involving an inter-base rotation of the nucleotides. Our results finally complete the exciton relaxation mechanism for adenosine single strands and offer a direct view into the coupling of electronic and structural dynamics in aggregated photochemical systems.
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http://dx.doi.org/10.1039/d1sc06450aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9093102PMC
May 2022

Multifunctional Lanthanide-Doped Binary Fluorides and Graphene Oxide Nanocomposites Via a Task-Specific Ionic Liquid.

ACS Omega 2022 May 11;7(20):16906-16916. Epub 2022 May 11.

Department of Chemistry, Dr. H.S. Gour University (A Central University), Sagar 470003, Madhya Pradesh, India.

Graphene oxide-based nanocomposites (NCMs) exhibit diverse photonic and biophotonic applications. Innovative nanoengineering using a task-specific ionic liquid (IL), namely, 1-butyl-3-methyl tetrafluoroborate [Cmim][BF], allows one to access a unique class of luminescent nanocomposites formed between lanthanide-doped binary fluorides and graphene oxide (GO). Here the IL is used as a solvent, templating agent, and as a reaction partner for the nanocomposite synthesis, that is, "all three in one". Our study shows that GO controls the size of the NCMs; however, it can tune the luminescence properties too. For example, the excitation spectrum of Ce is higher-energy shifted when GO is attached. In addition, magnetic properties of GdF:Tb nanoparticles (NPs) and GdF:Tb-GO NCMs are also studied at room temperature (300 K) and very low temperature (2 K). High magnetization results for the NPs (e.g., 6.676 emu g at 300 K and 184.449 emu g at 2 K in the applied magnetic field from +50 to -50 kOe) and NCMs promises their uses in many photonic and biphotonic applications including magnetic resonance imaging, etc.
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http://dx.doi.org/10.1021/acsomega.1c06875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134252PMC
May 2022

Geriatric Burn Injuries Presenting to the Emergency Department of a Major Burn Center: Clinical Characteristics and Outcomes.

J Emerg Med 2022 May 27. Epub 2022 May 27.

Department of Emergency Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York. Electronic address:

Background: Burn injuries in geriatric patients are common and may have significant associated morbidity and mortality. Most research has focused on the care of hospitalized patients after admission to burn units. Little is known about the clinical characteristics of geriatric burn victims who present to the emergency department (ED) and their ED assessment and management.

Objective: Our aim was to describe the clinical characteristics and outcomes of geriatric patients presenting to the ED with burn injuries.

Methods: We performed a comprehensive retrospective chart review on all patients 60 years and older with a burn injury presenting from January 2011 through September 2015 to a large, urban, academic ED in a hospital with a 20-bed burn center.

Results: A total of 459 patients 60 years and older were treated for burn injuries during the study period. Median age of burn patients was 71 years, 23.7% were 80 years and older, and 56.6% were female. The most common burn types were hot water scalds (43.6%) and flame burns (23.1%). Median burn size was 3% total body surface area (TBSA), 17.1% had burns > 10% TBSA, and 7.8% of patients had inhalation injuries. After initial evaluation, 46.4% of patients were discharged from the ED. Among patients discharged from the ED, only 1.9% were re-admitted for any reason within 30 days. Of the patients intubated in the ED, 7.1% were extubated during the first 2 days of admission, and 64.3% contracted ventilator-associated pneumonia.

Conclusions: Better understanding of ED care for geriatric burn injuries may identify areas in which to improve emergency care for these vulnerable patients.
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http://dx.doi.org/10.1016/j.jemermed.2022.01.016DOI Listing
May 2022

Carotid artery injury in endoscopic endonasal surgery: Risk factors, prevention, and management.

World J Otorhinolaryngol Head Neck Surg 2022 Mar 22;8(1):54-60. Epub 2022 Mar 22.

Department of Otolaryngology-Head and Neck Surgery Columbia University Irving Medical Center, NewYork-Presbyterian Hospital New York New York USA.

Objective: Endoscopic approaches for sinus and skull base surgery are increasing in popularity. The objective of this narrative review is to characterize risk factors for internal carotid artery injury in endoscopic endonasal surgery (EES), highlight preventative measures, and illustrate key management principles.

Data Sources: Comprehensive literature review.

Methods: Relevant literature was reviewed using PubMed/MEDLINE.

