Greater COVID-19 Severity and Mortality in Hospitalized Patients in the Delta-phase Compared to the Others: A Single Center Prospective Registry.

BACKGROUND AND OBJECTIVE: To compare clinical and laboratory features, and outcomes in the second COVID-19 phase (delta variant) with the first and third phases in India we performed a registry-based study. METHODS: Patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were recruited over the study period from March 2020 to July 2022. In the first phase (wild type, March-December 2020) of the 7,476 suspected, 1,395 (18.7%) were positive and 863 (61.8%) were hospitalized, in the second phase (delta, January-July 2021) out of 8,680 suspected, 1,641 (19.4%) tested positive and 388 (23.6%) were hospitalized, and in the third phase (omicron, January-July 2022) out of 5,188 suspected patients, 886 (17.1%) tested positive and 94 (10.6%) were hospitalized. We compared details of admission clinical and laboratory features and in-hospital management and outcomes in the three phases. RESULTS: A total of 2,352 patients were recruited. The majority of the patients were men, aged <45 years were 20% and about 20% of patients had hypertension, diabetes, and cardiovascular diseases. Patients in the second phase had significantly more cough, fever, shortness of breath, and lower oxygen saturation (SpO2) at admission and also had more lymphopenia, C-reactive proteins (CRPs), interleukin-6, ferritin, lactic dehydrogenase, and transaminases than patients in the other two phases. In the second vs the first and third phases, the requirement of supplementary oxygen (47.9 vs 33.1 and 23.4%), proning (89.2 vs 37.1 and 5.3%), high flow nasal oxygen (15.7 vs 8.71 and 5.3%), noninvasive ventilation (14.4 vs 9.1 and 11.7%), invasive ventilation (16.2 vs 9.1 and 9.6%), steroids (94.1 vs 83.4 and 37.2%), remdesivir (91.2 vs 73.8 and 39.4%), and anticoagulants (94.3 vs 83.0 and 61.7%) was significantly more (p < 0.001). The median length of stay in days [interquartile range (IQR)] was longer in the second phase [8 (6-10)] vs the first [7 (5-10)] and the third phase [4 (3-6) days]. The intensive care unit (ICU) stay in the second phase [9 (5-13) days] was also significantly more than the first [6 (2-10)] and third [0 (0-3)] phases (p <0.001). Overall, in-hospital deaths occurred in 176 patients (12.8%). Deaths were significantly higher in the second phase (19.3%), compared to the first (11.0%) and the third (3.3%) phases (p <0.01). We also observed that greater disease severity at presentation was associated with higher mortality in all the phases. CONCLUSION: This study shows that COVID-19 patients that were hospitalized in the second (delta) phase of the epidemic had more severe disease compared to the first and third phases. In the second phase of patients, there was a significantly higher duration of hospitalization, ICU hospitalization, greater oxygen requirement, noninvasive and invasive ventilatory support, and more deaths.

Biomarkers and outcomes in hospitalised patients with COVID-19: a prospective registry.

