Assessment of a Medical Student-Run Multidisciplinary Oncology Shadowing Program.

Clinical exposures during the first two years of medical school (MS1-2) provide students an opportunity for early networking, mentorship and career exploration. The feasibility and perceived value of an extracurricular, student-run multidisciplinary oncology shadowing program was evaluated in this study. At a single institution, an oncology interest group collaborated with oncologists to create a shadowing program for MS1-2 students. Three radiation oncology (RO), two medical oncology (MO), and four surgical oncology (SO) faculty participated. A quarterly sign-up form was emailed to all MS1-2 students with available shadowing sessions. Electronic surveys were sent to students (after shadowing) and faculty (after 18 months of program operation) with multiple choice and 5-point Likert-type (1 = low, 5 = high) questions about their experiences. A total of 57 of the 97 participating students, and all 9 of the 9 participating faculty, responded to surveys (response rates 59% and 100%, respectively). Thirty students (53%) shadowed in RO, 23 (40%) in SO, and 4 (7%) in MO. Most students were very satisfied with their interactions with faculty (mean Likert-type rating of 4.14 ± standard deviation 0.85) and their overall experience compared to prior shadowing experiences (3.84 ± 0.85). Fifty-four students (96%) would recommend the experience to a classmate. Four faculty (44%) reported much more shadowing than before. Seven faculty (78%) felt the experience was best when residents or fellows were also present. All physicians planned to continue participating. This study demonstrated that a student-run, oncology shadowing program was feasible to implement, and viewed favorably by faculty and student participants.

Caenorhabditis elegans as a Convenient Animal Model for Microbiome Studies.

Microbes constitute the most prevalent life form on Earth, yet their remarkable diversity remains mostly unrecognized. Microbial diversity in vertebrate models presents a significant challenge for investigating host-microbiome interactions. The model organism Caenorhabditis elegans has many advantages for delineating the effects of host genetics on microbial composition. In the wild, the C. elegans gut contains various microbial species, while in the laboratory it is usually a host for a single bacterial species. There is a potential host-microbe interaction between microbial metabolites, drugs, and C. elegans phenotypes. This mini-review aims to summarize the current understanding regarding the microbiome in C. elegans. Examples using C. elegans to study host-microbe-metabolite interactions are discussed.

Analysis of neurosurgery resident research activity in the United States.

OBJECTIVE: Evaluation of the demographic and academic characteristics of current neurosurgery residents may provide prospective students with insight into factors that affect research output. Therefore, this study aimed to evaluate the research output among neurosurgery residents. METHODS: US neurosurgery residency programs were abstracted from the American Association of Neurological Surgeons website. Demographic data on 1690 current residents across 119 programs were collected using publicly available institutional websites, Doximity, and LinkedIn. The h-index of each resident was recorded using Scopus and exported into the NIH iCite tool to determine the weighted relative citation ratio (w-RCR) and mean relative citation ratio (m-RCR). The total number of publications, h-index, and w-RCR were used as a proxy for research output, while m-RCR was used to measure research impact. One-way ANOVA and Kruskal-Wallis H-tests were used to assess the statistical significance of relationships between demographic data and measures of research activity. RESULTS: A total of 1690 residents (25.4% female), representing 119 programs, were evaluated. Neurosurgery residents had an average of 17 publications, h-index of 5.5, m-RCR of 1.4, and w-RCR of 16.9, with an upward trend of research activity by postgraduate year (PGY) class. Male residents on average had a greater total number of publications (p < 0.001), higher h-index (p < 0.001), and higher w-RCR (p = 0.002) compared with their female peers. Significant differences in research activity were also observed by degree (Doctor of Medicine [MD], Doctor of Osteopathy [DO], or other), where those with MD and other degrees had higher metrics than those with DO degrees. International medical graduates (IMGs) also had higher research output than American medical graduates (AMGs) (p < 0.001). Differences in all measures of research activity except impact were also observed in research activity when pre-residency medical school ranks were compared. CONCLUSIONS: The authors observed overall high research activity among neurosurgery residents. Factors such as gender, degree, PGY, IMG/AMG status, and medical school rank may therefore be related to the success of matching within neurological surgery. Although large disparities in gender representation have been identified in neurosurgery, newer classes are trending toward shrinking the gap. These data may be used by prospective residents to gauge changes and progress occurring in the neurosurgery match.