Results: Carotid artery injury in EES is rare, with most studies reporting an incidence below 0.1%. Anatomic aberrancies, wide dissection margins, as well as specific provider and hospital factors, may increase the risk of injury. Multidisciplinary teams, comprehensive preoperative imaging, patient risk assessment, and formal training in vascular emergencies may reduce the risk. Management protocols should emphasize proper visualization of the injury site, fluid replacement, rapid packing, angiography, and endovascular techniques to achieve hemostasis.

Conclusions: While EES is a relatively safe procedure, carotid artery injury is a devastating complication that warrants full consideration in surgical planning. Important preventative measures include identifying patients with notable risk factors and obtaining preoperative imaging. Multidisciplinary teams and management protocols are ultimately necessary to reduce morbidity and mortality.
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http://dx.doi.org/10.1002/wjo2.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9126167PMC
March 2022

Phytochemically stabilized chitosan encapsulated Cu and Ag nanocomposites to remove cefuroxime axetil and pathogens from the environment.

Int J Biol Macromol 2022 Jul 23;212:451-464. Epub 2022 May 23.

Department of Chemistry, Career Point University, Bhoranj (Tikker - Kharwarian), Hamirpur, MDR 35, Himachal Pradesh 176041, India. Electronic address:

Antibiotics have been a source of concern since they are causing resistance in bacteria that live in water and air. As a result, green technology was used to manufacture silver and copper nanoparticles, which were encapsulated with the biopolymer chitosan derived from the root extract of the Potentilla astrosanguinea plant. XRD, FTIR, TEM, EDX, and UV-Visible spectroscopy were methods used for structural and spectroscopic analysis. These nanomaterials have a roughly spherical 2-30 nm average size and a face-centered cubic (FCC) shape, according to the findings. The photocatalytic drug degradation and antibacterial properties of the produced nanocomposites were outstanding, with some resistance lasting longer than 180 days. The current study discovered that under UV light exposure, silver nanocomposites degrade drugs rapidly within 40 min, with an average rate of over 95%, while copper nanocomposites degrade drugs rapidly within 70 min, with an average rate of 84%. These nanocomposites have demonstrated exceptionally compelling antibacterial action against Gram-positive, Gram-negative, and fungal pathogens in addition to photocatalytic activity. The lowest recorded MIC values were 10.30 μg/mL and 10.84 μg/mL, respectively, whereas the lowest MBC values were 91.24 μg/mL and 99.50 μg/mL.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.05.143DOI Listing
July 2022

Obese gastroparesis inpatient admissions: trends and outcomes from 2007-2017 in the United States.

Ann Gastroenterol 2022 May-Jun;35(3):249-259. Epub 2022 Mar 25.

Department of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA (Rahul Sharma, Sumant Inamdar).

Background: The aim of this study was to investigate obese gastroparesis (GP) hospitalizations in the United States (US).

Methods: We analyzed the National Inpatient Sample (NIS) from 2007-2017 to identify all adult obese (body mass index ≥30 kg/m) GP hospitalizations. These were compared with non-obese GP hospitalizations. The demographic trends, adverse outcomes, and healthcare burden were analyzed.

Results: From 2007-2017, obese GP hospitalizations accounted for 13.75% of all GP hospitalizations in the US. There was an increasing trend in obese GP hospitalizations, from 2286 in 2007 to 47,265 in 2017 (P=0.0019), and in the proportion of obese GP hospitalizations, from 6.16% in 2007 to 17.96% in 2017 (P<0.001). Males, Blacks, Hispanics, and Asians showed a rising trend in obese GP hospitalizations. Although rates of upper endoscopy declined from 8.28% in 2007 to 5.36% in 2017 (P<0.001), obese GP hospitalizations had higher rates of upper endoscopy utilization (6.05 vs. 5.42%, P<0.001) compared to the non-obese cohort. Inpatient mortality for obese GP hospitalizations increased from 0.64% in 2007 to 1.10% in 2017 (P<0.001). Furthermore, we noted a rising trend in mean length of stay (LOS), from 4.64 in 2007 to 6.05 days in 2017 (P=0.0029), and mean total hospital charge (THC), from $22,306 in 2007 to $62,220 in 2017 (P<0.001) for obese GP hospitalizations.

Conclusions: The prevalence of obese GP hospitalizations along with inpatient mortality, LOS, and THC rose significantly. However, the overall rate of upper endoscopy utilization has decreased for these patients.
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http://dx.doi.org/10.20524/aog.2022.0702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9062847PMC
March 2022

Triple-helix potential of the mouse genome.