OBJECTIVES: To determine association of biomarkers-high-sensitivity C reactive protein (hsCRP), D-dimer, interleukin-6 (IL-6), lactic dehydrogenase (LDH), ferritin and neutrophil-lymphocyte ratio (NLR)-at hospitalisation with outcomes in COVID-19. DESIGN AND SETTING: Tertiary-care hospital based prospective registry. PARTICIPANTS: Successive virologically confirmed patients with COVID-19 hospitalised from April 2020 to July 2021 were prospectively recruited. Details of clinical presentation, investigations, management and outcomes were obtained. PRIMARY AND SECONDARY OUTCOME MEASURES: All biomarkers were divided into tertiles to determine associations with clinical features and outcomes. Primary outcome was all-cause deaths and secondary outcome was oxygen requirement, non-invasive and invasive ventilation, dialysis, duration of stay in ICU and hospital. Numerical data are presented in median and interquartile range (IQR 25-75). Univariate and multivariate (age, sex, risk factors, comorbidities, treatments) ORs and 95% CIs were calculated. RESULTS: 3036 virologically confirmed patients with COVID-19 were detected and 1251 hospitalised. Men were 70.0%, aged >60 years 44.8%, hypertension 44.1%, diabetes 39.6% and cardiovascular disease 18.9%. Median symptom duration was 5 days (IQR 4-7) and oxygen saturation 95% (90%-97%). Total white cell count was 6.9×109/L (5.0-9.8), neutrophils 79.2% (68.1%-88.2%), lymphocytes 15.8% (8.7%-25.5%) and creatinine 0.93 mg/dL (0.78-1.22). Median (IQR) for biomarkers were hsCRP 6.9 mg/dL (2.2-18.9), D-dimer 464 ng/dL (201-982), IL-6 20.1 ng/dL (6.5-60.4), LDH 284 mg/dL (220-396) and ferritin 351 mg/dL (159-676). Oxygen support at admission was in 38.6%, subsequent non-invasive or invasive ventilatory support in 11.0% and 11.6%, and haemodialysis in 38 (3.1%). 173 (13.9%) patients died and 15 (1.2%) transferred to hospice care. For each biomarker, compared with the first, those in the second and third tertiles had more clinical and laboratory abnormalities, and oxygen, ventilatory and dialysis support. Multivariate-adjusted ORs (95% CI) for deaths in second and third versus first tertiles, respectively, were hsCRP 2.24 (1.11 to 4.50) and 12.56 (6.76 to 23.35); D-dimer 3.44 (1.59 to 7.44) and 14.42 (7.09 to 29.30); IL-6 2.56 (1.13 to 5.10) and 10.85 (5.82 to 20.22); ferritin 2.88 (1.49 to 5.58) and 8.19 (4.41 to 15.20); LDH 1.75 (0.81 to 3.75) and 9.29 (4.75 to 18.14); and NLR 3.47 (1.68 to 7.14) and 17.71 (9.12 to 34.39) (p<0.001). CONCLUSION: High levels of biomarkers-hsCRP, D-dimer, IL-6, LDH, ferritin and NLR-in COVID-19 are associated with more severe illness and higher in-hospital mortality. NLR, a widely available investigation, provides information similar to more expensive biomarkers.

Characterization of solution stress degradation products of aliskiren and prediction of their physicochemical and ADMET properties.

Forced degradation studies on aliskiren were carried out according to ICH and WHO guidelines. Six degradation products were formed in total in the solution state. Their separation among themselves and from the drug was successfully achieved on a C-18 column utilizing acetonitrile and phosphate buffer (pH 3.0) in the mobile phase, which was run in a gradient mode. To characterize them, a complete mass fragmentation pathway of the drug was first established with the help of MS/TOF and MSn data. This was followed by LC-MS/TOF studies on the degradation products. Some of the degradation products were also isolated and subjected to 1D (1H, 13C and DEPT-135) and 2D (COSY, HSQC and HMBC) NMR studies for confirmation of their structures. An interesting observation was hydrolysis followed by cyclization in case of three degradation products. Also, acetonitrile was found to react with aliskiren, leading to formation of a pseudo degradation product. Additionally, comparative ADMET properties of the drug and degradation products were established using ADMET Predictor™.

Evaluation Series on Safety and Efficacy of Nutritional Supplements in Newly Diagnosed Hyperglycemia: A Placebo-Controlled, Randomized Study.

