Dynamics of phase-separated microdroplets near the contact line of evaporating all-aqueous drops.

Evaporation of multicomponent drops can induce liquid-liquid phase separation and spatial reconfiguration of phases. Here, we unveil several novel dynamics near the contact line of evaporating multicomponent drops containing polyethylene glycol and dextran. The interplay between background Marangoni flow and self-migration of nucleated microdroplets creates both unstable and stable equilibrium points. This leads to either continuous migration or stepwise advancement of microdroplets, influenced by random coalescence events. Tiny dextran microdroplets nucleating at the contact line can migrate toward the bulk only by growing in size with coalescence events. Our findings offer new insights into the fundamental understanding of evaporating multicomponent drops and factors influencing the spatial segregation of phases in evaporative liquid-liquid phase separation with implications in prebiotic biomolecular reactions to industrial applications.

Correlation Between Radiological and Functional Outcomes Following Operative and Nonoperative Management of Acetabular Fractures: A Prospective Observational Study.

INTRODUCTION: The management of acetabular fractures is a complicated orthopedic procedure that has been advancing with time. Newer radiological tools like CT scans help surgeons to identify and manage these fractures more attentively. The study was conducted to evaluate the clinical and radiographic outcomes in patients with acetabular fractures managed either conservatively or by open reduction and internal fixation. MATERIALS AND METHOD: The study was done on 35 patients aged 18-60 years, with acetabular fractures treated either surgically or conservatively. Clinical scorings and radiological scoring were only taken and noted at three- and six-month intervals using Matta's radiographic scoring and modified Merle d'Aubigne and Postel clinical hip scoring. Clinico-radiological variables and complications were compared between the two groups. The data obtained was subjected to statistical analyses using IBM Statistical Package of Social Sciences (SPSS) 2.0 version software (Chicago, IL, USA) at a level of significance being p<0.05. RESULTS:  Out of a total of 35 patients, 19 were treated surgically and 16 conservatively. In patients belonging to the surgical treatment group, a maximum of 57.9% were aged 40-50 years, whereas the maximum patients (50%) of the conservative treatment group were aged <40 years, with male predominance in both groups. The type of fracture was recorded according to Judet and Letournel in both groups. Merle d'Aubigne's scoring and Matta's hip score were recorded at three and six months in both groups. A positive correlation was seen between radiological and functional outcomes at three and six months, which means that the higher the radiological scoring, the better the functional outcome of the patient managed either conservatively or surgically in the entire cohort. CONCLUSION:  Our study revealed that surgically managed patients had better functional and radiological outcomes than the patients who were conservatively managed at six months of follow-up. However, this is associated with more complications depending on fracture complexity and initial presentation of hip dislocation. The higher the radiological scoring, the better the functional outcome of the patient managed either conservatively or surgically in the entire cohort.

Comparison of Different Endodontic Access Cavity Designs on the Fracture Resistance of Tooth in WaveOne Gold and TruNatomy Instrumentation.

Background: An important aspect of the preparation of the access cavity and biomechanical preparation of the root canal is to safeguard as much of the tooth's framework as possible without affecting access and visibility. Objectives: To compare the impact of the conservative design of access preparation and traditional design of access preparation in association with TruNatomy endodontic instrumentation and WaveOne Gold endodontic instrumentation on resistance to fracture by the design of a cavity for endodontic access using finite element analysis. Materials and Methods: Micro-CT radiographic images of 16 human first permanent molars of the mandible were included in the study to create representative finite element analysis computational models. Results: A significant reduction in load for failure after endodontic preparation was observed in TDAP subcategories as compared to specimens with CDAP. However, the reduction in load for failure was comparable in both endodontic instrument systems within the CDAP and TDAP. Conclusion: A significant reduction in load for failure after endodontic preparation was observed in the traditional design of access preparation subcategories as compared to specimens with the conventional design of access preparation.

Efficacy of Inclisiran in Patients Having Familial Hypercholesterolemia: Heterozygous Compared to Homozygous Trait, a Systematic Review and Meta-analysis.

