Seropersistence of SII-ChAdOx1 nCoV-19 (COVID-19 vaccine): 6-month follow-up of a randomized, controlled, observer-blind, phase 2/3 immuno-bridging study in Indian adults.

AZD1222 (ChAdOx1 nCoV-19) is a replication-deficient adenoviral vectored coronavirus disease-19 (COVID-19) vaccine that is manufactured as SII-ChAdOx1 nCoV-19 by the Serum Institute of India Pvt Ltd following technology transfer from Oxford University/AstraZeneca. The non-inferiority of SII-ChAdOx1 nCoV-19 with AZD1222 was previously demonstrated in an observer-blind, phase 2/3 immuno-bridging study (trial registration: CTRI/2020/08/027170). In this analysis of immunogenicity and safety data 6 months post first vaccination (Day 180), 1,601 participants were randomized 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (immunogenicity/reactogenicity cohort n = 401) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort n = 1,200). Immunogenicity was measured by anti-severe acute respiratory syndrome coronavirus 2 spike (anti-S) binding immunoglobulin G and neutralizing antibody (nAb) titers. A decline in anti-S titers was observed in both vaccine groups, albeit with a greater decline in SII-ChAdOx1 nCoV-19 vaccinees (geometric mean titer [GMT] ratio [95% confidence interval (CI) of SII-ChAdOx1 nCoV-19 to AZD1222]: 0.60 [0.41-0.87]). Consistent similar decreases in nAb titers were observed between vaccine groups (GMT ratio [95% CI]: 0.88 [0.44-1.73]). No cases of severe COVID-19 were reported following vaccination, while one case was observed in the placebo group. No causally related serious adverse events were reported through 180 days. No thromboembolic or autoimmune adverse events of special interest were reported. Collectively, these data illustrate that SII-ChAdOx1 nCoV-19 maintained a high level of immunogenicity 6 months post-vaccination. SII-ChAdOx1 nCoV-19 was safe and well tolerated.

Clinical practice guideline-inconsistent management of fever and neutropenia in pediatric oncology: A Children's Oncology Group study.

BACKGROUND: The primary objective was to measure the proportion of episodes where care delivery was inconsistent with selected recommendations of a clinical practice guideline (CPG) on fever and neutropenia (FN) management. The influence of site size on CPG-inconsistent care delivery, and association between patient outcomes and CPG-inconsistent care were described. METHODS: This retrospective, multicenter study included patients less than 21 years old with cancer who were at high risk of poor FN outcomes and were previously enrolled to a Children's Oncology Group (COG) study at participating National Cancer Institute Community Oncology Research Program (NCORP) institutions from January 2014 through December 2015. Patients were randomly selected for chart review by participating sites from a COG-generated list. Care delivered in each episode was adjudicated (CPG-consistent or CPG-inconsistent) against each of five selected recommendations. RESULTS: A total of 107 patients from 22 sites, representing 157 FN episodes, were included. The most common CPG-inconsistent care delivered was omission of pulmonary computerized tomography in patients with persistent FN (60.3%). Of 74 episodes where assessment of four (episodes without persistent FN) or five (episodes with persistent FN) recommendations was possible, CPG-inconsistent care was delivered with respect to at least one recommendation in 63 (85%) episodes. Site size was not associated with CPG-inconsistent care delivery. No statistically significant association between CPG-inconsistent care and fever recurrence was observed. CONCLUSIONS: In this cohort of pediatric patients at high risk of poor FN outcomes, CPG-inconsistent care was common. Opportunities to optimize resource stewardship by boosting supportive care CPG implementation are highlighted.

Hyperbranched polymers: growing richer in flavours with time.

Hyperbranched polymers (HBPs) have been studied for over three decades now; yet several interesting aspects continue to draw the attention of researchers worldwide. This is because of the simplicity of synthesis, their unique globular structure, and the numerous peripherally located functional groups that can be utilised to impart a variety of attributes, such as core-shell amphiphilicity, Janus amphiphilicity, clickable polymeric scaffolds, multifunctional crosslinkers, etc. Several reviews have been written on HBPs with a focus on synthetic strategies, structural diversity, and their potential applications; in this short feature article, we have taken an alternate approach to highlight some of the unique structural features of HBPs and their influence on the properties of HBPs. We also discuss their versatility and adaptability for the generation of several interesting functional polymeric systems. In the latter half, we focus on the utilisation of HBPs as multifunctional scaffolds, that rely on the numerous peripheral terminal groups. We conclude by drawing a structuro-functional analogy between the range of peripherally functionalised HBPs and other analogous, but more complex, polymeric systems. We believe that this review will serve as a visual sounding board that would encourage the development of several other applications for this class of unique polymers.