Advancing immunotherapy using biomaterials to control tissue, cellular, and molecular level immune signaling in skin.

Immunotherapies have been transformative in many areas, including cancer treatments, allergies, and autoimmune diseases. However, significant challenges persist in extending the reach of these technologies to new indications and patients. Some of the major hurdles include narrow applicability to patient groups, transient efficacy, high cost burdens, poor immunogenicity, and side effects or off-target toxicity that results from lack of disease-specificity and inefficient delivery. Thus, there is a significant need for strategies that control immune responses generated by immunotherapies while targeting infection, cancer, allergy, and autoimmunity. Being the outermost barrier of the body and the first line of host defense, the skin presents a unique immunological interface to achieve these goals. The skin contains a high concentration of specialized immune cells, such as antigen-presenting cells and tissue-resident memory T cells. These cells feature diverse and potent combinations of immune receptors, providing access to cellular and molecular level control to modulate immune responses. Thus, skin provides accessible tissue, cellular, and molecular level controls that can be harnessed to improve immunotherapies. Biomaterial platforms - microneedles, nano- and micro-particles, scaffolds, and other technologies - are uniquely capable of modulating the specialized immunological niche in skin by targeting these distinct biological levels of control. This review highlights recent pre-clinical and clinical advances in biomaterial-based approaches to target and modulate immune signaling in the skin at the tissue, cellular, and molecular levels for immunotherapeutic applications. We begin by discussing skin cytoarchitecture and resident immune cells to establish the biological rationale for skin-targeting immunotherapies. This is followed by a critical presentation of biomaterial-based pre-clinical and clinical studies aimed at controlling the immune response in the skin for immunotherapy and therapeutic vaccine applications in cancer, allergy, and autoimmunity.

GEOMETRIC DETERMINANTS OF CELL VIABILITY FOR 3D-PRINTED HOLLOW MICRONEEDLE ARRAY-MEDIATED DELIVERY.

A wide range of emerging biomedical applications and clinical interventions rely on the ability to deliver living cells via hollow, high-aspect-ratio microneedles. Recently, microneedle arrays (MNA) have gained increasing interest due to inherent benefits for drug delivery; however, studies exploring the potential to harness such advantages for cell delivery have been impeded due to the difficulties in manufacturing high-aspect-ratio MNAs suitable for delivering mammalian cells. To bypass these challenges, here we leverage and extend our previously reported hybrid additive manufacturing (or "three-dimensional (3D) printing) strategy-i.e., the combined the "Vat Photopolymerization (VPP)" technique, "Liquid Crystal Display (LCD)" 3D printing with "Two-Photon Direct Laser Writing (DLW)"-to 3D print hollow MNAs that are suitable for cell delivery investigations. Specifically, we 3D printed four sets of 650 µm-tall MNAs corresponding to needle-specific inner diameters (IDs) of 25 µm, 50 µm, 75 µm, and 100 µm, and then examined the effects of these MNAs on the post-delivery viability of both dendritic cells (DCs) and HEK293 cells. Experimental results revealed that the 25 µm-ID case led to a statistically significant reduction in post-MNA-delivery cell viability for both cell types; however, MNAs with needle-specific IDs ≥ 50 µm were statistically indistinguishable from one another as well as conventional 32G single needles, thereby providing an important benchmark for MNA-mediated cell delivery.

Iron oxide nanozymes stabilize stannous fluoride for targeted biofilm killing and synergistic oral disease prevention.

Dental caries is the most common human disease caused by oral biofilms despite the widespread use of fluoride as the primary anticaries agent. Recently, an FDA-approved iron oxide nanoparticle (ferumoxytol, Fer) has shown to kill and degrade caries-causing biofilms through catalytic activation of hydrogen peroxide. However, Fer cannot interfere with enamel acid demineralization. Here, we show notable synergy when Fer is combined with stannous fluoride (SnF2), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, we discover that the stability of SnF2 is enhanced when mixed with Fer in aqueous solutions while increasing catalytic activity of Fer without any additives. Notably, Fer in combination with SnF2 is exceptionally effective in controlling dental caries in vivo, even at four times lower concentrations, without adverse effects on host tissues or oral microbiome. Our results reveal a potent therapeutic synergism using approved agents while providing facile SnF2 stabilization, to prevent a widespread oral disease with reduced fluoride exposure.