BACKGROUND: Diabetes is endemic with developing economies contributing to the bulk of this pandemic. Despite the evidence of incremental benefit of glycemic control starting early in life, acceptance of and adherence to modern medications remain suboptimal. AIMS: To determine the hemoglobin A1c (HbA1c)-lowering efficacy and safety of nutritional supplement, PreCrea(®), in adult Indians with newly diagnosed hyperglycemia. MATERIALS AND METHODS: Double-blind, randomized study conducted in six diabetes centers in India. A total of 193 treatment-naïve subjects with newly diagnosed hyperglycemia and fasting plasma glucose (FPG) >100 mg/dL were randomized into either PreCrea(®) 600 mg (n = 90) or matched placebo (n = 89) capsules twice daily, along with lifestyle modification, for 12 weeks. The main outcomes were changes in HbA1c and FPG levels, attainment of the American Diabetes Association (ADA)-defined goals for HbA1c, and clinical and biochemical measures of safety. RESULTS: At 12 weeks, mean HbA1c in PreCrea(®) group reduced by 0.91% compared with 0.08% increase in the placebo group (P < .001). The reductions in the mean FPG at week 4 (P < .001) and week 12 (P = 0.04) were significant compared to the baseline. ADA goal of HbA1c <7% increased from 15.5% at the baseline to 35.6% at week 12 in PreCrea(®) subjects. Clinical safety and biochemical safety did not change. Hypoglycemia and weight gain were not observed with PreCrea(®). CONCLUSIONS: Nearly 1% point reduction in HbA1c at week 12 with PreCrea(®) is comparable with most first-line glucose-lowering drugs. The safety and tolerability of PreCrea(®) highlights its potential as a first-line therapy in newly detected hyperglycemia.

Adult rumination syndrome: Differentiation from psychogenic intractable vomiting.

Rumination syndrome is known to exist in infants and mentally retarded adults since long time. In past few years, some reports appeared that showed its existence in adult patients also. It is frequently confused with the intractable vomiting in adults and misdiagnosis leads to delay in appropriate management. We are here describing the case of a female patient with rumination syndrome where specific points in the history delineated the presence of this illness and helped in appropriate management. The patient became symptom free soon after the diagnosis was reached.

Influence of specific anions on the orientational ordering of thermotropic liquid crystals at aqueous interfaces.

We report that specific anions (of sodium salts) added to aqueous phases at molar concentrations can trigger rapid, orientational ordering transitions in water-immiscible, thermotropic liquid crystals (LCs; e.g., nematic phase of 4'-pentyl-4-cyanobiphenyl, 5CB) contacting the aqueous phases. Anions classified as chaotropic, specifically iodide, perchlorate, and thiocyanate, cause 5CB to undergo continuous, concentration-dependent transitions from planar to homeotropic (perpendicular) orientations at LC-aqueous interfaces within 20 s of addition of the anions. In contrast, anions classified as relatively more kosmotropic in nature (fluoride, sulfate, phosphate, acetate, chloride, nitrate, bromide, and chlorate) do not perturb the LC orientation from that observed without added salts (i.e., planar orientation). Surface pressure-area isotherms of Langmuir films of 5CB supported on aqueous salt solutions reveal ion-specific effects ranking in a manner similar to the LC ordering transitions. Specifically, chaotropic salts stabilized monolayers of 5CB to higher surface pressures and areal densities (12.6 mN/m at 27 Å(2)/molecule for NaClO(4)) and thus smaller molecular tilt angles (30° from the surface normal for NaClO(4)) than kosmotropic salts (5.0 mN/m at 38 Å(2)/molecule with a corresponding tilt angle of 53° for NaCl). These results and others reported herein suggest that anion-specific interactions with 5CB monolayers lead to bulk LC ordering transitions. Support for the proposition that these ion-specific interactions involve the nitrile group was obtained by using a second LC with nitrile groups (E7; ion-specific effects similar to 5CB were observed) and a third LC with fluorine-substituted aromatic groups (TL205; weak dipole and no ion-specific effects were measured). Finally, we also establish that anion-induced orientational transitions in micrometer-thick LC films involve a change in the easy axis of the LC. Overall, these results provide new insights into ionic phenomena occurring at LC-aqueous interfaces, and reveal that the long-range ordering of LC oils can amplify ion-specific interactions at these interfaces into macroscopic ordering transitions.

Hypoglycemia in patients with type 2 diabetes from India and Malaysia treated with sitagliptin or a sulfonylurea during Ramadan: a randomized, pragmatic study.