Amphiphilic Polymer Hydrogel-supported Catalysts: Tuning the Accessibility to the Catalytic Site by Molecular Jacketing.

Crosslinked amphiphilic hydrogels, prepared using a peripherally clickable hyperbranched polyester (HBP) and PEG-diazides of different molecular weights, were used to ligate Cu utilizing the triazole rings formed by the alkyne-azide click reaction. Since only a fraction of the peripheral propargyl groups in the HB polyester are needed to generate the crosslinked polymer, the remaining were clicked with different types of azides, such as MPEG azide, decyl azide or 4-methylbenzyl azide, to create a molecular jacket around the catalytic sites that can potentially influence the catalytic activity and reaction outcome. The crosslinked films ligated with Cu functioned very effectively to catalyse alkyne-azide click reactions, both in water and in organic solvents; the nature of the molecular jacket around the catalytic site had a clear influence the reaction rate, which depended upon the relative solubilities of the reactants. The gel-supported catalyst films were reused multiple times with little loss in catalytic activity.

Genome wide identification and evolutionary analysis of vat like NBS-LRR genes potentially associated with resistance to aphids in cotton.

Nucleotide Binding Site - Leucine Rich Repeat (NBS-LRR) genes play a significant role in plant defense against biotic stresses and are an integral part of signal transduction pathways. Vat gene has been well reported for their role in resistance to Aphis gossypii and viruses transmitted by them. Despite their importance, Vat like NBS-LRR resistance genes have not yet been identified and studied in cotton species. This study report hundreds of orthologous Vat like NBS-LRR genes from the genomes of 18 cotton species through homology searches and the distribution of those identified genes were tend to be clustered on different chromosome. Especially, in a majority of the cases, Vat like genes were located on chromosome number 13 and they all shared two conserved NBS-LRR domains, one disease resistant domain and several repeats of LRR on the investigated cotton Vat like proteins. Gene ontology study on Vat like NBS-LRR genes revealed the molecular functions viz., ADP and protein binding. Phylogenetic analysis also revealed that Vat like sequences of two diploid species, viz., G. arboreum and G. anomalum, were closely related to the sequences of the tetraploids than all other diploids. The Vat like genes of G. aridum and G. schwendimanii were distantly related among diploids and tetraploids species. Various hormones and defense related cis-acting regulatory elements were identified from the 2 kb upstream sequences of the Vat like genes implying their defensive response towards the biotic stresses. Interestingly, G. arboreum and G. trilobum were found to have more regulatory elements than larger genomes of tetraploid cotton species. Thus, the present study provides the evidence for the evolution of Vat like genes in defense mechanisms against aphids infestation in cotton genomes and allows further characterization of candidate genes for developing aphid and aphid transmitted viruses resistant crops through cotton breeding.

A unique bilateral accessory forearm flexor muscle.

Muscular and neurovascular variations in the upper extremity are of utmost clinical significance. Here we report a unique bilateral accessory muscle in the forearm and palm of an 89-year-old male cadaver. The accessory muscle presented two bellies on the right side, one in the forearm, innervated by the anterior interosseous nerve, and the other in the palm, innervated by a branch of the median nerve. A long tendon interconnected the two bellies. On the left side, the muscle had a single belly in the palm, which began at the end of a long tendon that extended from the forearm. However, on both sides, the muscle originated from the posterior surface of the flexor digitorum superficialis belly and inserted along with the first lumbrical muscle into the dorsal digital expansion of the index finger. The proximal parts of the variant muscles were sandwiched between the flexor digitorum muscles. The palmar bellies coursed distally through the carpal canal and lay deep to the superficial palmar arch, and superficial to the first lumbrical, between the thenar muscles and the lateral-most tendon of the flexor digitorum superficialis. Arguably, the accessory muscle might be a variant of a lumbrical muscle, as reported before, but innervation of the proximal belly by the anterior interosseous nerve suggests that the muscle may well be a deep accessory muscle at the forearm, probably appeared as a diverted part of the flexor digitorum profundus. Its space-occupying course through the forearm and palm, especially through the carpal canal, might be clinically significant as it might contribute to nerve compression pathologies in the upper extremity. This accessory muscle also indicates the complex nature of individual muscle formation and evolution of the upper extremity with constant changes in the morphology of muscles based on their changing functions.