Proc Natl Acad Sci U S A 2022 05 3;119(19):e2203967119. Epub 2022 May 3.

Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.

Certain DNA sequences, including mirror-symmetric polypyrimidine•polypurine runs, are capable of folding into a triple-helix–containing non–B-form DNA structure called H-DNA. Such H-DNA–forming sequences occur frequently in many eukaryotic genomes, including in mammals, and multiple lines of evidence indicate that these motifs are mutagenic and can impinge on DNA replication, transcription, and other aspects of genome function. In this study, we show that the triplex-forming potential of H-DNA motifs in the mouse genome can be evaluated using S1-sequencing (S1-seq), which uses the single-stranded DNA (ssDNA)–specific nuclease S1 to generate deep-sequencing libraries that report on the position of ssDNA throughout the genome. When S1-seq was applied to genomic DNA isolated from mouse testis cells and splenic B cells, we observed prominent clusters of S1-seq reads that appeared to be independent of endogenous double-strand breaks, that coincided with H-DNA motifs, and that correlated strongly with the triplex-forming potential of the motifs. Fine-scale patterns of S1-seq reads, including a pronounced strand asymmetry in favor of centrally positioned reads on the pyrimidine-containing strand, suggested that this S1-seq signal is specific for one of the four possible isomers of H-DNA (H-y5). By leveraging the abundance and complexity of naturally occurring H-DNA motifs across the mouse genome, we further defined how polypyrimidine repeat length and the presence of repeat-interrupting substitutions modify the structure of H-DNA. This study provides an approach for studying DNA secondary structure genome-wide at high spatial resolution.
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http://dx.doi.org/10.1073/pnas.2203967119DOI Listing
May 2022

Socioeconomic Predictors of Access to Care for Patients with Operatively Managed Pancreatic Cancer in New York State.

J Gastrointest Surg 2022 May 2. Epub 2022 May 2.

Division of GI/Endocrine Surgery, Department of Surgery, Columbia University Irving Medical Center: Herbert Irving Pavilion, 177 Fort Washington Ave, New York, NY, 10032, USA.

Purpose: We evaluated how race and socioeconomic factors impact access to high-volume surgical centers, treatment initiation, and postoperative care for pancreatic cancer in a state with robust safety net insurance coverage and healthcare infrastructure.

Methods: The New York Statewide Planning and Research Cooperative System was analyzed. Patients with pancreatic cancer resected from 2007 to 2017 were identified by ICD and CPT codes. Primary outcomes included surgery at low-volume facilities (< 20 pancreatectomies/year), time to therapy initiation, and time to postoperative surveillance imaging (within 60-180 days after surgery).

Results: In total, 3312 patients underwent pancreatectomy across 124 facilities. Median age was 67 years (IQR 59, 75) and 55% of patients were male. Most (72.7%) had surgery at high-volume centers. On multivariable analysis, odds ratios for surgery at low-volume centers were increased for Black race (2.21 (95% CI 1.69-2.88)), Asian race (1.64 (95% CI 1.09-2.43)), Hispanic ethnicity (1.68 (95% CI 1.24-2.28)), Medicaid insurance (2.52 (95% CI 1.79-3.56)), no insurance (2.24 (95% CI 1.38-3.61)), lowest income quartile (3.31 (95% CI 2.14-5.32)), and rural zip code (2.49 (95% CI 1.69-3.65)). Patients treated at low-volume centers waited longer to initiate treatment (hazard ratio (HR) 0.91 (95% CI 0.81-1.01)). Black patients underwent the least surveillance imaging (50.4%; p < 0.0001), while Asian (HR 2.04, 95% CI 1.40-2.98)) and Hispanic patients (HR 1.36 (95% CI 1.00-1.84)) were more likely to have surveillance imaging.

Conclusions: Race independently affected access to high-volume facilities and surveillance imaging. When considered in light of other accumulating evidence, future efforts might investigate the perceptions and logistical considerations noted by providers and patients alike to identify the etiology of these disparities and then institute corrective measures.
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http://dx.doi.org/10.1007/s11605-022-05320-1DOI Listing
May 2022

PIMT/TGS1: An evolving metabolic molecular switch with conserved methyl transferase activity.

Drug Discov Today 2022 Aug 21;27(8):2386-2393. Epub 2022 Apr 21.

Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India. Electronic address:

Transcriptional coactivators play a crucial role in regulating gene expression. PRIP interacting protein with methyl transferase domain (PIMT)/trimethyl guanosine synthase 1 (TGS1) is a co-activator interacting protein with an RNA methyl transferase domain. PIMT serves as a bridge between HAT and non-HAT coactivators and differentially modulates gene expression. Disruption of PIMT is embryonic lethal. PIMT regulates hepatic gluconeogenesis and TNF-α-induced insulin resistance in the skeletal muscle. As a methyl transferase, PIMT controls post-transcriptional regulation of HIV-1 and is essential for human telomerase RNA biogenesis. This review comprehensively describes the dual role of PIMT, which promises to be a putative target in metabolic disorders.
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http://dx.doi.org/10.1016/j.drudis.2022.04.018DOI Listing
August 2022

Impact of mail-based continuous positive airway pressure initiation on treatment usage and effectiveness.

Sleep Breath 2022 Mar 26. Epub 2022 Mar 26.

HSR&D Center of Innovation for Veteran-Centered and Value-Driven Care, Division of Pulmonary, Critical Care and Sleep Medicine, Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA, 98108, USA.

Purpose: In-person visits with a trained therapist have been standard care for patients initiating continuous positive airway pressure (CPAP). These visits provide an opportunity for hands-on training and an in-person assessment of mask fit. However, to improve access, many health systems are shifting to remote CPAP initiation with equipment mailed to patients. While there are potential benefits of a mailed approach, relative patient outcomes are unclear. Specifically, many have concerns that a lack of in-person training may contribute to reduced CPAP adherence. To inform this knowledge gap, we aimed to compare treatment usage after in-person or mailed CPAP initiation.

Methods: Our medical center shifted from in-person to mailed CPAP dispensation in March 2020 during the COVID-19 pandemic. We assembled a cohort of patients with newly diagnosed obstructive sleep apnea (OSA) who initiated CPAP in the months before (n = 433) and after (n = 186) this shift. We compared 90-day adherence between groups.

Results: Mean nightly PAP usage was modest in both groups (in-person 145.2, mailed 140.6 min/night). We did not detect between-group differences in either unadjusted or adjusted analyses (adjusted difference - 0.2 min/night, 95% - 27.0 to + 26.5).

Conclusions: Mail-based systems of CPAP initiation may be able to improve access without reducing CPAP usage. Future work should consider the impact of mailed CPAP on patient-reported outcomes and the impact of different remote setup strategies.
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http://dx.doi.org/10.1007/s11325-022-02608-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960106PMC
March 2022

Unusual presentation of superior mesenteric artery syndrome in a child.

BMJ Case Rep 2022 Mar 18;15(3). Epub 2022 Mar 18.

Paediatric Surgery, Lilavati Hospital and Research Centre, Mumbai, India.

Superior mesenteric artery syndrome (SMAS), also known as Wilkie's syndrome, is a rare cause of upper gastrointestinal tract obstruction. We report a case of a 10-year-old girl with persistent abdominal pain for over 3 months, who on extensive investigations was diagnosed with SMAS. She underwent a surgical procedure to bypass the obstructed portion of the intestine for relief of her symptoms.
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http://dx.doi.org/10.1136/bcr-2021-246041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935179PMC
March 2022

The Longitudinal Association of Subclinical Hearing Loss With Cognition in the Health, Aging and Body Composition Study.

Front Aging Neurosci 2021 1;13:789515. Epub 2022 Mar 1.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Irving Medical Center, NewYork-Presbyterian Hospital, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States.

Objectives: To examine the longitudinal association between subclinical hearing loss (SCHL) and neurocognitive performance.

Design: Longitudinal analyses were conducted among 2,110 subjects who underwent audiometric testing in a US multi-centered epidemiologic cohort study. The primary exposure was better ear hearing (pure tone average). SCHL was defined as hearing ≤ 25 dB. The primary outcome was neurocognitive performance, measured by Digit Symbol Substitution Test (DSST), Modified Mini Mental State Examination (3MS), and CLOX1. Linear mixed models were performed to assess the longitudinal association between hearing and cognitive performance, adjusting for covariates. Models were fit among all individuals and among individuals with SCHL only.

