Comparison of Perioperative Complication Rates of Total Extraperitoneal and Transabdominal Preperitoneal Repairs in Primary Inguinal Hernia.

Background: Hernia may be defined as a protrusion of viscus through layers anatomically designed to contain that viscus. Most abdominal hernias occur at well-described sites of potential weakness. Repair of inguinal hernia is one of the most common operations in general surgery. Objectives: To compare the perioperative complication rates of total extraperitoneal (TEP) and transabdominal preperitoneal (TAPP) repairs of primary inguinal hernias. Materials and Methods: It is a randomised comparative study, conducted at the department of general surgery. A total of 50 patients were included and divided into two groups with 25 in each. Group A represents the laparoscopic TEP repair and group B represents the laparoscopic TAPP repair. Patients above 18 years with primary unilateral inguinal hernia were included. Patients having complicated inguinal hernia and history of previous abdominal surgery were excluded. Results: We observed that hernia occurrence is more common in the 31-50 years of age group and right-sided hernia is more common. Scrotal oedema and conversion to open surgery chances are similar in both TEP and TAPP groups. The duration of surgery in TEP is significantly higher as compared to TAPP. Patients who underwent TEP experienced less pain as compared to TAPP as per visual analogue scale. Postoperative hospital stay and time taken to resume the routine activity were significantly less in case of TEP. Conclusion: TEP is preferred over TAPP for laparoscopic hernia repair because it preserves the peritoneal integrity and has lesser postoperative pain. The early recovery and return to the routine work were seen with the patient treated with the TEP and also showed better visual analogue score than the TAPP repair group.

Resectable Distal Duodenal Gastrointestinal Stromal Tumour Presenting with Features of Anaemia.

Although gastrointestinal stromal tumours (GISTs) are encountered all along the gastrointestinal tract, duodenal GISTs are uncommon and account for <5% of the cases. A 45-year-old woman presented chiefly with anaemia and associated symptoms, whom on further evaluation was found to have a non-metastatic GIST in the distal duodenum sparing the pancreas and major vasculature. Patient was undertaken for segmental duodenectomy with the help of advanced bipolar energy device (tumour occupying D3-D4 with 1 cm proximal margin and 15 cm jejunum) preserving the pancreas and ampulla with end-to-end duodenojejunostomy with an uneventful postoperative course and clear margins on histopathology. Thus, the patient underwent a less morbid procedure with satisfactory oncological outcome and early resumption of activity. This highlights the need to conduct more trials to gather high level evidence in favour of conservative resection and its oncological adequacy and impact on overall survival and recurrence.

Multi-criteria decision making to validate performance of RBC-based formulae to screen [Formula: see text]-thalassemia trait in heterogeneous haemoglobinopathies.

BACKGROUND: India has the most significant number of children with thalassemia major worldwide, and about 10,000-15,000 children with the disease are born yearly. Scaling up e-health initiatives in rural areas using a cost-effective digital tool to provide healthcare access for all sections of people remains a challenge for government or semi-governmental institutions and agencies. METHODS: We compared the performance of a recently developed formula SCS[Formula: see text] and its web application SUSOKA with 42 discrimination formulae presently available in the literature. 6,388 samples were collected from the Postgraduate Institute of Medical Education and Research, Chandigarh, in North-Western India. Performances of the formulae were evaluated by eight different measures: sensitivity, specificity, Youden's Index, AUC-ROC, accuracy, positive predictive value, negative predictive value, and false omission rate. Three multi-criteria decision-making (MCDM) methods, TOPSIS, COPRAS, and SECA, were implemented to rank formulae by ensuring a trade-off among the eight measures. RESULTS: MCDM methods revealed that the Shine & Lal and SCS[Formula: see text] were the best-performing formulae. Further, a modification of the SCS[Formula: see text] formula was proposed, and validation was conducted with a data set containing 939 samples collected from Nil Ratan Sircar (NRS) Medical College and Hospital, Kolkata, in Eastern India. Our two-step approach emphasized the necessity of a molecular diagnosis for a lower number of the population. SCS[Formula: see text] along with the condition MCV[Formula: see text] 80 fl was recommended for a higher heterogeneous population set. It was found that SCS[Formula: see text] can classify all BTT samples with 100% sensitivity when MCV[Formula: see text] 80 fl. CONCLUSIONS: We addressed the issue of how to integrate the higher-ranked formulae in mass screening to ensure higher performance through the MCDM approach. In real-life practice, it is sufficient for a screening algorithm to flag a particular sample as requiring or not requiring further specific confirmatory testing. Implementing discriminate functions in routine screening programs allows early identification; consequently, the cost will decrease, and the turnaround time in everyday workflows will also increase. Our proposed two-step procedure expedites such a process. It is concluded that for mass screening of BTT in a heterogeneous set of data, SCS[Formula: see text] and its web application SUSOKA can provide 100% sensitivity when MCV[Formula: see text] 80 fl.

