Defining the association between the prolonged operative time and 90-day complications in patients undergoing radical cystectomy

Objective:Radical cystectomy is a complex lengthy procedure associated with postoperative morbidity.We aimed to assess the operative time(OT)in patients undergoing radical cystectomy and its impact on 90-day postoperative complications and readmission rates.Methods:The retrospective cohort study included 296 patients undergoing radical cystectomy and urinary diversion from May 2010 to December 2018 in our institution.The OT of 369 min was set as a cutoff value between short and long OT groups.The primary outcome was 90-day postoperative complication rates.Secondary outcomes were gastrointestinal recovery time,length of hospital stay,and 90-day readmission rates.Results:The overall incidence of 90-day postoperative complications was 79.7%where 43.2%representing low-grade complications according to the ClavieneDindo classification(Grade 1 and Grade 2),and 36.5%representing high-grade complications(Grade3).Gastrointestinal tract and infectious complications are the most common complications in our data set(45.9%and 45.6%,respectively).On multivariable analysis,prolonged OT was significantly associated with odds of high-grade complications(odds ratio 2.340,95%confidence interval 1.288e4.250,p=0.005).After propensity score-matched analysis,a higher incidence of major complications was identified in the long OT group 55(51.4%)compared to 35(32.7%)in the short OT group(p=0.006).A shorter gastrointestinal tract recovery time was noticed in the short OT group(p=0.009).Prolonged OT was associated with a higher 90-day readmission rate on univariate and multivariate analyses(p<0.001,p=0.001,respectively).

Prevention of ventilator-associated pneumonia with inhaled antibiotics

The direct delivery of inhaled antibiotics to the respiratory tract has been a subject of enduring interest among medical practitioners and researchers due to the associated favorable pharmacokinetics.This interest has been particularly pronounced in the context of critically illpatients,wherehealthcare-associatedpulmonary infections represent a significant challenge,driving continued exploration of inhaled antibiotics for intubated patients.Recent high-level evidence has shown a very promising application in the field of ventilator-associated pneumonia (VAP) prevention.^([1]).

Treadmill training in Parkinson's disease:possible role of prefrontal modifications in the improved cortical-subcortical network function

Parkinson’s disease(PD)is a complex neurodegenerative disorder characterized by a range of motor symptoms such as bradykinesia,resting tremor,rigidity,and postural instability,as well as non-motor symptoms,such as depression,anxiety,sleep disturbances,and fatigue(Bloem et al.,2021).

Cardiovascular risk burden,dementia risk and brain structural imaging markers:a study from UK Biobank

Background Cardiovascular risk burden is associated with dementia risk and neurodegeneration-related brain structure,while the role of genetics and incident cardiovascular disease(CVD)remains unclear.Aims To examine the association of overall cardiovascular risk burden with the risk of major dementia subtypes and volumes of related brain regions in a large sample,and to explore the role of genetics and CVD onset.Methods A prospective study among 354 654 participants free of CVD and dementia(2006-2010,mean age 56.4 years)was conducted within the UK Biobank,with brain magnetic resonance imaging(MRl)measurement availablefor 15104participants since 2014.CVD risk burden was evaluated by the Framingham General Cardiovascular Risk Score(FGCRS).Dementia diagnosis was ascertained from inpatient and death register data.Results Overamedian 12.0-yearfollow-up,3998 all-cause dementia cases were identified.Higher FGCRS was associated with increasedall-cause dementia risk after adjusting for demographic,major lifestyle,clinical factors and the polygenic risk score(PRS)of Alzheimer's disease.Comparing the high versus low tertile of FGCRS,the odds ratios(ORs)and 95%confidence intervals(Cls)were 1.26(1.12 to 1.41)for all-cause dementia,1.67(1.33 to 2.09)for Alzheimer's disease and 1.53(1.07 to 2.16)for vascular dementia(all p_(treng)<0.05).Incident stroke and coronary heart disease accounted for 14%(95%Cl:9% to 21%)of the association between FGCRS and all-cause dementia.Interactions were not detected for FGCRS and PRS on the risk of any dementia subtype.We observed an 83%(95%Cl:47%to 128%)higher all-cause dementia risk comparing the high-high versus low-low FGCRS-PRS category.For brain volumes,higher FGCRS was associated with greater log-transformed white matter hyperintensities,smaller cortical volume and smaller grey matter volume.Conclusions Our findings suggest that the positive association of cardiovascular risk burden with dementia risk also applies to major dementia subtypes.The association of cardiovascular risk burden with all-cause dementia is largely independent of CVD onset and genetic predisposition to dementia.