Exome-wide association study of treatment-resistant depression suggests novel treatment targets.

Treatment-resistant depression (TRD) is a severe form of major depressive disorder (MDD) with substantial public health impact and poor treatment outcome. Treatment outcome in MDD is significantly heritable, but genome-wide association studies have failed to identify replicable common marker alleles, suggesting a potential role for uncommon variants. Here we investigated the hypothesis that uncommon, putatively functional genetic variants are associated with TRD. Whole-exome sequencing data was obtained from 182 TRD cases and 2021 psychiatrically healthy controls. After quality control, the remaining 149 TRD cases and 1976 controls were analyzed with tests designed to detect excess burdens of uncommon variants. At the gene level, 5 genes, ZNF248, PRKRA, PYHIN1, SLC7A8, and STK19 each carried exome-wide significant excess burdens of variants in TRD cases (q < 0.05). Analysis of 41 pre-selected gene sets suggested an excess of uncommon, functional variants among genes involved in lithium response. Among the genes identified in previous TRD studies, ZDHHC3 was also significant in this sample after multiple test correction. ZNF248 and STK19 are involved in transcriptional regulation, PHYIN1 and PRKRA are involved in immune response, SLC7A8 is associated with thyroid hormone transporter activity, and ZDHHC3 regulates synaptic clustering of GABA and glutamate receptors. These results implicate uncommon, functional alleles in TRD and suggest promising novel targets for future research.

Dissecting regulatory T cell expansion using polymer microparticles presenting defined ratios of self-antigen and regulatory cues.

Biomaterials allow for the precision control over the combination and release of cargo needed to engineer cell outcomes. These capabilities are particularly attractive as new candidate therapies to treat autoimmune diseases, conditions where dysfunctional immune cells create pathogenic tissue environments during attack of self-molecules termed self-antigens. Here we extend past studies showing combinations of a small molecule immunomodulator co-delivered with self-antigen induces antigen-specific regulatory T cells. In particular, we sought to elucidate how different ratios of these components loaded in degradable polymer particles shape the antigen presenting cell (APC) -T cell interactions that drive differentiation of T cells toward either inflammatory or regulatory phenotypes. Using rapamycin (rapa) as a modulatory cue and myelin self-peptide (myelin oligodendrocyte glycoprotein- MOG) - self-antigen attacked during multiple sclerosis (MS), we integrate these components into polymer particles over a range of ratios and concentrations without altering the physicochemical properties of the particles. Using primary cell co-cultures, we show that while all ratios of rapa:MOG significantly decreased expression of co-stimulation molecules on dendritic cells (DCs), these levels were insensitive to the specific ratio. During co-culture with primary T cell receptor transgenic T cells, we demonstrate that the ratio of rapa:MOG controls the expansion and differentiation of these cells. In particular, at shorter time points, higher ratios induce regulatory T cells most efficiently, while at longer time points the processes are not sensitive to the specific ratio. We also found corresponding changes in gene expression and inflammatory cytokine secretion during these times. The in vitro results in this study contribute to in vitro regulatory T cell expansion techniques, as well as provide insight into future studies to explore other modulatory effects of rapa such as induction of maintenance or survival cues.

Exploiting Unique Features of Microneedles to Modulate Immunity.

Microneedle arrays (MNAs) are small patches containing hundreds of short projections that deliver signals directly to dermal layers without causing pain. These technologies are of special interest for immunotherapy and vaccine delivery because they directly target immune cells concentrated in the skin. The targeting abilities of MNAs result in efficient immune responses-often more protective or therapeutic-compared to conventional needle delivery. MNAs also offer logistical benefits, such as self-administration and transportation without refrigeration. Thus, numerous preclinical and clinical studies are exploring these technologies. Here the unique advantages of MNA, as well as critical challenges-such as manufacturing and sterility issues-the field faces to enable widespread deployment are discussed. How MNA design parameters can be exploited for controlled release of vaccines and immunotherapies, and the application to preclinical models of infection, cancer, autoimmunity, and allergies are explained. Specific strategies are also discussed to reduce off-target effects compared to conventional vaccine delivery routes, and novel chemical and manufacturing controls that enable cargo stability in MNAs across flexible intervals and temperatures. Clinical research using MNAs is then examined. Drawbacks of MNAs and the implications, and emerging opportunities to exploit MNAs for immune engineering and clinical use are concluded.