QbD-driven development of phospholipid-embedded lipidic nanocarriers of raloxifene: extensive in vitro and in vivo evaluation studies.

Raloxifene (RLX) is popularly indicated in treatment of osteoporosis and prevention of breast cancer. Owing to its poor aqueous solubility, high pre-systemic metabolism, intestinal glucuronidation, and P-glycoprotein (P-gp) efflux, however, it demonstrates low (< 2%) and inconsistent oral bioavailability. The current work, Quality by Design (QbD)-driven development of phospholipid-embedded nanostructured lipidic carriers (NLCs) of RLX, accordingly, was undertaken to potentiate its lymphatic uptake, augment oral bioavailability, and possibly reduce drug dosage. Factor screening and failure mode effect analysis (FMEA) studies were performed to delineate high-risk factors using solid lipid (glyceryl monostearate), liquid lipid (vitamin E), and surfactant (Tween 80). Response surface optimization studies were performed employing the Box-Behnken design. Mathematical and graphical methods were adopted to embark upon the selection of optimized NLCs with various critical quality attributes (CQAs) of mean particle size as 186 nm, zeta potential of - 23.6 mV, entrapment efficiency of 80.09%, and cumulative drug release at 12 h of 83.87%. The DSC and FTIR studies, conducted on optimized NLCs, indicated successful entrapment of drug into the lipid matrix. In vitro drug release studies demonstrated Fickian diffusion mechanism. In vivo pharmacokinetic studies in rats construed significant improvement in AUC0-72 h (4.48-folds) and in Cmax (5.11-folds), unequivocally indicating markedly superior (p < 0.001) oral bioavailability of RLX-NLCs vis-à-vis marketed tablet formulation. Subsequently, level "A" in vitro/in vivo correlation (IVIVC) was also successfully attempted between the percentages of in vitro drug dissolved and of in vivo drug absorbed at the matching time points. In vitro cytotoxicity and cellular uptake studies also corroborated higher efficacy and successful localization of coumarin-6-loaded NLCs into MG-63 cells through microfluidic channels.

Optimization and Characterization of a Novel Antioxidant Naringenin-Loaded Hydrogel for Encouraging Re-Epithelization in Chronic Diabetic Wounds: A Preclinical Study.

Nonhealed wounds are one of the most dangerous side effects of type-2 diabetes, which is linked to a high frequency of bacterial infections around the globe that eventually results in amputation of limbs. The present investigation aimed to explore the drug-loaded (naringenin) hydrogel system for chronic wound healing. The hydrogel membranes comprising Na-alginate with F-127 and poly(vinyl alcohol) were developed to treat chronic wounds using the quality-by-design (QbD) approach. The optimized formulation was tested for various parameters, such as swelling, gel fraction, water vapor transition rate (WVTR), etc. In vitro evaluation indicated that a drug-loaded hydrogel displayed better tissue adhesiveness and can release drugs for a prolonged duration of 12 h. Scratch assay performed on L929 cell lines demonstrated good cell migration. The diabetic wound healing potential of the hydrogel membrane was assessed in streptozotocin-induced male Wistar rats (50 mg/kg). Higher rates of wound closure, re-epithelialization, and accumulation of collagen were seen in in vivo experiments. Histopathologic investigation correspondingly implied that the drug-loaded hydrogel could enhance dermal wound repair. The improved antimicrobial and antioxidant properties with expedited healing indicated that the drug-loaded hydrogel is a perfect dressing for chronic wounds.