Results: Among 2,110 participants, mean (SD) age was 73.5 (2.9) years; 52.3% were women. Mean (SD) better ear pure tone average was 30.0 (13.1) dB. Mean follow-up was 9.1 years (range 3-16). Among all participants, worse hearing was associated with significantly steeper cognitive decline measured by the DSST [0.054-point/year steeper decrease per 10 dB worse hearing, 95% confidence interval (CI): 0.026-0.082] and 3MS (0.044-point/year steeper decrease per 10 dB worse hearing, CI: 0.026-0.062), but not CLOX1. Among those with SCHL, worse hearing was associated with significantly steeper cognitive performance decline as measured by DSST (0.121-point/year steeper decrease per 10 dB worse hearing, CI: 0.013-0.228), but not CLOX1 or 3MS.

Conclusion: Among those with SCHL, worse hearing was associated with steeper cognitive performance declines over time as measured by DSST. The relationship between hearing loss and cognition may begin at earlier levels of hearing loss than previously recognized.
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http://dx.doi.org/10.3389/fnagi.2021.789515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923153PMC
March 2022

Well-Defined NNS-Mn Complex Catalyzed Selective Synthesis of C-3 Alkylated Indoles and Bisindolylmethanes Using Alcohols.

J Org Chem 2022 03 8;87(6):3989-4000. Epub 2022 Mar 8.

Department of Chemistry, Indian Institute of Technology-Guwahati, Kamrup, Assam 781039, India.

Herein, we demonstrated Mn-catalyzed selective C-3 functionalization of indoles with alcohols. The developed catalyst can also furnish bis(indolyl)methanes from the same set of substrates under slightly modified reaction conditions. Mechanistic studies reveal that the C-3 functionalization of indoles is going via a borrowing hydrogen pathway. To highlight the practical utility, a diverse range of substrates including nine structurally important drug molecules are synthesized. Furthermore, we also introduced a one-pot cascade strategy for synthesizing C-3 functionalized indoles directly from 2-aminophenyl ethanol and alcohol.
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http://dx.doi.org/10.1021/acs.joc.1c02702DOI Listing
March 2022

Improving the efficiency and effectiveness of an industrial SARS-CoV-2 diagnostic facility.

Sci Rep 2022 02 24;12(1):3114. Epub 2022 Feb 24.

GSK R&D, Stevenage, UK.

On 11th March 2020, the UK government announced plans for the scaling of COVID-19 testing, and on 27th March 2020 it was announced that a new alliance of private sector and academic collaborative laboratories were being created to generate the testing capacity required. The Cambridge COVID-19 Testing Centre (CCTC) was established during April 2020 through collaboration between AstraZeneca, GlaxoSmithKline, and the University of Cambridge, with Charles River Laboratories joining the collaboration at the end of July 2020. The CCTC lab operation focussed on the optimised use of automation, introduction of novel technologies and process modelling to enable a testing capacity of 22,000 tests per day. Here we describe the optimisation of the laboratory process through the continued exploitation of internal performance metrics, while introducing new technologies including the Heat Inactivation of clinical samples upon receipt into the laboratory and a Direct to PCR protocol that removed the requirement for the RNA extraction step. We anticipate that these methods will have value in driving continued efficiency and effectiveness within all large scale viral diagnostic testing laboratories.
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http://dx.doi.org/10.1038/s41598-022-06873-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8873195PMC
February 2022

Prognostic Value of the Neurological Pupil Index in Patients With Acute Subarachnoid Hemorrhage.

J Neuroophthalmol 2022 06 15;42(2):256-259. Epub 2022 Feb 15.

Department of Ophthalmology (RAS, PSG, VB, NJN, BBB), Emory University School of Medicine, Atlanta, Georgia; Department of Neurology (VB, NJN), Emory University School of Medicine, Atlanta, Georgia; Department of Neurological Surgery (OBS, NJN), Emory University School of Medicine, Atlanta, Georgia and Department of Epidemiology (BBB), Emory University School of Medicine, Atlanta, Georgia.

Background: The Neurological Pupil index (NPi) provides a quantitative assessment of pupil reactivity and may have prognostic value in patients with subarachnoid hemorrhage (SAH). We aimed to explore associations between the NPi and clinical outcomes in patients with SAH.

Methods: A retrospective analysis of 79 consecutive patients with acute SAH. Age, sex, Acute Physiology and Chronic Health Evaluation-II score, and respiratory failure and NPi in each eye were recorded at admission. The primary outcomes included death and poor clinical outcome (defined as inpatient death, care withdrawal, or discharge Glasgow Outcome Score <4). Groups were compared using the Fisher exact test, and predictive models developed with fast-and-frugal trees (FFTs).