OBJECTIVE: To find out whether inclisiran sodium has different efficacy in heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH) patient groups. METHODS: We conducted the systematic review and meta-analysis of ORION clinical trials. PubMed, Embase, and Clinicaltrials.gov databases were searched for the relevant studies. Atheroscalerotic parameters considered for our objective were low-density lipoprotein cholesterol, total cholesterol, proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B, and nonhigh-density lipoprotein cholesterol. Primary outcomes were the percentage difference in atheroscalerotic parameters at follow-up relative to baseline values. Our study examined these primary outcomes to determine whether there is a statistically significant difference between the HeFH and HoFH groups. Risk of bias was assessed by the Cochrane risk of bias tool. Meta-analysis was performed when at least 2 studies reported on the same variable. RESULTS: Four ORION clinical trials provided the data related to the mean difference in the atheroscalerotic parameters at follow-up relative to baseline, of HeFH and HoFH patient populations, after administration of 300 mg inclisiran subcutaneously. We pooled together these mean differences for each group and applied a statistical test to analyze if the values were significantly different between the groups. The results of our study unveiled the significant difference in pooled mean differences in low-density lipoprotein cholesterol (HeFH: -48.62%; HoFH: -9.12%; P < 0.05), total cholesterol (HeFH: -30.31%; HoFH: -11.50%; P < 0.05), apolipoprotein (HeFH: -39.97%; HoFH: -14.68%; P < 0.05), and nonhigh-density lipoprotein (HeFH: -44.51%; HoFH: -12.22%; P < 0.05) between HeFH and HoFH groups. However, the difference in pooled mean difference in PCSK9 values (HeFH: -68.41%; HoFH: -56.25%; P = 0.2) between HeFH and HoFH groups was statistically insignificant. Studies were of high quality. CONCLUSIONS: There was a significant difference in the reductions in atherosclerotic lipid parameters in heterozygous and homozygous populations after the administration of inclisiran except for PCSK9 parameter. Further studies are needed to support this conclusion.

Phase 3 RCT comparing docetaxel-platinum with docetaxel-platinum-5FU as neoadjuvant chemotherapy in borderline resectable oral cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) with TPF (docetaxel, cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer with a survival advantage over PF (cisplatin and 5FU). TP (docetaxel and cisplatin) has shown promising results with a lower rate of adverse events but has never been compared to TPF. METHODS: In this phase 3 randomized superiority study, adult patients with borderline resectable locally advanced oral cancers were randomized in a 1:1 fashion to either TP or TPF. After the administration of 2 cycles, patients were evaluated in a multidisciplinary clinic and further treatment was planned. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and adverse events. RESULTS: 495 patients were randomized in this study, 248 patients in TP arm and 247 in TPF arm. The 5-year OS was 18.5% (95% CI 13.8-23.7) and 23.9% (95% CI 18.1-30.1) in TP and TPF arms, respectively (Hazard ratio 0.778; 95% CI 0.637-0.952; P = 0.015). Following NACT, 43.8% were deemed resectable, but 34.5% underwent surgery. The 5-year OS was 50.7% (95% CI 41.5-59.1) and 5% (95%CI 2.9-8.1), respectively, in the surgically resected versus unresected cohort post NACT (P < 0.0001). Grade 3 or above adverse events were seen in 97 (39.1%) and 179 (72.5%) patients in the TP and TPF arms, respectively (P < 0.0001). CONCLUSION: NACT with TPF has a survival benefit over TP in borderline resectable oral cancers, with an increase in toxicity which is manageable. Patients who undergo surgery achieve a relatively good, sustained survival.

Incurable advanced salivary gland tumours: a retrospective analysis and peek into the perplexing clinical and molecular intricacies from a tertiary care centre in India.