Quality by design-steered development and validation of analytical and bioanalytical methods for raloxifene: Application of Monte Carlo simulations and variance inflation factor.

A sensitive, rapid, reproducible, and economical HPLC method is reported for the quantification of raloxifene hydrochloride employing Quality by Design (QbD) principles. Factor screening studies, employing Taguchi design, indicated buffer volume percentage and isocratic flow rate as the critical method parameters (CMPs), which significantly influence the chosen critical analytical attributes, that is, tailing factor and theoretical plate number. Method conditions were subsequently optimized using face-centered cubic design with magnitude of variance inflation factor for assessing multicollinearity among CMPs. Method operable design region (MODR) was earmarked and liquid chromatographic separation optimized using 0.05 M citrate buffer, acetonitrile, and methanol (57:40:3 v/v/v) as ggmobile phase at 0.9 mL min-1 flow rate, λmax of 280 nm, and column temperature of 40°C. Validation of the developed analytical method was accomplished as per International Council on Harmonization (ICH) guidelines confirming high levels of linearity, precision, accuracy, robustness, and sensitivity. Application of Monte Carlo simulations enabled the attainment of best plausible chromatographic resolution and corroboration of the demarcated MODR. Establishment and validation of the bioanalytical method using rat plasma samples, along with forced degradation and stability studies, corroborated the aptness of developed HPLC methods for drug quantification in the biological fluids, as well as in bulk and marketed dosage forms.

Soil respiration-driven CO2 pulses dominate Australia's flux variability.

The Australian continent contributes substantially to the year-to-year variability of the global terrestrial carbon dioxide (CO2) sink. However, the scarcity of in situ observations in remote areas prevents the deciphering of processes that force the CO2 flux variability. In this study, by examining atmospheric CO2 measurements from satellites in the period 2009-2018, we find recurrent end-of-dry-season CO2 pulses over the Australian continent. These pulses largely control the year-to-year variability of Australia's CO2 balance. They cause two to three times larger seasonal variations compared with previous top-down inversions and bottom-up estimates. The pulses occur shortly after the onset of rainfall and are driven by enhanced soil respiration preceding photosynthetic uptake in Australia's semiarid regions. The suggested continental-scale relevance of soil-rewetting processes has substantial implications for our understanding and modeling of global climate-carbon cycle feedbacks.

Diagnosing destabilization risk in global land carbon sinks.

Global net land carbon uptake or net biome production (NBP) has increased during recent decades1. Whether its temporal variability and autocorrelation have changed during this period, however, remains elusive, even though an increase in both could indicate an increased potential for a destabilized carbon sink2,3. Here, we investigate the trends and controls of net terrestrial carbon uptake and its temporal variability and autocorrelation from 1981 to 2018 using two atmospheric-inversion models, the amplitude of the seasonal cycle of atmospheric CO2 concentration derived from nine monitoring stations distributed across the Pacific Ocean and dynamic global vegetation models. We find that annual NBP and its interdecadal variability increased globally whereas temporal autocorrelation decreased. We observe a separation of regions characterized by increasingly variable NBP, associated with warm regions and increasingly variable temperatures, lower and weaker positive trends in NBP and regions where NBP became stronger and less variable. Plant species richness presented a concave-down parabolic spatial relationship with NBP and its variability at the global scale whereas nitrogen deposition generally increased NBP. Increasing temperature and its increasing variability appear as the most important drivers of declining and increasingly variable NBP. Our results show increasing variability of NBP regionally that can be mostly attributed to climate change and that may point to destabilization of the coupled carbon-climate system.

Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models.

Myeloproliferative neoplasms (MPNs) are characterized by the activated JAK2/STAT pathway. Pleckstrin-2 (Plek2) is a downstream target of the JAK2/STAT5 pathway and is overexpressed in patients with MPNs. We previously revealed that Plek2 plays critical roles in the pathogenesis of JAK2-mutated MPNs. The nonessential roles of Plek2 under physiologic conditions make it an ideal target for MPN therapy. Here, we identified first-in-class Plek2 inhibitors through an in silico high-throughput screening approach and cell-based assays, followed by the synthesis of analogs. Plek2-specific small-molecule inhibitors showed potent inhibitory effects on cell proliferation. Mechanistically, Plek2 interacts with and enhances the activity of Akt through the recruitment of downstream effector proteins. The Plek2-signaling complex also includes Hsp72, which protects Akt from degradation. These functions were blocked by Plek2 inhibitors via their direct binding to the Plek2 dishevelled, Egl-10 and pleckstrin (DEP) domain. The role of Plek2 in activating Akt signaling was further confirmed in vivo using a hematopoietic-specific Pten-knockout mouse model. We next tested Plek2 inhibitors alone or in combination with an Akt inhibitor in various MPN mouse models, which showed significant therapeutic efficacies similar to that seen with the genetic depletion of Plek2. The Plek2 inhibitor was also effective in reducing proliferation of CD34-positive cells from MPN patients. Our studies reveal a Plek2/Akt complex that drives cell proliferation and can be targeted by a class of antiproliferative compounds for MPN therapy.

Resident factors associated with American board of internal medicine certification exam failure.

INTRODUCTION: Performance on the certifying examinations such as the American Board of Internal Medicine Certification Exam (ABIM-CE) is of great interest to residents and their residency programs. Identification of factors associated with certification exam result may allow residency programs to recognize and intervene for residents at risk of failing. Despite this, residency programs have few evidence-based predictors of certification exam outcome. The change to pass-or-fail score reporting of the USA Medical Licensing Exam (USMLE) Step 1 removes one such predictor. MATERIALS AND METHODS: We performed a retrospective study of residents from a medium-sized internal medicine residency program who graduated from 1998 through 2017. We used univariate tests of associations between ABIM-CE result and various demographic and scholastic factors. RESULTS: Of 166 graduates, 14 (8.4%) failed the ABIM-CE on the first attempt. Failing the first attempt of the ABIM-CE was associated with older median age on entering residency (29 vs 27 years; P = 0.01); lower percentile rank on the Internal Medicine In-Training Examination (IM-ITE) in each of the first, second, and third years of training (P < 0.001 for all); and lower scores on the USMLE Steps 1, 2 Clinical Knowledge, and 3 (P < 0.05 for all). No association was seen between a variety of other scholastic or demographic factors and first-attempt ABIM-CE result. DISCUSSION: Although USMLE step 1 has changed to a pass-or-fail reporting structure, there are still other characteristics that allow residency programs to identify residents at risk of ABIM-CE first time failure and who may benefit from intervention.

A Prospective Study of Surgical Site Infection with its Risk Factors and Their Correlation with the NNIS Risk Index.

