Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Modeling Pressure Drop Using Generalized Scaffold Characteristics in an Axial-Flow Bioreactor for Soft Tissue Regeneration

The goal of this study was to better understand how analytical permeability models based on scaffold architecture can facilitate a non-invasive technique to real time monitoring of pressure drop in bioreactors. In particular, we evaluated the permeability equations for electrospun and freeze dried scaffolds via pressure drop comparison in an axial-flow bioreactor using computational fluid dynamic (CFD) and experimentation. The polycaprolactone–cellulose acetate fibers obtained by co-axial electrospinning technique and Chitosan–Gelatin scaffolds prepared using freeze-drying techniques were utilized. Initially, the structural properties (fiber size, pore size and porosity) and mechanical properties (elastic modulus and Poisson’s ratio) of scaffolds in phosphate buffered saline at 37 °C were evaluated. The CFD simulations were performed by coupling fluid flow, described by Brinkman equation, with structural mechanics using a moving mesh. The experimentally obtained pressure drop values for both 1 mm thick and 2 mm thick scaffolds agreed with simulation results. To evaluate the effect of permeability and elastic modulus on pressure drop, CFD predictions were extended to a broad range of permeabilities spanning synthetic scaffolds and tissues, elastic moduli, and Poisson’s ratio. Results indicated an increase in pressure drop with increase in permeability. Scaffolds with higher elastic modulus performed better and the effect of Poisson’s ratio was insignificant. Flow induced deformation was negligible in axial-flow bioreactor. In summary, scaffold permeabilities can be calculated using scaffold microarchitecture and can be used in non-invasive monitoring of tissue regeneration.     

Do men with normal testosterone–oestradiol ratios benefit from letrozole for the treatment of male infertility?

Research question

Previous studies of aromatase inhibitors on male infertility have focused on men with low testosterone–oestradiol ratio of less than 10. Can aromatase inhibitors improve spermatogenesis in men with idiopathic male infertility with normal testosterone–oestradiol ratio?

Design and Development of Acetylthiocholine Electrochemical Biosensor Based on Zinc Oxide–Cerium Oxide Nanohybrid Modified Platinum Electrode

Acetylcholinesterase (AChE) enzyme has been predominantly used for the detection of pesticides and metal ions. But, these sensors respond to pesticides as well as metal ions at certain concentration, which results in poor selectivity. Hence in this work, the amount of thiocholine produced during AChE inhibition has been estimated to detect the residual activity of AChE enzyme in-turn to enhance the efficiency of the biosensor. In this context, Pt/ZnO–CeO₂/AChE/Chitosan based biosensor has been developed for sensitive voltammetric quantification of thiocholine in AChE. The sensor exhibited enhanced electron transfer rate, good conductivity and biocompatibility. Both the intrinsic and extrinsic parameters were simultaneously optimized using second order polynomial regression to get the best conditions for ATCh determination. Under optimized experimental conditions, the redox peak current was linear over the concentration range of 0.1–1.5 mM with detection and quantification limit of 0.05 and 0.15 μM respectively and the sensitivity of 1.47 μA mM^?1.     

Higher levels of brain derived neurotrophic factor but similar nerve growth factor in human milk in women with preeclampsia

Children born to mothers with preeclampsia have consistently been suggested to be at risk for cognitive and behavioral disorders in later life. Breastfeeding is said to be associated with better neurodevelopment outcomes. Our earlier studies indicated higher levels of docosahexaenoic acid (DHA) in human milk in women with preeclampsia. DHA is known to regulate the expression of neurotrophins and together they play a vital role in neurodevelopment and cognitive performance. The present study examines the levels of maternal plasma and milk neurotrophins [(nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF)] in women with preeclampsia and compares them with normotensive women who served as controls. Singleton pregnant women diagnosed with preeclampsia (n = 72) and controls (n = 102) were recruited for this study from Bharati Hospital, Pune. Plasma and milk samples were analyzed for NGF and BDNF levels using the Emax Immuno Assay System using promega kits. Maternal plasma NGF and BDNF levels were lower (p < 0.01 for both) in women with preeclampsia as compared to the control women. Milk NGF levels were similar while milk BDNF levels were higher (p < 0.05) in the preeclampsia group as compared to controls. Plasma NGF levels were positively correlated with milk NGF levels in the control group. Our results indicate the differential regulation of milk NGF and BDNF levels in women with preeclampsia. The present study suggests a role for both NGF and BDNF in human milk for postnatal brain development. Further studies need to examine the associations of DHA and BDNF in human milk with cognition at later ages.     