Muscle Fatigue Analysis by Visualization of Dynamic Surface EMG Signals Using Markov Transition Field.

Muscle fatigue analysis is important in the diagnosis of neuromuscular diseases. Analysis of surface electromyography (sEMG) signals by non-linear probabilistic approach is useful in studying their transitions and thus the neuromuscular system. In this study, a method to visualize sEMG signals using Markov transition field (MTF) under fatigue conditions is proposed. sEMG signals are acquired from 45 healthy participants during biceps curl exercise. They are filtered and divided into ten equal segments. Markov transition matrix is constructed and corresponding MTF image is generated. The average self-transition probability is extracted and compared for both non-fatigue and fatigue segments. It is observed that the extracted feature shows high statistical significance with p value less than 0.001. The increase in average self-transition probability under fatigue condition correlates with the reduction in the degree of signal complexity. Thus, encoding of sEMG signals to images is helpful in analyzing the complexity of the neuromuscular system. Clinical Relevance- This approach may be helpful in analyzing muscle fatigue related with various myoneural conditions.

Efficacy of add-on Ayurveda and Yoga intervention in health care workers of tertiary care hospital during COVID-19: Randomized controlled trial.

BACKGROUND: The present study aimed to evaluate the safety and prophylactic efficacy of add-on Comprehensive Ayurveda and mindfulness-based Yoga (CAY) regimen to standard care among HealthCare Workers (HCWs) against COVID-19. MATERIALS AND METHODS: This prospective single-blind (outcome assessor-blinded) RCT was conducted in tertiary care hospital in Delhi during July 2020-April 2021. HCWs of both sexes were randomized to add-on CAY intervention or control group. The primary outcomes were the incidence of confirmed COVID-19 positive cases and influenza-like illness events (ILI). Secondary outcomes were anxiety (GAD-7), depression (PHQ-9), and quality of life (SF-36) at the end of 12 weeks. RESULTS: Three hundred fifty-six participants (181 in intervention and 175 in the control group) were randomized. With the modified intention to treat approach, we analyzed 309 participants. The mean age for the intervention and control group was 39.3 ± 10.1 and 36.6 ± 10 years, respectively. Incidence of COVID-19 event was higher in control group compared to CAY group (16 of 164 [9.8%] vs. 11 of 145 [7.6%]; P = 0.50). The incidence of ILI events was also higher in the control group as compared to the CAY group (14 of 164 [8.5%] vs 9 of 145 [6.2%]). The health change domain of the SF-36 questionnaire showed statistically significant improvement in the CAY group as compared to the control group (P < 0.01). CONCLUSION: Incidence of COVID-19 and ILI events was lower in the CAY group compared with the contr ol group, though the difference is not statistically significant.

Machine learning based model for risk prediction after ST-Elevation myocardial infarction: Insights from the North India ST elevation myocardial infarction (NORIN-STEMI) registry.

BACKGROUND: Risk prediction following ST-Elevation Myocardial Infarction (STEMI) in resource limited countries is critical to identify patients at an increased risk of mortality who might benefit from intensive management. METHODS: North India ST-Elevation Myocardial Infarction (NORIN-STEMI) is an ongoing registry that has prospectively enrolled 3,635 STEMI patients. Of these, 3191 patients with first STEMI were included. Patients were divided into two groups: development (n=2668) and validation (unseen) dataset (n=523). Various ML strategies were used to train and tune the model based on validation dataset results that included 31 clinical characteristics. These models were compared in sensitivity, specificity, F1-score, receiver operating characteristic area under the curve (AUC), and overall accuracy to predict mortality at 30 days. ML model decision making was analyzed using the Shapley Additive exPlanations (ShAP) summary plot. RESULTS: At 30 days, the mortality was 7.7%. On the validation dataset, Extra Tree ML model had the best predictive ability with sensitivity: 85%, AUC: 79.7%, and Accuracy: 75%. ShAP interpretable summary plot determined delay in time to revascularization, baseline cardiogenic shock, left ventricular ejection fraction <30%, age, serum creatinine, heart failure on presentation, female sex, and moderate-severe mitral regurgitation to be major predictors of all-cause mortality at 30 days (P<0.001 for all). CONCLUSION: ML models lead to an improved mortality prediction following STEMI. ShAP summary plot for the interpretability of the AI model helps to understand the model's decision in identifying high-risk individuals who may benefit from intensified follow-up and close monitoring.