Background: Surgical site infection (SSI) is the third most commonly reported nosocomial infection, accounting for 10%-40% of all nosocomial infections and is a major cause of postoperative morbidity. Knowledge of factors related to SSI can help in reducing its incidence and related morbidity, which in many studies is shown to account for 38% of all infections in surgical patients. Lack of extending nosocomial infection surveillance programme and prevention measures in countries like India is viewed as a major challenge for the future. Objectives: The aims of this work were (1) to study the SSI rate in patients undergoing both elective and emergency abdominal surgery and SSI with CDC, and NNIS risk index; and (2) to assess SSI along with body mass index (BMI), glycaemic status, smoking and duration of pre-operative hospital stay of patients. Materials and Methods: In total, 300 patients who underwent elective and emergency abdominal surgery were enrolled in the study as per inclusion and exclusion criteria. SSI with CDC's NNIS risk index were analysed considering BMI, glycaemic status, smoking and duration of pre-operative hospital stay of patients. Results: In total, 300 cases of abdominal surgeries (elective and emergency) were analysed, out of which 60 cases were diagnosed to have SSI as per the criteria. Conclusion: This study demonstrated that there is a significant increase in SSI with increasing NNIS score that is, the greater the NNIS score, the greater the risk of SSI. With an increase in age, BMI, glycaemic index and preoperative hospital stay, the risk of SSI increases. Smoking and associated comorbidities also increase the risk of SSI.

Wound-Healing Effects of Curcumin and Its Nanoformulations: A Comprehensive Review.

Wound healing is an intricate process of tissue repair or remodeling that occurs in response to injury. Plants and plant-derived bioactive constituents are well explored in the treatment of various types of wounds. Curcumin is a natural polyphenolic substance that has been used since ancient times in Ayurveda for its healing properties, as it reduces inflammation and acts on several healing stages. Several research studies for curcumin delivery at the wound site reported the effectiveness of curcumin in eradicating reactive oxygen species and its ability to enhance the deposition of collagen, granulation tissue formation, and finally, expedite wound contraction. Curcumin has been widely investigated for its wound healing potential but its lower solubility and rapid metabolism, in addition to its shorter plasma half-life, have limited its applications in wound healing. As nanotechnology has proven to be an effective technique to accelerate wound healing by stimulating appropriate mobility through various healing phases, curcumin-loaded nanocarriers are used for targeted delivery at the wound sites. This review highlights the potential of curcumin and its nanoformulations, such as liposomes, nanoparticles, and nano-emulsions, etc. in wound healing. This paper emphasizes the numerous biomedical applications of curcumin which collectively prepare a base for its antibiofilm and wound-healing action.

Assessing Patient-Reported Financial Hardship in Patients With Cancer in Routine Clinical Care.

PURPOSE: Financial hardship (FH) in cancer care is a growing challenge for patients, their caregivers, and health care providers with impact on morbidity and mortality. In this study, we report on a standardized approach to describe the prevalence and predictors for FH as part of routine clinical workflow. We also report on the association of FH with survival in our cancer patient population. METHODS: This study includes patients who completed a FH screen at least once between 2018 and 2020. Demographics, disease state, and mortality data were extracted from the medical records. Multivariable logistic regression models were used to examine association of sociodemographic and disease variables with FH. By using propensity score weighting to account for differences in demographic and clinical factors between patients with and without FH, we then fit Cox proportional hazards models to examine the relationship between FH and survival. RESULTS: The study cohort included 31,154 patients. FH was reported by 14% (n = 4,250) of the patients. A significantly higher likelihood of having FH (P < .001 for all) was reported by racial/ethnic minority patients; those who were unemployed/disabled, single, or divorced; patients from disadvantaged neighborhoods; and those who were self-pay or had government insurance. Older age, being retired, and living farther from the cancer center were associated with significantly less likelihood of endorsing FH. Patients who endorsed FH had a lower survival (hazard ratio for mortality 1.46). CONCLUSION: Our study identified key groups more likely to report FH in a relatively affluent population at a large cancer center and showed an adverse association between FH and survival. Further research is needed to develop clinical care pathways for patients at high risk for worse financial and clinical outcomes.

Forest expansion dominates China's land carbon sink since 1980.