Results: A total of 53 patients were included: 21 (40%) had poor clinical outcomes and 2 (4%) died. Univariate analysis found that only APACHE-II score (P < 0.001) and respiratory failure (P = 0.04) were significantly associated with poor clinical outcomes. NPi was lower among patients with poor clinical outcomes (mean 4.3 in the right eye and 4.2 in the left eye) vs those without (mean 4.5 in the right eye and 4.5 in the left eye), but neither was significant. However, the most accurate FFTs for death and poor clinical outcome included NPi after accounting for age in the death FFT and APACHE-II score in the poor outcome FFT (sensitivity [sn] = 100%, specificity [sp] = 94%, and accuracy (ac) = 94% in a model for death; sn = 100%, sp = 50%, and ac = 70%) in a model for poor clinical outcome.

Conclusions: Our study supports the NPi as a useful prognostic marker for poor outcomes in acute SAH after accounting for age and APACHE-II score.
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http://dx.doi.org/10.1097/WNO.0000000000001474DOI Listing
June 2022

Association of Race, Ethnicity, and Socioeconomic Status With Esthesioneuroblastoma Presentation, Treatment, and Survival.

OTO Open 2022 Jan-Mar;6(1):2473974X221075210. Epub 2022 Feb 9.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Irving Medical Center, NewYork-Presbyterian Hospital, New York, New York, USA.

Objective: Socioeconomic and other demographic factors are associated with outcomes in head and neck cancer. This study uses a national cancer database to explore how patient race, ethnicity, and socioeconomic status (SES) are associated with esthesioneuroblastoma outcomes, including 5-year disease-specific survival (DSS), conditional DSS, stage at diagnosis, and treatment.

Study Design: Retrospective cohort analysis.

Setting: Patients with esthesioneuroblastomas between 1973 and 2015 from the SEER registry (Surveillance, Epidemiology, and End Results).

Methods: The National Cancer Institute Yost Index, a census tract-level composite score composed of 7 parameters, was used to categorize the SES of patients. Kaplan-Meier analysis and Cox regression were conducted to assess DSS. Conditional DSS was calculated per estimates from simplified Cox models. Logistic regression was conducted to identify risk factors for advanced cancer stage at diagnosis and the likelihood of receiving multimodal therapy.

Results: Complete data were included for 561 patients. DSS was significantly associated with SES (log-rank, < .01) but not race. According to Cox regression, DSS was worse for the lowest SES tertile vs the highest (hazard ratio, 1.70 [95% CI, 1.05-2.75]; = .03). Patients of the lowest SES tertile exhibited an increased risk of advanced cancer stage at diagnosis as compared with the highest SES tertile (odds ratio, 1.84 [95% CI, 1.06-3.30]; = .035). Black patients (odds ratio, 0.44 [95% CI, 0.24-0.84]; = .011) were less likely than other patients to receive multimodal therapy. SES alone was not associated with receiving multimodal therapy.

Conclusion: SES is significantly associated with DSS and conditional DSS for patients with esthesioneuroblastomas. Inequalities in access to care and treatment likely contribute to these disparities.
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http://dx.doi.org/10.1177/2473974X221075210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841922PMC
February 2022

Impact of Medicaid Expansion on Rhinologic Cancer Presentation, Treatment, and Outcomes.

Laryngoscope 2022 Feb 11. Epub 2022 Feb 11.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York-Presbyterian/Columbia University Irving Medical Center, New York, New York, U.S.A.

Objective: The United States Patient Protection and Affordable Care Act allocated funds for states to expand Medicaid coverage. However, several states declined expansion. We aim to determine whether Medicaid expansion is associated with healthcare coverage, cancer stage at diagnosis, treatment, and survival among patients with rhinologic cancer. Rhinologic cancer was defined to include cancer of the nasal cavity, paranasal sinus, nasopharynx, or olfactory nerve.

Study Design: Cohort study.

Methods: Patients diagnosed with primary rhinologic malignancies between 2007 to 2016 were extracted from the National Cancer Institute Surveillance, Epidemiology, End Results (SEER) registry. Patients were grouped by diagnosis before and after 2014 (when Medicaid expansion became effective) and whether their state had expanded Medicaid. Multivariable logistic regression controlling for age, sex, race, ethnicity, and income/education was utilized to examine associations between Medicaid expansion/insurance status and stage at diagnosis, treatment, and survival. Overall and disease-specific survival were examined using Kaplan-Meier analysis.