Background: Salivary gland tumours are rare cancers with variable course and prognosis. There is a paucity of data, especially for the advanced stages. Materials and methods: This is a retrospective analysis carried out in our institute. All patients seeking treatment for incurable advanced salivary gland tumours from October 2018 to September 2022 were included. Relevant clinical data were collected and appropriate statistical analysis was applied. Results: 30 patients were included in the analysis. The parotid gland was the most common site of origin (73%). Adenoid cystic carcinoma (ACC) and salivary duct carcinoma (SDC) were equally (37%) the most common pathological subtypes. The majority of patients were males (73%) and lungs (57%) were the most common site of metastases. On molecular analysis, SDC had high rates of androgen receptor (AR) (90%) and human epidermal growth factor receptor 2 (HER2) (55%) positivity. Mucoepidermoid carcinoma (MEC) had AR and HER2 positivity rates of 17% and 20%, respectively, while for ACC it was even lower. A variety of treatment regimens including hormonal therapy, anti-HER2 targeted therapy and chemotherapy were used in first-line treatment. With an overall response rate (ORR) of 10/21 (48%), only 9/21 (43%) went on to receive second-line treatment with an ORR of 4/9 (44%). The progression-free survival (PFS) with first-line treatment (PFS1) was a median of 5 months. The median PFS1 was worst for MEC. The median overall survival (OS) was 10 months. Median OS for ACC, SDC and MEC were 11, 10 and 7 months, respectively. At 24 months, ACC had much higher survival (50%) than others (10%) indicating a proportion of ACC with an indolent course. Conclusion: Our analysis highlights the variable disease biology of advanced salivary gland tumours and throws light on the various possible treatment targets and strategies. Molecular profiling and advancement in targeted therapies are expected to increase survival in this group of rare cancers.

Surface Acoustic Wave Propagation of GaN/Sapphire Integrated with a Gold Guiding Layer.

Gallium nitride (GaN), widely known as a wide bandgap semiconductor material, has been mostly employed in high power devices, light emitting diodes (LED), and optoelectronic applications. However, it could be exploited differently due to its piezoelectric properties, such as its higher SAW velocity and strong electromechanical coupling. In this study, we investigated the affect of the presence of a guiding layer made from titanium/gold on the surface acoustic wave propagation of the GaN/sapphire substrate. By fixing the minimum thickness of the guiding layer at 200 nm, we could observe a slight frequency shift compared to the sample without a guiding layer, with the presence of different types of surface mode waves (Rayleigh and Sezawa). This thin guiding layer could be efficient in transforming the propagation modes, acting as a sensing layer for the binding of biomolecules to the gold layer, and influencing the output signal in terms of frequency or velocity. The proposed GaN/sapphire device integrated with a guiding layer could possibly be used as a biosensor and in wireless telecommunication applications.

Predicting Corrosion Damage in the Human Body Using Artificial Intelligence: In Vitro Progress and Future Applications.

Artificial intelligence (AI) is used in the clinic to improve patient care. While the successes illustrate AI's impact, few studies have led to improved clinical outcomes. In this review, we focus on how AI models implemented in nonorthopedic fields of corrosion science may apply to the study of orthopedic alloys. We first define and introduce fundamental AI concepts and models, as well as physiologically relevant corrosion damage modes. We then systematically review the corrosion/AI literature. Finally, we identify several AI models that may be implemented to study fretting, crevice, and pitting corrosion of titanium and cobalt chrome alloys.

Management of non-functioning kidney due to pelvi-ureteric junction obstruction in pediatric age group: an observational study.

INTRODUCTION: A non-functional kidney (NFK) has been defined as one having paper-thin parenchyma, and split renal function (SRF) of < 10% on a nuclear scan. There are differences of opinion about nephrectomy or pyeloplasty in these patients. The present study was conducted to assess our management strategy of renal salvage for NFK. MATERIALS AND METHODS: It was a retrospective cohort study from January 2015 to July 2022, patients having SRF < 10% were included. These patients underwent ultrasound-guided percutaneous nephrostomy (PCN). A repeat nuclear scan was performed after 3 months. If SRF increased to > 10%, pyeloplasty was performed. RESULTS: Fifteen patients were managed. The mean age was 24.67 ± 23.61 months. Male to female ratio was 4:1. The initial mean SRF was 6.67 ± 2.85, which improved to 16.80 ± 4.69 after 3 months of placing the PCN (p < 0.001). The corresponding changes in the mean effective renal plasma flow (ERPF) were 60.13 ± 24.08 to 106.53 ± 24.61 (p < 0.001). There was no complaint after the placement of PCN. All patients underwent dismembered pyeloplasty. CONCLUSION: In NFK due to PUJO, expectant treatment in form of PCN followed by pyeloplasty appears to be the primary treatment modality, and nephrectomy may not be needed in any of them.