Carbon budget accounting relies heavily on Food and Agriculture Organization land-use data reported by governments. Here we develop a new land-use and cover-change database for China, finding that differing historical survey methods biased China's reported data causing large errors in Food and Agriculture Organization databases. Land ecosystem model simulations driven with the new data reveal a strong carbon sink of 8.9 ± 0.8 Pg carbon from 1980 to 2019 in China, which was not captured in Food and Agriculture Organization data-based estimations due to biased land-use and cover-change signals. The land-use and cover-change in China, characterized by a rapid forest expansion from 1980 to 2019, contributed to nearly 44% of the national terrestrial carbon sink. In contrast, climate changes (22.3%), increasing nitrogen deposition (12.9%), and rising carbon dioxide (8.1%) are less important contributors. This indicates that previous studies have greatly underestimated the impact of land-use and cover-change on the terrestrial carbon balance of China. This study underlines the importance of reliable land-use and cover-change databases in global carbon budget accounting.

Process-oriented analysis of dominant sources of uncertainty in the land carbon sink.

The observed global net land carbon sink is captured by current land models. All models agree that atmospheric CO2 and nitrogen deposition driven gains in carbon stocks are partially offset by climate and land-use and land-cover change (LULCC) losses. However, there is a lack of consensus in the partitioning of the sink between vegetation and soil, where models do not even agree on the direction of change in carbon stocks over the past 60 years. This uncertainty is driven by plant productivity, allocation, and turnover response to atmospheric CO2 (and to a smaller extent to LULCC), and the response of soil to LULCC (and to a lesser extent climate). Overall, differences in turnover explain ~70% of model spread in both vegetation and soil carbon changes. Further analysis of internal plant and soil (individual pools) cycling is needed to reduce uncertainty in the controlling processes behind the global land carbon sink.

Role of Serum Interleukin-6 and C-reactive Protein in Early Prediction of Severe Acute Pancreatitis.

Background: Early prediction of severity is an important goal in acute pancreatitis (AP), to identify 20% of patients who are likely to have a severe course. Such patients have an expected mortality of 15-20% and may benefit from early admission to high dependency or intensive care units, with parenteral or nasojejunal feeding and prophylactic antibiotics. In severe AP (SAP), multiorgan dysfunction accounts for most of early deaths. Aims: The aim of this article is to assess the role of serum interleukin (IL)-6 and serum C-reactive protein (CRP) in early prediction of severity of AP. Materials and Methods: This observational analytical study was conducted in the Department of General Surgery and Department of Biochemistry in our hospital in 62 patients as per inclusion and exclusion criteria. Results: IL-6 on day 1 and day 2 as well as CRP on day 2 was 100% sensitive but IL-6 on day 1 and day 2 had a maximum specificity of 88.37% among them when compared with a specificity of 81.4% of CRP on day 2. Though CRP on day 1 also had a specificity of 88.37%, its sensitivity was 89.47%. Conclusion: IL-6 and CRP together appear to be a promising marker for assessing the severity of AP within 48 h. We recommend to do IL-6 and CRP in patients with AP, which can help in predicting severity of the disease in patients.

Difficult Laparoscopic Cholecystectomy Predictors and its Significance: Our Experience.

Background: Laparoscopic cholecystectomy (LC) has become the procedure of choice for the management of symptomatic gallstone disease. In LC, the surgeons encountered difficulties with acutely inflamed or gangrenous gallbladder (GB), dense adhesions at Calot's triangle, fibrotic and contracted GB, and cholecystoenteric fistula. Depending on the difficulty faced during the surgery, the outcome of LC may vary from abandoning the procedure or partial cholecystectomy to conversion into open cholecystectomy. Complications related to biliary tract or adjoining structures or vessels may also occur. Our aim was to assess the different preoperative factors in patients of cholelithiasis and ascertain the validity of the scoring system devised by Randhawa and Pujahari in preoperatively predicting the difficult LC in our hospital scenario. Materials and Methods: This hospital-based observational study was conducted in the Department of General Surgery for a period of 2 years. All diagnosed cases of cholelithiasis admitted for elective LC during the study period in our hospital were included in the study. Results: In total, 154 patients, aged≥50 years, history of hospitalization for acute cholecystitis (AC), body mass index of 25 kg/m2 and more, abdominal scar, palpable GB, GB wall thickness ≥4 mm, pericholecystic collection, impacted stone found to be significant factors to predict difficult LC preoperatively. Endoscopic retrograde cholangiopancreatography and pancreatitis were found as independent risk factor for difficult LC. Conclusion: We recommend that the scoring system should be regularly used as a protocol for predicting difficulty levels preoperatively in LC. It can help to decide the surgical approach, counsel the patients, and reduce the complication rate, rate of conversion, and overall medical cost. The scoring system proposed by Randhawa and Pujahari is effective but has some lacunae.