Iron oxide nanozymes stabilize stannous fluoride for targeted biofilm killing and synergistic oral disease prevention.

Dental caries (tooth decay) is the most prevalent human disease caused by oral biofilms, affecting nearly half of the global population despite increased use of fluoride, the mainstay anticaries (tooth-enamel protective) agent. Recently, an FDA-approved iron oxide nanozyme formulation (ferumoxytol, Fer) has been shown to disrupt caries-causing biofilms with high specificity via catalytic activation of hydrogen peroxide, but it is incapable of interfering with enamel acid demineralization. Here, we find notable synergy when Fer is combined with stannous fluoride (SnF 2 ), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, our data show that SnF 2 enhances the catalytic activity of Fer, significantly increasing reactive oxygen species (ROS) generation and antibiofilm activity. We discover that the stability of SnF 2 (unstable in water) is markedly enhanced when mixed with Fer in aqueous solutions without any additives. Further analyses reveal that Sn 2+ is bound by carboxylate groups in the carboxymethyl-dextran coating of Fer, thus stabilizing SnF 2 and boosting the catalytic activity. Notably, Fer in combination with SnF 2 is exceptionally effective in controlling dental caries in vivo , preventing enamel demineralization and cavitation altogether without adverse effects on the host tissues or causing changes in the oral microbiome diversity. The efficacy of SnF 2 is also enhanced when combined with Fer, showing comparable therapeutic effects at four times lower fluoride concentration. Enamel ultrastructure examination shows that fluoride, iron, and tin are detected in the outer layers of the enamel forming a polyion-rich film, indicating co-delivery onto the tooth surface. Overall, our results reveal a unique therapeutic synergism using approved agents that target complementary biological and physicochemical traits, while providing facile SnF 2 stabilization, to prevent a widespread oral disease more effectively with reduced fluoride exposure.

Kwashiorkor after gastric bypass.

Gastric bypass has grown in popularity in recent years due to its high efficacy in achieving long-term weight loss in patients with morbid obesity. Gastric bypass has been described to further exacerbate baseline nutritional deficiencies due to reduced gastric capacity and malabsorption. In rare cases, when protein deficiency is severe, Kwashiorkor disease may arise. The incidence of Kwashiorkor specifically following gastric bypass is rare, with an incidence of 4.7%. We report a case of a female patient who underwent a gastric bypass and subsequently developed Kwashiorkor. Physicians' suspicion of index for Kwashiorkor should be high for patients presenting with signs or symptoms of severe malnutrition following weight-loss procedures.

Streptococcus pneumoniae Coinfection in COVID-19 in the Intensive Care Unit: A Series of Four Cases.

Bacterial coinfections in patients infected with SARS-CoV-2 pneumonia are uncommon, when compared to coinfections with other respiratory viruses. For example, the prevalence of bacterial coinfections in hospitalized seasonal influenza patients can exceed 30%, whereas the prevalence of bacterial coinfections in SARS-CoV-2 infection is less than 4%. Bacterial coinfections increase the severity of respiratory viral infections and have been associated with higher mortality and morbidity. Current literature shows that diagnostic testing and antibiotic therapy for bacterial infections are not necessary upon admission in majority of patients with SARS-CoV-2 patients. It is however important for the clinician to be cognizant of these coinfections since missing the diagnosis may pose a substantial risk to vulnerable COVID-19 patients. In that light, we present four cases of Streptococcus pneumoniae coinfections complicating confirmed SARS-CoV-2 infections.

Large Pituitary Adenoma: Strategies to Maximize Volumetric Resection Using Endoscopic Endonasal Approaches and an Analysis of Factors Limiting Resection.