Results of Phase III Randomized Trial for Use of Docetaxel as a Radiosensitizer in Patients With Head and Neck Cancer, Unsuitable for Cisplatin-Based Chemoradiation.

PURPOSE: There is a lack of published literature on systemic therapeutic options in cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) undergoing chemoradiation. Docetaxel was assessed as a radiosensitizer in this situation. METHODS: This was a randomized phase II/III study. Adult patients (age ≥ 18 years) with LAHNSCC planned for chemoradiation and an Eastern Cooperative Oncology Group performance status of 0-2 and who were cisplatin-ineligible were randomly assigned in 1:1 to either radiation alone or radiation with concurrent docetaxel 15 mg/m2 once weekly for a maximum of seven cycles. The primary end point was 2-year disease-free survival (DFS). RESULTS: The study recruited 356 patients between July 2017 and May 2021. The 2-year DFS was 30.3% (95% CI, 23.6 to 37.4) versus 42% (95% CI, 34.6 to 49.2) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.673; 95% CI, 0.521 to 0.868; P value = .002). The corresponding median overall survival (OS) was 15.3 months (95% CI, 13.1 to 22.0) and 25.5 months (95% CI, 17.6 to 32.5), respectively (log-rank P value = .035). The 2-year OS was 41.7% (95% CI, 34.1 to 49.1) versus 50.8% (95% CI, 43.1 to 58.1) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.747; 95% CI, 0.569 to 0.980; P value = .035). There was a higher incidence of grade 3 or above mucositis (22.2% v 49.7%; P < .001), odynophagia (33.5% v 52.5%; P < .001), and dysphagia (33% v 49.7%; P = .002) with the addition of docetaxel. CONCLUSION: The addition of docetaxel to radiation improved DFS and OS in cisplatin-ineligible patients with LAHNSCC.[Media: see text].

Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study.

PURPOSE: The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1%-3% of patients in low- and middle-income countries because of their cost. In our previous study, metronomic chemotherapy improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC) improved overall survival (OS). METHODS: This was a randomized phase III superiority study. Adult patients with recurrent or newly diagnosed advanced head and neck squamous cell carcinoma being treated with palliative intent with an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Patients were randomly assigned 1:1 to TMC consisting of oral methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily, or TMC with intravenous nivolumab (TMC-I) 20 mg flat dose once every 3 weeks. The primary end point was 1-year OS. RESULTS: One hundred fifty-one patients were randomly assigned, 75 in TMC and 76 in the TMC-I arm. The addition of low-dose nivolumab led to an improvement in the 1-year OS from 16.3% (95% CI, 8.0 to 27.4) to 43.4% (95% CI, 30.8 to 55.3; hazard ratio, 0.545; 95% CI, 0.362 to 0.820; P = .0036). The median OS in TMC and TMC-I arms was 6.7 months (95% CI, 5.8 to 8.1) and 10.1 months (95% CI, 7.4 to 12.6), respectively (P = .0052). The rate of grade 3 and above adverse events was 50% and 46.1% in TMC and TMC-I arms, respectively (P = .744). CONCLUSION: To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved OS and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.

Study the Possibility of Creating Mucosal Valve Mechanism at Ureteric Orifice without Obstructing the Urine Outflow but Preventing the Urine Backflow into the Ureters.