OBJECTIVE: To compare the incidence of symptomatic hypoglycemia between sitagliptin and sulfonylurea in Muslim patients with type 2 diabetes who fasted during Ramadan. METHODS: In a multicenter, pragmatic, randomized study, patients with type 2 diabetes were recruited from clinical centers in India (n = 765) and Malaysia (n = 105). Eligible patients (age ≥ 18 yrs) expressed their intention to daytime fast during Ramadan, were treated with a stable dose of sulfonylurea with or without metformin for ≥3 months prior to screening visit, and had an HbA(1c) ≤ 10%. Patients were randomized in a 1:1 ratio to either switch to sitagliptin 100 mg q.d. or remain on their pre-study sulfonylurea. Daily diary cards were completed to document information on hypoglycemic symptoms and complications. The primary endpoint was the overall incidence of symptomatic hypoglycemia during Ramadan. RESULTS: Of the 870 patients randomized, 848 (n = 421 for sitagliptin and 427 for sulfonylurea) returned ≥1 completed diary card and were included in the analysis. The proportion of patients who recorded ≥1 symptomatic hypoglycemic event during Ramadan was lower with sitagliptin (3.8%) compared to sulfonylurea (7.3%). The risk of symptomatic hypoglycemia was significantly lower with sitagliptin (risk ratio [95% CI] = 0.52 [0.29, 0.94]; p = 0.028). By country, the proportions of patients who recorded ≥1 symptomatic hypoglycemic event during Ramadan were 4.1% vs. 7.7% in India and 1.9% vs. 3.8% in Malaysia for sitagliptin and sulfonylurea, respectively. No patient discontinued treatment due to a hypoglycemic event. One patient on sitagliptin and seven on sulfonylurea had an event that required non-medical assistance. No events required medical assistance. Both treatments were generally well tolerated. LIMITATIONS: Symptomatic hypoglycemic events did not require a confirmatory blood glucose measurement, which may have overestimated hypoglycemic events. Measures of glycemic control and body weight were not assessed. CONCLUSION: Switching antihyperglycemic treatment to sitagliptin from a sulfonylurea reduced the risk of symptomatic hypoglycemia by approximately 50% for Muslim patients with type 2 diabetes who fasted during Ramadan. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT01340768.

Influence of simple electrolytes on the orientational ordering of thermotropic liquid crystals at aqueous interfaces.

We report orientational anchoring transitions at aqueous interfaces of a water-immiscible, thermotropic liquid crystal (LC; nematic phase of 4'-pentyl-4-cyanobiphenyl (5CB)) that are induced by changes in pH and the addition of simple electrolytes (NaCl) to the aqueous phase. Whereas measurements of the zeta potential on the aqueous side of the interface of LC-in-water emulsions prepared with 5CB confirm pH-dependent formation of an electrical double layer extending into the aqueous phase, quantification of the orientational ordering of the LC leads to the proposition that an electrical double layer is also formed on the LC-side of the interface with an internal electric field that drives the LC anchoring transition. Further support for this conclusion is obtained from measurements of the dependence of LC ordering on pH and ionic strength, as well as a simple model based on the Poisson-Boltzmann equation from which we calculate the contribution of an electrical double layer to the orientational anchoring energy of the LC. Overall, the results presented herein provide new fundamental insights into ionic phenomena at LC-aqueous interfaces, and expand the range of solutes known to cause orientational anchoring transitions at LC-aqueous interfaces beyond previously examined amphiphilic adsorbates.

Design of Biomolecular Interfaces using Liquid Crystals Containing Oligomeric Ethylene Glycol.