BACKGROUND: Large pituitary adenomas (LPAs), which constitute ∼5%-14% of all pituitary adenomas, are considered challenging tumors owing to their locally aggressive behavior, low gross total resection rate, and high prevalence of visual deficits and hypopituitarism. We evaluated the utility of various extended endoscopic endonasal approaches in maximizing the resection of LPAs and studied the factors affecting the extent of surgical resection. METHODS: A retrospective study of all LPAs (defined as a minimum diameter >3 cm and tumor volume >10 cm3) treated via an endoscopic endonasal approach between January 2015 and December 2020 was performed. The volumetric extent of resection (3-dimensional volumetric analysis software) was correlated with various demographic, tumor-related, pathologic, and immunohistochemical factors and its effects on the clinical outcomes studied. RESULTS: The present study included 106 patients with LPAs. The mean extent of the resection volume was 79.18 ± 21.75 cm3. The factors that affected the extent of resection included the preoperative tumor volume (P = 0.03) and Knosp grade (P = 0.03). The percentage increase in the extent of resection with the use of 2 endonasal corridors was 10.6% and with 3 corridors was 14%. Visual improvement occurred in 82% of patients, and new-onset persistent hormonal insufficiency occurred in 2.9% of patients. Mortality directly related to surgery occurred in 1.8% of cases. CONCLUSIONS: Extended endoscopic endonasal approaches can safely and effectively be used for gross total resection of LPAs. However, we found that the preoperative tumor volume and Knosp grade were significant factors affecting the extent of tumor resection. The use of multiple endoscopic endonasal corridors can increase the volumetric extent of resection for LPAs.

Spatial delivery of immune cues to lymph nodes to define therapeutic outcomes in cancer vaccination.

Recently approved cancer immunotherapies - including CAR-T cells and cancer vaccination, - show great promise. However, these technologies are hindered by the complexity and cost of isolating and engineering patient cells ex vivo. Lymph nodes (LNs) are key tissues that integrate immune signals to coordinate adaptive immunity. Directly controlling the signals and local environment in LNs could enable potent and safe immunotherapies without cell isolation, engineering, and reinfusion. Here we employ intra-LN (i.LN.) injection of immune signal-loaded biomaterial depots to directly control cancer vaccine deposition, revealing how the combination and geographic distribution of signals in and between LNs impact anti-tumor response. We show in healthy and diseased mice that relative proximity of antigen and adjuvant in LNs - and to tumors - defines unique local and systemic characteristics of innate and adaptive response. These factors ultimately control survival in mouse models of lymphoma and melanoma. Of note, with appropriate geographic signal distributions, a single i.LN. vaccine treatment confers near-complete survival to tumor challenge and re-challenge 100 days later, without additional treatments. These data inform design criteria for immunotherapies that leverage biomaterials for loco-regional LN therapy to generate responses that are systemic and specific, without systemically exposing patients to potent or immunotoxic drugs.

Efficacy of Pippali in vardhamana and fixed dosage pattern in primary hypothyroidism - A randomized clinical trial.

INTRODUCTION: Hypothyroidism is an endocrine condition. The signs and symptoms of Hypothyroidism match with the descriptions of several conditions like Vataja Shotha, Rasa Pradoshaja Vikara or a disorder Agni. In the current study two different dosage forms i.e., Vardhamana (Increasing & Decreasing pattern) and fixed Dosage to evaluate its efficacy on Primary Hypothyroidism. MATERIALS AND METHODS: 40 patients randomized into two groups Escalating and Fixed were administered Vardhamana Pippali in two dosage forms for 19 days. Serum T3, T4, and TSH were assessed at baseline and on the 20th day along with the assessment of clinical score through Zulewskis's clinical score for measuring tissue hypothyroidism. The total pippali administered in both groups was 69 g. RESULTS: The mean levels of TSH were 9.52 ± 3.97 mIU/ml, 10 ± 6.02 mIU/ml, and 10.21 ± 8.49 mIU/ml at baseline, 20th day and 40th day respectively in group A. In group B it was 9.21 ± 3.72 mIU/ml, 8.23 ± 4.62 mIU/ml, and 9.15 ± 4.67 mIU/ml at baseline, 20th day and 40th day respectively. The mean Zulewski's clinical score was 3.67 ± 1.49, 2.28 ± 1.32, and 2.06 ± 1.25 at baseline, 20th day, and 40th day respectively in Escalating group. In Fixed group it was 3.83 ± 1.20, 2.50 ± 1.42, and 3.44 ± 1.33 at baseline, 20th day, and 40th day respectively. DISCUSSION: Zulewski's clinical scores were statically non-significant in both the groups on the 20th-day respectively, suggesting minimal efficacy of the interventions. But subjects administered with Vardhamana Pippali exhibited better long-lasting effects suggesting sustained effects of the drug. CONCLUSION: Pippali is efficacious in reducing the signs and symptoms of Primary Hypothyroidism and also has a positive impact on the Thyroid profile but is more effective when administered in Vardhamana dosage compared to fixed dose.