Cervical cancer diagnosis based on modified uniform local ternary patterns and feed forward multilayer network optimized by genetic algorithm.

Cervical cancer is one of the most common types of cancer for women. Early and accurate diagnosis can save the patient's life. Pap smear testing is nowadays commonly used to diagnose cervical cancer. The type, structure and size of the cervical cells in pap smears images are major factors which are used by specialist doctors to diagnosis abnormality. Various image processing-based approaches have been proposed to acquire pap smear images and diagnose cervical cancer in pap smears images. Accuracy is usually the primary objective in evaluating the performance of these systems. In this paper, a two-stage method for pap smear image classification is presented. The aim of the first stage is to extract texture information of the cytoplasm and nucleolus jointly. For this purpose, the pap smear image is first segmented using the appropriate threshold. Then, a texture descriptor is proposed titled modified uniform local ternary patterns (MULTP), to describe the local textural features. Secondly, an optimized multi-layer feed-forward neural network is used to classify the pap smear images. The proposed deep neural network is optimized using genetic algorithm in terms of number of hidden layers and hidden nodes. In this respect, an innovative chromosome representation and cross-over process is proposed to handle these parameters. The performance of the proposed method is evaluated on the Herlev database and compared with many other efficient methods in this scope under the same validation conditions. The results show that the detection accuracy of the proposed method is higher than the compared methods. Insensitivity to image rotation is one of the major advantages of the proposed method. Results show that the proposed method has the capability to be used in online problems because of low run time. The proposed texture descriptor, MULTP is a general operator which can be used in many computer vision problems to describe texture properties of image. Also, the proposed optimization algorithm can be used in deep-networks to improve performance.

Superconductivity in Heusler compound ScAu2Al.

We report superconducting state properties and electronic structure of a full Heusler material ScAu2Al. The resistivity measurement indicates a zero-field (at nominal Earth's field) superconducting transition temperature,Tc= 5.12 K (in contrary to the previously reported value of 4.4 K), which falls in the highestTc-regime among the Heusler superconductors. The magnetization data shows that ScAu2Al is a moderate type-II superconductor, where the critical field values can be estimated from the Ginzburg-Landau-Abrikosov-Gorkov theory. The field-dependent magnetization response further shows signatures of flux jump in ScAu2Al. A sharp jump in the temperature dependent specific heat (Cp) data confirms bulk superconductivity. We report that the electron-phonon coupling constant,λe-ph= 0.77, suggesting a moderate electron-phonon coupling in ScAu2Al. Further, we show that the observedλe-phvalue in ScAu2Al is the highest amongst the reported Heusler superconductors, indicating strong correlation betweenTcandλe-phvalues and significant role of electron-phonon coupling in mediating superconductivity in Heusler superconductors. Finally, we discuss the electronic properties and reveal the existence of van Hove singularity near the Fermi level in ScAu2Al.

A phase 2/3, participant-blind, observer-blind, randomised, controlled study to assess the safety and immunogenicity of SII-ChAdOx1 nCoV-19 (COVID-19 vaccine) in adults in India.