Objective: To study the possibility of creating mucosal valve mechanism at ureteric orifice without obstructing the urine outflow but preventing the urine backflow into the ureters. Materials and Methods: Ethical waiver was obtained from the institutional ethical committee. Prospective experimental study was conducted on the post-mortem specimen of intact bladder with urethra and bilateral ureters retrieved from the already slaughtered lamb available in the meat market. Feeding tube inserted via urethral opening into the bladder lumen and bladder inflated with saline demonstrated no reflux of urine via transverse cut opening of ureters. Bladder lumen opened, ureteric orifices incised backwards to eliminate the obliquity. After closing the bladder opening, saline inflation test demonstrated bilateral reflux of saline via cut openings of bilateral ureters. Bladder was re-opened. The upper limb of horizontal U started 10 mm lateral and 8 mm above the refluxing ureteric orifice. Distal most curvature of horizontal U was kept 5 mm medial to ureteric orifice continuing along the lower limb of horizontal U terminating 10 mm lateral and 8 mm below the refluxing ureteric orifice, mucosal flaps from superior and inferior incision mobilized and edges joined to cover the ureteric orifice creating a flap valve mechanism. Influx of saline via cut end of ureters demonstrated no obstruction. Bladder was closed. Saline inflation test and contrast study demonstrated abolition of reflux on flap side and persistence of reflux on another side. Results: Five such experiments were conducted. On the side where the valve was created, Vesicoureteral reflux was abolished in four but in one minimal reflux still persisted. Conclusion: Creating a mucosal flap valve around the ureteric orifice can prevent reflux in 80% of cases without obstruction and without the necessity of ureteric mobilization or creating submucosal tunnel.

Angiotensin-converting Enzyme Inhibitors: Can it be a Potential Treatment of Infantile Hemangioma.

AIMS: The aim of the sudy was to evaluate potential role of oral captopril, an angiotensin-converting enzyme (ACE) inhibitor, and in treatment of infantile hemagioma (IH) and report our preliminary results. METHODS: This prospective study included 18 children with IH admitted in the department of pediatric surgery with no history of prior treatment of any type. Baseline blood pressure (BP), electrocardiogram, two-dimensional echocardiography, serum electrolytes, and renal function test (RFT) were noted. Oral captopril was started as first-line drug at a dose of 0.1 mg/kg orally 12 h with gradually increase of dosage up to 2.0 mg/kg 12 h over the period of 10 days with monitoring of BP, serum electrolytes, RFT, and occurrence of any side effect. If no side effects were noted and patients were stable, they were discharged and followed up until 6 months after stopping treatment. During follow-up, response to treatment was documented clinically and photographically. Development of any side effect was also noted. RESULTS: Excellent response to captopril was noticed in nine patients over 16-18 months. Four patients showed good response. Oral propranolol had to be administered alternatively in one patient showing fair response during the initial 4 months but no response afterward and in four patients showing no response at all. One patient developed an allergic reaction to propranolol and was started oral corticosteroid. These five patients had near complete resolution of lesion for the next 8-10 months. CONCLUSIONS: ACE inhibitors might have a role, though slow, in the involution of IHs. Therefore, these may have the potential to emerge as an alternative treatment for IH in future after confirmation with randomized studies with propranolol.

The wandering ventriculoperitoneal shunt and the scope of its salvage.

PURPOSE: Distal shunt tube migration following ventriculoperitoneal (VP) shunt placement in children is mostly managed by an initial shunt diversion/removal and subsequent replacement. Lately, shunt salvage is being used as an alternative in certain conditions. We have focused on the situations where one can consider or disregard shunt salvage in such cases. METHOD: A retrospective study of children treated for distal shunt migration following VP shunt placement between January 2013 and December 2019. RESULT: Seventeen children were managed for over 7 years. These included cutaneous extrusions (n = 4), hollow viscus perforation (n = 6), inguinal hernias (n = 5), and umbilical extrusion (n = 2). The surgical treatment varied from a cutaneous wound closure (with a tube in situ), temporary external shunt diversion, and laparotomy with shunt reposition into the peritoneal cavity. Shunt salvage was possible in three cases, whereas in 2 cases even though shunt salvage was possible, it was not feasible due to a short residual shunt length. CONCLUSION: VP shunt salvage is possible in certain cases of distal shunt migration with a functional uninfected shunt. Small cutaneous extrusions can be covered by a local skin flap. Also, one should consider the residual intraperitoneal shunt length before its salvage in small children.