Results: Analysis included 10,164 patients. The proportion of uninsured patients decreased after 2014 (2.4%) compared to before 2014 (4.8%, P < .001). After 2014, patients in nonexpanded states were more likely to be diagnosed with advanced stage disease compared to patients in expanded states (N = 2,364; OR = 1.27, 95% CI 1.01-1.60). Being uninsured in any state was associated with advanced stage disease at diagnosis (OR = 1.75, 95% CI 1.41-2.22) and increased risk of disease-specific death (HR = 1.54, 95% CI 1.32-1.82). Survival measures were not associated with diagnosis before versus after 2014 or Medicaid expansion.

Conclusions: Patients lacking insurance or residing in nonexpanded states may be more likely to present with advanced stage rhinologic cancer. Longitudinal studies should validate these findings.

Level Of Evidence: Level 3 Laryngoscope, 2022.
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http://dx.doi.org/10.1002/lary.30049DOI Listing
February 2022

Targeting Bcl6 in the TREX1 D18N murine model ameliorates autoimmunity by modulating T-follicular helper cells and germinal center B cells.

Eur J Immunol 2022 05 15;52(5):825-834. Epub 2022 Feb 15.

Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation and Regenerative Medicine (CIIR), University of Virginia, Charlottesville, Virginia, United States.

The Three Prime Repair EXonuclease I (TREX1) is critical for degrading post-apoptosis DNA. Mice expressing catalytically inactive TREX1 (TREX1 D18N) develop lupus-like autoimmunity due to chronic sensing of undegraded TREX1 DNA substrates, production of the inflammatory cytokines, and the inappropriate activation of innate and adaptive immunity. This study aimed to investigate Thelper (Th) dysregulation in the TREX1 D18N model system as a potential mechanism for lupus-like autoimmunity. Comparison of immune cells in secondary lymphoid organs, spleen and peripheral lymph nodes (LNs) between TREX1 D18N mice and the TREX1 null mice revealed that the TREX1 D18N mice exhibit a Th1 bias. Additionally, the T-follicular helper cells (Tfh) and the germinal celter (GC) B cells were also elevated in the TREX1 D18N mice. Targeting Bcl6, a lineage-defining transcription factor for Tfh and GC B cells, with a commercially available Bcl6 inhibitor, FX1, attenuated Tfh, GC, and Th1 responses, and rescued TREX1 D18N mice from autoimmunity. The study presents Tfh and GC B-cell responses as potential targets in autoimmunity and that Bcl6 inhibitors may offer therapeutic approach in TREX1-associated or other lupus-like diseases.
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http://dx.doi.org/10.1002/eji.202149324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089306PMC
May 2022

Targeting Regulatory T Cells for Therapy of Lupus Nephritis.

Front Pharmacol 2021 6;12:806612. Epub 2022 Jan 6.

Center for Immunity, Inflammation and Regenerative Medicine (CIIR), Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, United States.

Lupus glomerulonephritis (LN) is a complex autoimmune disease characterized by circulating autoantibodies, immune-complex deposition, immune dysregulation and defects in regulatory T cell (Tregs). Treatment options rely on general immunosuppressants and steroids that have serious side effects. Approaches to target immune cells, such as B cells in particular, has had limited success and new approaches are being investigated. Defects in Tregs in the setting of autoimmunity is well known and Treg-replacement strategies are currently being explored. The aim of this minireview is to rekindle interest on Treg-targeting strategies. We discuss the existing evidences for Treg-enhancement strategies using key cytokines interleukin (IL)-2, IL-33 and IL-6 that have shown to provide remission in LN. We also discuss strategies for indirect Treg-modulation for protection from LN.
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http://dx.doi.org/10.3389/fphar.2021.806612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775001PMC
January 2022

Sequence-dependent structural properties of B-DNA: what have we learned in 40 years?

Biophys Rev 2021 Dec 13;13(6):995-1005. Epub 2021 Nov 13.

Computational Biophysics Group, Department of Biological Sciences, CENUR Litoral Norte, Universidad de la República, Salto, Uruguay.