Mapping the Mechanical and Immunological Profiles of Polymeric Microneedles to Enable Vaccine and Immunotherapy Applications.

Biomaterials hold great promise for vaccines and immunotherapy. One emerging biomaterials technology is microneedle (MNs) delivery. MNs are arrays of micrometer-sized needles that are painless and efficiently deliver cargo to the specialized immunological niche of the skin. MNs typically do not require cold storage and eliminate medical sharps. Nearly all materials exhibit intrinsic properties that can bias immune responses toward either pro-immune or inhibitory effects. Thus, because MNs are fabricated from degradable polymers to enable cargo loading and release, understanding the immunological profiles of these matrices is essential to enable new MN vaccines and immunotherapies. Additionally, understanding the mechanical properties is important because MNs must penetrate the skin and conform to a variety of skin or tissue geometries. Here we fabricated MNs from important polymer classes - including extracellular matrix biopolymers, naturally-derived polymers, and synthetic polymers - with both high- and low-molecular-weights (MW). We then characterized the mechanical properties and intrinsic immunological properties of these designs. The library of polymer MNs exhibited diverse mechanical properties, while causing only modest changes in innate signaling and antigen-specific T cell proliferation. These data help inform the selection of MN substrates based on the mechanical and immunological requirements needed for a specific vaccine or immunotherapy application.

Sentiment Analysis of Twitter Feeds Using Flask Environment: A Superior Application of Data Analysis.

In this challenging world, social media plays a vital role as it is at the pinnacle of data sharing. The advancement in technology has made a huge amount of information available for data analysis and it is on the hotlist nowadays. Opinions of the people are expressed and shared across various social media platforms like Twitter, Facebook, and Instagram. Twitter is a prodigious platform containing an ample amount of data and analyzing the data is of topmost priority. One of the most widely utilized approaches for classifying an individual's emotions displayed in subjective data is sentiment analysis. Sentiment analysis is done using various algorithms of machine learning like Support Vector Machine, Naive Bayes, Long Short-Term Memory, Decision Tree Classifier, and many more, but this paper aims at the generalized way of performing Twitter sentiment analysis using flask environment. Flask environment provides various inbuilt functionalities to analyze the sentiments of text into three different categories: positive, negative, and neutral. Also, it makes API calls to the Twitter Developer account to fetch the Twitter data. After fetching and analyzing the data, the results get displayed on a webpage containing the percentage of positive, negative, and neutral tweets for a phrase in a pie chart. It displays the language analysis for the same phrase. Furthermore, the webpage calls attention to the tweets done on that phrase and reveals the details of the tweets. Considering the major industry runners of three different sectors namely Enterprises, Sports Apparel Industry, and Multimedia Industry, we have analyzed and compared sentiments of two different Multinational companies from each sector.

Synthesis of Triphenylphosphonium Phospholipid Conjugates for the Preparation of Mitochondriotropic Liposomes.

Surface modification of liposomes with a ligand is facilitated by the conjugation of the ligand to a hydrophobic molecule that serves to anchor the ligand to the liposomal bilayer. We describe here a simple protocol to conjugate a triphenylphosphonium group to several commercially available functionalized phospholipids. The resulting triphenylphosphonium-conjugated lipids can be used to prepare liposomes that preferentially associate with mitochondria when exposed to live mammalian cells in culture.

Characterisation of hydration water in Nafion membrane.

Nafion, a polytetrafluoroethylene polymer with perfluorinated-vinyl-polyether side chains ending in sulfonic acid groups, is widely used as the proton-exchange membrane in polymer electrolyte fuel cells, particularly low temperature hydrogen-oxygen fuel cells. The state of hydration of the sulfonic acid groups is crucial to its operation. By using a combination of inelastic neutron scattering (INS) and infrared spectroscopies, and by comparison to a series of trifluoromethanesulfonic acid hydrates of well-defined stoichiometry, we characterise how the hydration changes as a function of water content.