Supernumerary Kidney Associated With Horseshoe Malformation and Ureteric Stricture With Hydroureteronephrosis - A Rare Case.

Supernumerary kidney is an accessory kidney with its own vasculature, collecting-system and encapsulated parenchyma with about 100 cases reported in the literature. However, there is no report of supernumerary kidney associated with horseshoe malformation with ureteric stricture. We report a rare case of 20 months old female admitted with left-sided abdomen lump and mild abdominal pain. During surgery, supernumerary kidney with horseshoe component with grossly-dilated left-sided pelvicalyceal system and proximal 1-cm of left-ureter, distal to which whole of left-ureter was noncanalized, was seen. Right-ureter was normal. Distal dilated part of left-ureter was anastomosed to bladder-dome after excision of strictured segment of left-ureter with placement of nephrostomy.

Detecting functional field units from satellite images in smallholder farming systems using a deep learning based computer vision approach: A case study from Bangladesh.

Improving agricultural productivity of smallholder farms (which are typically less than 2 ha) is key to food security for millions of people in developing nations. Knowledge of the size and location of crop fields forms the basis for crop statistics, yield forecasting, resource allocation, economic planning, and for monitoring the effectiveness of development interventions and investments. We evaluated three different full convolutional neural network (F-CNN) models (U-Net, SegNet, and DenseNet) with deep neural architecture to detect functional field boundaries from the very high resolution (VHR) WorldView-3 satellite imagery from Southern Bangladesh. The precision of the three F-CNN was up to 0.8, and among the three F-CNN models, the highest precision, recalls, and F-1 score was obtained using a DenseNet model. This architecture provided the highest area under the receiver operating characteristic (ROC) curve (AUC) when tested with independent images. We also found that 4-channel images (blue, green, red, and near-infrared) provided small gains in performance when compared to 3-channel images (blue, green, and red). Our results indicate the potential of using CNN based computer vision techniques to detect field boundaries of small, irregularly shaped agricultural fields.

Neo-adjuvant chemotherapy followed by either continuous hyper-fractionated accelerated radiation therapy week-end less or conventional chemo-radiotherapy in locally advanced NSCLC-A randomised prospective single institute study.

CONTEXT: Better locoregional control and increased overall survival by continuous hyper fractionated accelerated radiotherapy have been shown in unresectable nonsmall cell lung carcinoma (NSCLC). Dose escalation and neoadjuvant chemotherapy (NACT) along with continuous hyperfractionated accelerated radiotherapy week end-less (CHARTWEL) were also tried for improved survival. In this present study, we compared the results of NACT followed by CHARTWEL against NACT followed by conventional concurrent chemo-radiation therapy. AIMS: The aim of this study is to compare the locoregional control and toxicities in NSCLC Stage IIIA and B in both arms. SETTINGS AND DESIGN: Randomized, prospective single-institutional study with a study population comprising all locally advanced unresectable NSCLC patients enrolled in 2014 at our institute. SUBJECTS AND METHODS: All enrolled patients were randomized into two arms-CHARTWEL and concomitant chemo-radiotherapy (CCRT), after three weeks of the fourth cycle of NACT. In CHARTWEL arm 30 patients received two-dimensional radiotherapy (RT) 58.5 Gy/39 fr/2.5 weeks while in CCRT arm 30 received 66 Gy/33 fr/6.5 weeks. Disease response was evaluated at 6 months and toxicity assessment during and after treatment completion. Data were analyzed using tools such as percentage, mean, Chi-square test and P value. Chi-square and P value was calculated by statistical online software (http://quantpsy.org). RESULTS: 28% of patients in study arm and 20% in control arm had complete response at 6 months after RT. Locoregional disease control was observed in 44% in study arm and 32% in control arm of patients. There was no statistical difference in grades of toxicities or overall survival (OS)/disease-free survival except persistent esophagitis Grade III seen in two patients of study arm. CONCLUSIONS: Study suggests that CHARTWEL in combination with NACT is an effective strategy to treat patients with locally advanced lung cancer with the advantage of a smaller dose and shorter duration. Although large multivariate studies still needed.