BACKGROUND: This phase 2/3 immunobridging study evaluated the safety and immunogenicity of the ChAdOx1 nCoV-19 Coronavirus Vaccine (Recombinant) (SII-ChAdOx1 nCoV-19), manufactured in India at the Serum Institute of India Pvt Ltd (SIIPL), following technology transfer from the AstraZeneca. METHODS: This participant-blind, observer-blind study randomised participants 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (ChAdOx1 nCoV-19) (immunogenicity/reactogenicity cohort) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort). The study participants were enrolled from 14 hospitals across India between August 25 and October 31, 2020. Two doses of study products were given 4 weeks apart. The primary objectives were to demonstrate non-inferiority of SII-ChAdOx1 nCoV-19 to AZD1222 in terms of geometric mean titre (GMT) ratio of anti-SARS-CoV-2 spike IgG antibodies 28 days after the second dose (defined as lower limit of 95% CI >0·67) and to determine the incidence of serious adverse events (SAEs) causally related to SII-ChAdOx1 nCoV-19. The anti-spike IgG response was assessed using a multiplexed electrochemiluminescence-based immunoassay. Safety follow-up continued until 6 months after first dose. Trial registration: CTRI/2020/08/027170. FINDINGS: 1601 participants were enrolled: 401 to the immunogenicity/reactogenicity cohort and 1200 to the safety cohort. After two doses, seroconversion rates for anti-spike IgG antibodies were more than 98·0% in both the groups. SII-ChAdOx1 nCoV-19 was non-inferior to AZD1222 (GMT ratio 0·98; 95% CI 0·78-1·23). SAEs were reported in ≤ 2·0% participants across the three groups; none were causally related. A total of 34 SARS-CoV-2 infections were reported; of which 6 occurred more than 2 weeks after the second dose; none were severe. INTERPRETATION: SII-ChAdOx1 nCoV-19 has a non-inferior immune response compared to AZD1222 and an acceptable safety/reactogenicity profile. Pharmacovigilance should be maintained to detect any safety signals. FUNDING: SIIPL funded the contract research organisation and laboratory costs, while the site costs were funded by the Indian Council of Medical Research. The study vaccines were supplied by SIIPL and AstraZeneca.

Probing Polymer Chain Folding in Solution Using Second Harmonic Light Scattering.

Periodically grafted amphiphilic copolymers (PGACs) were earlier shown by us to adopt a zigzag folded conformation in the solid state, which enabled the backbone and pendant segments to segregate and occupy alternate layers in a lamellar structure. The conformational transition from a random coil to a zigzag folded chain in solution is an interesting problem, which is largely unexplored. To examine this, an orthogonally clickable parent polyester was sequentially clicked with two types of poly(ethylene glycol) (PEG) segments: one is a simple PEG and the other is a PEG that carries a dipolar chromophore. These two hydrophilic PEG segments, installed in a periodic and alternating fashion along the hydrocarbon-rich (HC) polyester backbone, ensure that the Janus folded chains are formed upon folding and carry chromophoric dipoles oriented along the same direction, thereby generating a large net dipole. The folding-induced alignment of chromophores in solution was followed using second harmonic light scattering (SHLS), wherein the intensity of the frequency-doubled scattered light (I2ω) is measured. Folding was induced by adding a polar solvent, like methanol, to a chloroform solution of the polymer; methanol desolvates the HC backbone but solubilizes the pendant PEG segments, thus inducing folding. The second harmonic intensity (I2ω) increased initially with methanol concentration and then saturated; in contrast, I2ω remained invariant with the solvent composition in the case of an analogous model chromophore. Furthermore, in a model PGAC carrying chromophore-bearing PEG segments on every repeat unit, I2ω decreased with increasing methanol composition, revealing the formation of a centrosymmetric folded chain, wherein the chromophoric dipoles on either side cancel each other. Thus, this study clearly reveals that the zigzag chain folding of PGACs can be induced by a segment-selective solvent, resulting in the rather elusive directional ordering of chromophoric dipoles in solution.

Role of dietary polyphenols on gut microbiota, their metabolites and health benefits.

The beneficial health roles of dietary polyphenols in preventing oxidative stress related chronic diseases have been subjected to intense investigation over the last two decades. As our understanding of the role of gut microbiota advances our knowledge of the antioxidant and anti-inflammatory functions of polyphenols accumulates, there emerges a need to examine the prebiotic role of dietary polyphenols. This review focused onthe role of different types and sources of dietary polyphenols on the modulation of the gut microbiota, their metabolites and how they impact on host health benefits. Inter-dependence between the gut microbiota and polyphenol metabolites and the vital balance between the two in maintaining the host gut homeostasis were discussed with reference to different types and sources of dietary polyphenols. Similarly, the mechanisms behind the health benefits by various polyphenolic metabolites bio-transformed by gut microbiota were also explained. However, further research should focus on the importance of human trials and profound links of polyphenols-gut microbiota-nerve-brain as they provide the key to unlock the mechanisms behind the observed benefits of dietary polyphenols found in vitro and in vivo studies.