We report an investigation of nematic LCs formed from miscible mixtures of 4-cyano-4'-pentylbiphenyl (5CB) and 2-(2-[2-{2-(2,3-difluoro-4-{4-(4-trans-pentylcyclohexyl)-phenyl-phenoxy)ethoxy}ethoxy]ethoxy)ethanol (EG4-LC), the latter being a mesogen with a tetra(ethylene glycol) tail. Quantitative characterization of the ordering of this LC mixture at biologically-relevant aqueous interfaces revealed that addition of EG4-LC (1-5% by weight) to 5CB causes a continuous transition in the ordering of the LC from a planar (pure 5CB) to a perpendicular (homeotropic) orientation. The homeotropic ordering is also seen in aqueous dispersions of micrometer-sized droplets of the LC mixture, which exhibit enhanced stability against coalescence. These observations and others, all of which suggest partitioning of the EG4-LC from the bulk of the LC to its aqueous interface, were complemented by measurements of the adsorption of bovine serum albumin (BSA) to the aqueous-LC interface. Whereas adsorption of BSA to the interface of a LC mixture containing 1% wt/wt of EG4-LC triggered an ordering transition, higher concentrations of EG4-LC (>2% wt/wt) prevented this ordering transition, consistent with a decrease in adsorption of BSA. This conclusion is supported by epifluorescence measurements using fluorescently labeled BSA and comparisons to LC interfaces at which EG4-containing lipids are adsorbed. Overall, these results demonstrate a general and facile approach to the design of LCs with interfaces that present biologically relevant chemical functional groups, assume well-defined orientations at aqueous interfaces, and lower non-specific protein adsorption. The bulk of the LC serves as a reservoir of EG4-LC, thus permitting easy preparation of these interfaces and the potential for spontaneous repair of the EG4-decorated interfaces during contact with biological systems.

Characterization of adsorbate-induced ordering transitions of liquid crystals within monodisperse droplets.

The ordering of liquid crystals (LCs) within micrometer-sized droplets is known to depend strongly on the presence of interfacial adsorbates, although the exact sequence of ordered equilibrium states that accompany a change in interfacial anchoring from tangential to perpendicular has not been established. In this paper, we report use of a methodology that permits the preparation of monodisperse LC droplets in aqueous phases to investigate ordering transitions in the LC droplets that accompany the adsorption of amphiphiles at the aqueous-LC droplet interface. By using an amphiphile that undergoes reversible adsorption at the aqueous-LC interface (sodium dodecylsulfate, SDS), we identified six distinct topologically ordered states of the LC droplets as a function of increasing concentration of SDS. We exploited the reversible adsorption of the SDS to LC droplets with diameters of 8.0+/-0.2 microm to confirm that these topological states are equilibrium ones. We also exposed LC droplets to a continuous gradient in concentration of SDS to document the continuous transitions between topological states and to confirm the absence of additional, intermediate topological states. The formation of the LC droplets as aqueous dispersions also enabled an investigation of ordering transitions in LC droplets driven by biomolecular interactions. Surprisingly, enzymatic hydrolysis of the phospholipid L-dipalmitoyl phosphatidylcholine (L-DLPC) by phospholipase A2 at the interfaces of the LC droplets was observed to trigger the same progression of topologically ordered states of the LC as was observed with SDS. Overall, the results presented in this paper resolve prior conflicting data in the literature by providing an unambiguous set of observations regarding topologically ordered states encountered in LC droplets. This paper provides a data set against which future theories and simulations of LCs can be compared to develop a fundamental understanding of the competition between volumetric and interfacial effects in droplets. The results also suggest that topological ordering transitions in LC droplets can be exploited to report interfacial enzymatic reactions.

Principles for manipulation of the lateral organization of aqueous-soluble surface-active molecules at the liquid crystal-aqueous interface.