The structure of B-DNA, the physiological form of the DNA molecule, has been a central topic in biology, chemistry and physics. Far from uniform and rigid, the double helix was revealed as a flexible and structurally polymorphic molecule. Conformational changes that lead to local and global changes in the helix geometry are mediated by a complex choreography of base and backbone rearrangements affecting the ability of the B-DNA to recognize ligands and consequently on its functionality. In this sense, the knowledge obtained from the sequence-dependent structural properties of B-DNA has always been thought crucial to rationalize how ligands and, most notably, proteins recognize B-DNA and modulate its activity, i.e. the structural basis of gene regulation. Honouring the anniversary of the first high-resolution X-ray structure of a B-DNA molecule, in this contribution, we present the most important discoveries of the last 40 years on the sequence-dependent structural and dynamical properties of B-DNA, from the early beginnings to the current frontiers in the field.
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http://dx.doi.org/10.1007/s12551-021-00893-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724355PMC
December 2021

Morphological and functional adaptation of pancreatic islet blood vessels to insulin resistance is impaired in diabetic db/db mice.

Biochim Biophys Acta Mol Basis Dis 2022 04 8;1868(4):166339. Epub 2022 Jan 8.

Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Life Science Center of Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), 1-7-1, Ohte-machi, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address:

The pancreatic islet vasculature is of fundamental importance to the β-cell response to obesity-associated insulin resistance. To explore islet vascular alterations in the pathogenesis of type 2 diabetes, we evaluated two insulin resistance models: ob/ob mice, which sustain large β-cell mass and hyperinsulinemia, and db/db mice, which progress to diabetes due to secondary β-cell compensation failure for insulin secretion. Time-dependent changes in islet vasculature and blood flow were investigated using tomato lectin staining and in vivo live imaging. Marked islet capillary dilation was observed in ob/ob mice, but this adaptive change was blunted in db/db mice. Islet blood flow volume was augmented in ob/ob mice, whereas it was reduced in db/db mice. The protein concentrations of total and phosphorylated endothelial nitric oxide synthase (eNOS) at Ser1177 were increased in ob/ob islets, while they were diminished in db/db mice, indicating decreased eNOS activity. This was accompanied by an increased retention of advanced glycation end-products in db/db blood vessels. Amelioration of diabetes by Elovl6 deficiency involved a restoration of capillary dilation, blood flow, and eNOS phosphorylation in db/db islets. Our findings suggest that the disability of islet capillary dilation due to endothelial dysfunction impairs local islet blood flow, which may play a role in the loss of β-cell function and further exacerbate type 2 diabetes.
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http://dx.doi.org/10.1016/j.bbadis.2022.166339DOI Listing
April 2022

Time-to-event prediction using survival analysis methods for Alzheimer's disease progression.

Alzheimers Dement (N Y) 2021 31;7(1):e12229. Epub 2021 Dec 31.

The Pennsylvania State University Malvern Pennsylvania USA.

Introduction: Many research studies have well investigated Alzheimer's disease (AD) detection and progression. However, the continuous-time survival prediction of AD is not yet fully explored to support medical practitioners with predictive analytics. In this study, we develop a survival analysis approach to examine interactions between patients' inherent temporal and medical patterns and predict the probability of the AD next stage progression during a time period. The likelihood of reaching the following AD stage is unique to a patient, helping the medical practitioner analyze the patient's condition and provide personalized treatment recommendations ahead of time.

Methodologies: We simulate the disease progression based on patient profiles using non-linear survival methods-non-linear Cox proportional hazard model (Cox-PH) and neural multi-task logistic regression (N-MTLR). In addition, we evaluate the concordance index (C-index) and Integrated Brier Score (IBS) to describe the evolution to the next stage of AD. For personalized forecasting of disease, we also developed deep neural network models using the dataset provided by the National Alzheimer's Coordinating Center with their multiple-visit details between 2005 and 2017.

Results: The experiment results show that our N-MTLR based survival models outperform the CoxPH models, the best of which gives Concordance-Index of 0.79 and IBS of 0.09. We obtained 50 critical features out of 92 by applying recursive feature elimination and random forest techniques on the clinical data; the top ones include normal cognition and behavior, criteria for dementia, community affairs, etc. Our study demonstrates that selecting critical features can improve the effectiveness of probabilities at each time interval.

Conclusions: The proposed deep learning-based survival method and model can be used by medical practitioners to predict the patients' AD shift efficiently and recommend personalized treatment to mitigate or postpone the effects of AD. More generally, our proposed survival analysis approach for predicting disease stage shift can be used for other progressive diseases such as cancer, Huntington's disease, and scleroderma, just to mention a few, using the corresponding clinical data.
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http://dx.doi.org/10.1002/trc2.12229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719343PMC
December 2021
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