Raloxifene-loaded SLNs with enhanced biopharmaceutical potential: QbD-steered development, in vitro evaluation, in vivo pharmacokinetics, and IVIVC.

Raloxifene hydrochloride, a second-generation selective estrogen receptor modulator, has been approved for the management of breast cancer. However, it is known to exhibit poor (~ 2%) and inconsistent oral bioavailability in humans, primarily ascribable to its low aqueous solubility, extensive first-pass metabolism, P-gp efflux, and presystemic glucuronide conjugation. The present research work entails the systematic development and evaluation of SLNs of RLX for its enhanced biopharmaceutical performance against breast cancer. Factor screening studies were conducted using Taguchi design, followed by optimization studies employing Box-Behnken design. Preparation of SLNs was carried out using glyceryl monostearate and Compritol® 888 ATO (i.e., lipid), Phospholipid S-100 (i.e., co-surfactant), and TPGS-1000 (i.e., surfactant) employing solvent diffusion method. The optimized formulation was evaluated for zeta potential, average particle size, field emission scanning electron microscope, transmission electron microscopy, and in vitro release study. Further, MCF-7 cells (cell cytotoxicity assay, apoptosis assay, and reactive oxygen species assay) and Caco-2 cells (cell uptake studies and P-gp efflux assay) were employed to evaluate the in vitro anticancer potential of the developed optimized formulation. In vivo pharmacokinetic studies were conducted in Sprague-Dawley rats to evaluate the therapeutic profile of the developed formulation. The optimized SLN formulations exhibited a mean particle size of 109.7 nm, PDI 0.289 with a zeta potential of - 13.7 mV. In vitro drug dissolution studies showed Fickian release, with release exponent of 0.137. Cell cytotoxicity assay, apoptosis assay, and cellular uptake indicated 6.40-, 5.40-, and 3.18-fold improvement in the efficacy of RLX-SLNs vis-à-vis pure RLX. Besides, the pharmacokinetic studies indicated quite significantly improved biopharmaceutical performance of RLX-SLNs vis-à-vis pure drug, with 4.06-fold improvement in Cmax, 4.40-fold in AUC(0-72 h), 4.56-fold in AUC(0-∞), 1.53-fold in Ka, 2.12-fold in t1/2, and 1.22-fold in Tmax. Further, for RLX-SLNs and pure drug, high degree of level A linear correlation was established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) at the corresponding time-points. Stability studies indicated the robustness of RLX-SLNs when stored at for 3 months. Results obtained from the different studies construe promising the anticancer potential of the developed RLX-SLNs, thereby ratifying the lipidic nanocarriers as an efficient drug delivery strategy for improving the biopharmaceutical attributes of RLX.

Response to Comments on "Recent global decline of CO2 fertilization effects on vegetation photosynthesis".

Our study suggests that the global CO2 fertilization effect (CFE) on vegetation photosynthesis has declined during the past four decades. The Comments suggest that the temporal inconsistency in AVHRR data and the attribution method undermine the results' robustness. Here, we provide additional evidence that these arguments did not affect our finding and that the global decline in CFE is robust.