We report an investigation of the lateral organization of water-soluble, surface-active molecules within monolayers formed spontaneously at interfaces between aqueous phases and immiscible, micrometer-thick films of nematic liquid crystals (LCs; 4'-pentyl-4-cyanobiphenyl and TL205, a mixture of cyclohexanefluorinated biphenyls and fluorinated terphenyls). Using both anionic (sodium dodecyl sulfate) and cationic (dodecyltrimethylammonium bromide) surfactants, we demonstrate that the nematic order of the LCs can direct monolayers of surfactant in dynamic equilibria with bulk aqueous solutions to phase separate and assume lateral organizations at the interfaces of the LCs that are not seen in the absence of the nematic order. The lateral organization of the surfactants is readily evidenced by the patterned orientations assumed by the LCs and can be manipulated reversibly by changes in the bulk concentrations of the surfactants. Experimental observations of the effects of bulk surfactant concentration, thickness of the film of LC, nematic order, and aqueous electrolyte concentration are placed within the framework of a simple thermodynamic model. The model incorporates the dynamic equilibration of surfactant between the bulk and interface as well as the coupling between the elasticity of nematic LCs and the lateral organization of the water-soluble surfactants within the monolayers. Qualitative agreement is found between the model predictions and experimental observations, thus supporting our conclusion that LCs offer the basis of general and facile methods to direct the lateral organization of interfacial molecular assemblies.

Size-dependent ordering of liquid crystals observed in polymeric capsules with micrometer and smaller diameters.

Made to order: Aqueous dispersions of polymer-encapsulated liquid crystal (LC) droplets were synthesized with precise interfacial chemistry and sizes in the micrometer-to-sub-micrometer range. Size-dependent changes in LC ordering could be observed. Study of the competition between size and interfacial chemistry on LC ordering enables size-dependent properties of LC droplets to be exploited in applications such as photonics and sensing.

Characterization of the growth of polyelectrolyte multilayers formed at interfaces between aqueous phases and thermotropic liquid crystals.

Polyelectrolyte multilayers (PEMs) formed at interfaces between aqueous solutions and thermotropic (water-immiscible) liquid crystals (LCs) offer the basis of a new method to tailor the nanometer-scale structure and chemical functionality of these interfaces. Toward this end, we report a study that compares the growth of PEMs formed at mobile and deformable interfaces defined by LCs relative to growth observed at model (rigid) solid surfaces. Experiments aimed at determining if polyelectrolytes such as poly(sodium-4-styrenesulfonate) (PSS) can partition from the aqueous phase into the bulk of the LC yielded no evidence of such partitioning. Whereas measurements of the growth of PEMs formed from poly(allylamine hydrochloride) (PAH) and PSS at the aqueous-LC interface revealed growth characteristics similar to those measured at both hydrophobic and hydrophilic interfaces of solids, the growth of PEMs from PAH and poly(acrylic acid) (PAA) at the aqueous-LC interface was found to differ substantially from the solids investigated: (i) the linear growth of PEMs of PAH/PAA that was measured at the aqueous-LC interface under conditions that did not lead to the growth of PEMs at the interface of octadecyltrichlorosilane (OTS)-treated glass (a hydrophobic solid surface), and (ii) in comparison to the growth of PEMs of PAH/PAA at the surface of glass (a hydrophilic charged surface), a higher rate of growth was observed at the aqueous-LC interface. The finding that the growth rate of PEMs of PAH/PAA at aqueous-LC interfaces is greater than on solid surfaces is supported by additional measurements of growth as a function of pH. Finally, the pH-triggered reorganization of PAH/PAA PEMs supported at the aqueous-LC interface led to changes in the order and optical properties of the LC. These data are discussed in light of the nature of aqueous-LC interfaces, including the mobility and deformability of the interface and recent measurements of the zeta-potentials of aqueous-LC interfaces.

Elastic energy-driven phase separation of phospholipid monolayers at the nematic liquid-crystal-aqueous interface.

Experimental measurements and a thermodynamic model reveal that nematic elasticity can induce lateral phase separation of amphiphilic molecules assembled at interfaces between thermotropic liquid crystals (LCs) and immiscible aqueous phases. The morphologies of the phase-separated domains of amphiphiles induced by nematic elasticity are shown to be strongly dependent on the nature of the deformation of the LC. This study provides important insight into the physics that controls the ordering of molecules at interfaces of soft anisotropic materials, and identifies a new mechanism of phase separation at these interfaces.