Clinical validation of an artificial intelligence-enabled wound imaging mobile application in diabetic foot ulcers

There is a lifetime risk of 15% to 25% of development of diabetic foot ulcers (DFUs) in patients with diabetes mellitus. DFUs need to be followed up on and assessed for development of complications and/or resolution, which was traditionally performed using manual measurement. Our study aims to compare the intra- and inter-rater reliability of an artificial intelligence-enabled wound imaging mobile application (CARES4WOUNDS [C4W] system, Tetsuyu, Singapore) with traditional measurement. This is a prospective cross-sectional study on 28 patients with DFUs from June 2020 to January 2021. The main wound parameters assessed were length and width. For traditional manual measurement, area was calculated by overlaying traced wound on graphical paper. Intra- and inter-rater reliability was analysed using intra-class correlation statistics. A value of <0.5, 0.5–0.75, 0.75–0.9, and >0.9 indicates poor, moderate, good, and excellent reliability, respectively. Seventy-five wound episodes from 28 patients were collected and a total of 547 wound images were analysed in this study. The median wound area during the first clinic consultation and all wound episodes was 3.75 cm² (interquartile range [IQR] 1.40–16.50) and 3.10 cm² (IQR 0.60–14.84), respectively. There is excellent intra-rater reliability of C4W on three different image captures of the same wound (intra-rater reliability ranging 0.933–0.994). There is also excellent inter-rater reliability between three C4W devices for length (0.947), width (0.923), and area (0.965). Good inter-rater reliability for length, width, and area (range 0.825–0.934) was obtained between wound nurse measurement and each of the C4W devices. In conclusion, we obtained good inter-rater and intra-rater reliability of C4W measurements against traditional wound measurement. The C4W is a useful adjunct in monitoring DFU wound progress.     

Clinical and economic burden of wound care in the tropics: a 5‐year institutional population health review

The aim of this study is to evaluate the clinical and economic burden of wound care in the Tropics via a 5‐year institutional population health review. Within our data analysis, wounds are broadly classified into neuro‐ischaemic ulcers (NIUs), venous leg ulcers (VLUs), pressure injuries (PIs), and surgical site infections (SSIs). Between 2013 and 2017, there were a total of 56 583 wound‐related inpatient admissions for 41 461 patients, with a 95.1% increase in wound episodes per 1000 inpatient admissions over this period (142 and 277 wound episodes per 1000 inpatient admissions in 2013 and 2017, respectively). In 2017, the average length of stay for each wound episode was 17.7 days, which was 2.4 times that of an average acute admission at our institution. The average gross charge per wound episode was USD $12 967. Among the 12 218 patients with 16 674 wound episodes in 2017, 71.5% were more than 65 years of age with an average Charlson Comorbidity Index (CCI) of 7.2. Half (51.9%) were moderately or severely frail, while 41.3% had two or more wound‐related admission episodes. In 2017, within our healthcare cluster, the gross healthcare costs for all inpatient wound episodes stand at USD $216 million within hospital care and USD $596 000 within primary care. Most NIU patients (97.2%) had diabetes and they had the most comorbidities (average CCI 8.4) and were the frailest group of patients (44.9% severely frail). The majority of the VLU disease burden was at the specialist outpatient setting, with the average 1‐year VLU recurrence rate at 52.5% and median time between healing and recurrence at 9.5 months. PI patients were the oldest (86.5% more than 65 years‐old), constituted the largest cohort of patients with 3874 patients at an incidence of 64.6 per 1000 admissions in 2017, and have a 1‐year all‐cause mortality rate of 14.3%. For SSI patients, there was a 125% increase of 14.2 SSI wound episodes per 1000 inpatient admissions in 2013 to 32.0 in 2017, and a 413% increase in wound‐related 30‐day re‐admissions, from 40 in 2013 (4.1% of all surgeries) to 205 (8.3% of all surgeries) in 2017. The estimated gross healthcare cost per patient ranges from USD $15789–17 761 across the wound categories. Similar to global data, there is a significant and rising trend in the clinical and economic burden of wound care in Tropics.     

Outcomes of incisional negative pressure wound therapy following brachiobasilic transposition arteriovenous fistula creation: A 1:2 propensity score matched study