Differentiation of fluctuations in uterine contractions associated with Term pregnancies using adaptive fractal features of electromyography signals.

Analysis of uterine contractions using electromyography signals is gaining importance due to its capability to measure the dynamics of uterus. Uterine electromyography (uEMG) provides information on the nature of uterine contractions non-invasively. In this study, the fluctuations in uEMG signals associated with Term pregnancies are analyzed. For this, Term uEMG signals corresponding to second (T1) and third (T2) trimesters are considered. The signals are subjected to Adaptive Fractal Analysis (AFA), wherein a global trend is obtained by using overlapping windows of three orders namely, 25%, 50% and 75%. The signals are detrended and the fluctuation function is estimated. Two Hurst exponent features computed at short range (Hs) and long range (Hl) are extracted and statistically analyzed. Results show that AFA is able to characterize variations in the fluctuations of Term delivery signals. The feature values are observed to vary significantly during different weeks of gestation. It is found that features of T2 signals are higher than that of T1 signals for all the considered overlaps, indicating that T2 signals possess smoother characteristics than T1 signals. Further, coefficient of variation is observed to be low, indicating that these features are able to handle the inter-subject variations in Term signals. Therefore, it appears that the proposed approach could aid in investigation of progressive changes in uterine contractions during Term pregnancies.

Fine-Tuning Crystallization-Induced Gelation in Amphiphilic Double-Brush Polymers.

A series of amphiphilic double-brush polymers based on itaconate diesters were synthesized with the objective of tailoring the thermal and mechanical properties of hydrogels formed by them; the amphiphilic itaconate diesters carried an MPEG350 segment and an alkyl chain, whose length was varied from C12 to C18. As was reported by us earlier (Macromolecules 2017, 50, 5004), the formation of the hydrogel was due to the crystallization of alkyl segments, as confirmed by the match of the rheological gel-to-sol transition with that of differential scanning calorimetry melting transition of the gel. In an effort to fine-tune the hydrogel-melting temperature and its strength, we varied the length of the alkyl chain length while keeping the hydrophilic segment length constant at MPEG350; apart from varying the alkyl chain length, an oxyethylene spacer was incorporated to examine the effect of decoupling the alkyl side-chain crystallization from the backbone. With these modifications, the melting temperature of the hydrogel was varied from 30 to 56 °C. Likewise, the strength of the hydrogel, as reflected by its storage modulus, varied from around 220 to 970 Pa; the softer gels typically exhibited a slightly larger critical shear strain beyond which the gel transformed into a sol. The thermal and shear-induced gel-to-sol transitions were reversible; however, the modulus after the shear-induced transition did not fully recover instantly (∼80%), suggesting that the formation of the extended gel network is slow. Further fine-tuning could be achieved by copolymerization of two different amphiphilic itaconate monomers, namely, those with C16 and C18, which provided an intermediate gel-melting temperature; however, co-gelation of the two preformed homopolymer gels yielded two distinct gel-melting transitions. Thus, this class of tuneable stimuli-responsive polymeric hydrogels prepared from biobenign components, namely, itaconic acid, 1-alkanols, and MPEGs, could serve as potential candidates for biomedical applications.

Recurrent Scleritis and Immunoglobulin A Nephropathy - A Case Series and Literature Review of an Unusual Association.

Immunoglobulin A (IgA) nephropathy is usually restricted to the kidneys in most cases, but associations with other immune and inflammatory diseases exist. Scleritis, however, is an unusual association. We present an observational case series of two patients who initially presented with recurrent episodes of scleritis. A thorough evaluation for recurrent scleritis did not reveal any secondary cause per se. They were further evaluated extensively for incidental proteinuria and microscopic hematuria. Renal function was normal. Renal biopsy was performed which revealed IgA nephropathy in both the patients. They were given oral prednisolone and telmisartan for six months and followed for nine and six months, respectively, after steroids were discontinued. Proteinuria remitted, renal function remained normal, and there were no further episodes of scleritis in these patients.