Incisional negative wound pressure therapy (iNPWT) use on closed incisions has been shown to improve wound outcomes, but no studies have evaluated the use of iNPWT following brachiobasilic transposition arteriovenous fistula (BBT‐AVF). We aim to investigate the efficacy of iNPWT vs conventional wound therapy in reducing surgical site infections (SSIs) for BBT‐AVF incisions. This is a retrospective cohort study of patients who underwent BBT‐AVF creation between January 2010 and December 2017. A 1:2 propensity score matching (PSM) was performed to reduce selection bias and address for confounding factors. Study outcomes included SSI and haematoma incidence, 30‐day readmission, and 30‐day mortality. A total of 154 patients were reviewed in this study: 47 (30.5%) had iNPWT and 107 (69.5%) had conventional wound therapy. The overall median age was 60.5 (interquartile range 54–69). PSM with a 1:2 ratio resulted in a total of 117 patients (39 iNPWT and 78 conventional wound therapy). In the unmatched cohort, SSI incidence was lower in the iNPWT group (n = 1/47 [2.1%] vs n = 14/107 [13.1%], P = .035). However, incidence of SSI was comparable between iNPWT and conventional wound therapy after matching (n = 1/39 [2.6%] vs n = 9/78 [11.5%], P = .102). There was no significant difference in 30‐day readmission and 30‐day mortality. Within our study population of patients with BBT‐AVF incisions, there is a non‐statistically significant reduction in SSI incidence for patients who received iNPWT as compared with conventional wound therapy. Further prospective randomised controlled studies should be conducted to validate these findings.     

Epidemiological Investigation of the Jaundice Outbreak in Lalkuan,Nainital District,Uttarakhand

Background:

In March 2013, cases of acute hepatitis were reported from Lalkuan, Nainital district. We investigated the outbreak to identify the source of infection and to facilitate control measures.

Objectives:

To study the distribution of hepatitis cases, to find the source of infection, and to initiate the control measures in the affected area.

Materials and Methods:

We defined a case of acute hepatitis as those cases that had jaundice with at least one of the following symptoms: Dark urine, fever, pain in abdomen, vomiting, and loss of appetite in the affected area between January and March 2013. Door-to-door survey was carried out. Thirteen blood samples were randomly collected from jaundice cases for immunoglobulin M (IgM) antibody for hepatitis A virus (HAV) and hepatitis E virus (HEV). Water samples were collected to test residual chlorine.

Results:

Total 2,785 individuals were surveyed; of which 240 were suffering from acute viral hepatitis (attack rate (AR) = 8.61%). Out of 13 serum samples, 10 were found positive for HEV IgM antibodies and three cases had IgM antibodies for both HAV and HEV, which confirmed a hepatitis E outbreak. The difference in attack rate of hepatitis of both the sexes was statistically significant (P < 0.001). The attack rate was significantly higher in age groups >12 years of age (P < 0.001). Environmental investigation also confirmed the sewage contamination of drinking water in the distribution system. The attack rate was much higher (29.4%) among those who were exposed to the leaking pipeline than the nonexposed (χ² = 574.26, P < 0.01).

Conclusion:

HEV was confirmed as the major etiological agent in this outbreak that was transmitted by contaminated drinking water. The recognition of early warning signals, timely investigation, and application of specific control measures can contain the outbreak.     

Interleukin 6 −174G>C polymorphism and cancer risk: Meta-analysis reveals a site dependent differential influence in Ancestral North Indians

In our earlier studies, single nucleotide polymorphisms (SNPs) associated with anti-inflammatory cytokines were found to influence risk for breast cancer in western Indian women. Analysis of Interleukin 6 (IL-6) −174G>C polymorphism in this cohort (patients = 182; controls = 236) suggested a protective role for IL-6 −174C allele associated with the lower expression of the cytokine (OR = 0.54; 95% CI 0.32–0.89, dominant model). Together these observations suggested that in comparison to Caucasians, inflammation associated-cytokine gene polymorphisms may have higher influence on risk for cancer in this population. To examine this possibility we analyzed data assessing influence of Interleukin 6 (IL-6) −174G>C polymorphism on risk for various cancers. Overall, there was a marginally higher risk for rare allele homozygotes compared to wild type homozygotes (OR = 1.07; 95% CI 1.00–1.15). Increased risks for genitourinary cancers and for skin cancer were also indicated. The ethnicity based analysis indicated a protective effect of the minor allele in Ancestral North Indians (OR = 0.73; 95% CI 0.55–0.97). Site by ethnicity analysis once again revealed a significant protection against breast cancer (OR = 0.51; 95% CI = 0.37–0.70; dominant model) but an opposite influence on the risk of genitourinary malignancies (OR = 2.51; 95% CI 1.59–3.96; recessive model) in this population alone. The observations imply that contribution of IL-6 to inflammation or effector immunity may depend on the site of malignancy. Assessment of available data in relation to prognosis in breast cancer patients also revealed trends that are compatible with the observations of the meta-analysis. Thus, IL-6 −174G>C polymorphism clearly represents a potential modulator of risk for malignant disorders with ethnicity and site dependent trends. The results also support the possibility of higher influence of inflammation related cytokine gene polymorphisms on the risk for cancers in Ancestral North Indians.