The Versatility and Diagnostic Potential of VOC Profiling for Noninfectious Diseases

variety of volatile organic compounds(VOCs)are produced and emitted by the human body every day.The identity and concentration of these VOCs reflect an individual’s metabolic condition.Information regarding the production and origin of VOCs,however,has yet to be congruent among the scientific community.This review article focuses on the recent investigations of the source and detection of biological VOCs as a potential for noninvasive discrimination between healthy and diseased individuals.Analyzing the changes in the components of VOC profiles could provide information regarding the molecular mechanisms behind disease as well as presenting new approaches for personalized screening and diagnosis.VOC research has prioritized the study of cancer,resulting in many research articles and reviews being written on the topic.This review summarizes the information gained about VOC cancer studies over the past 10 years and looks at how this knowledge correlates with and can be expanded to new and upcoming fields of VOC research,including neurodegenerative and other noninfectious diseases.Recent advances in analytical techniques have allowed for the analysis of VOCs measured in breath,urine,blood,feces,and skin.New diagnostic approaches founded on sensor-based techniques allow for cheaper and quicker results,and we compare their diagnostic dependability with gas chromatography-and mass spectrometry-based techniques.The future of VOC analysis as a clinical practice and the challenges associated with this transition are also discussed and future research priorities are summarized.

Knowledge of radiation exposure associated with common trauma imaging modalities among orthopaedic surgeons,emergency medicine physicians,and general surgeons in the United States

BACKGROUND:Few contemporary studies have assessed physicians’knowledge of radiation exposure associated with common imaging studies,especially in trauma care.The purpose of this study was to assess the knowledge of physicians involved in caring for trauma patients regarding the effective radiation doses of musculoskeletal(MSK)imaging studies routinely utilized in the trauma setting.METHODS:An electronic survey was distributed to United States orthopaedic surgery,general surgery,and emergency medicine(EM)residency programs.Participants were asked to estimate the radiation dose for common imaging modalities of the pelvis,lumbar spine,and lower extremity,in terms of chest X-ray(CXR)equivalents.Physician estimates were compared to the true effective radiation doses.Additionally,participants were asked to report the frequency of discussing radiation risk with patients.RESULTS:A total of 218 physicians completed the survey;102(46.8%)were EM physicians,88(40.4%)wereorthopaedicsurgeons,and28(12.8%)weregeneralsurgeons.Physicians underestimated the effective radiation doses of nearly all imaging modalities,most notably for pelvic computed tomaography(CT)(median 50 CXR estimation vs.162 CXR actual)and lumbar CT(median 50 CXR estimation vs.638 CXR actual).There was no difference between physician specialties regarding estimation accuracy(P=0.133).Physicians who regularly discussed radiation risks with patients more accurately estimated radiation exposure(P=0.007).CONCLUSION:The knowledge among orthopaedic and general surgeons and EM physicians regarding the radiation exposure associated with common MSK trauma imaging is lacking.Further investigation with larger scale studies is warranted,and additional education in this area may improve care.

Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-linked hypophosphatemia

X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads tohypophosphatemia and impaired mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence ofdental abscesses and periodontal disease, likely driven by poorly formed structures of the dentoalveolar complex, including thealveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (SclAb) treatment improves phosphate homeostasis, and increases long bone mass, strength, and mineralization in the Hyp mousemodel of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male andfemale wild-type and Hyp littermates were injected with 25 mg·kg−1 of vehicle or Scl-Ab twice weekly beginning at 12 weeks of ageand euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineraldensity in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active(nonphosphorylated) β-catenin, dentin matrix protein 1 (DMP1) and osteopontin stained alveolar osteocytes. Scl-Ab had no effecton the mass and mineralization of dentin, enamel, acellular or cellular cementum. There was a nonsignificant trend towardincreased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fiber structural parameters were notaffected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in adult Hyp mice.

Robotic surgery in urology:Recent advances

The adoption of robotic-assisted surgery has determined a paradigm shift in delivery of urological surgery in the last two decades.It has been a privilege for us to serve as guest editors for this special issue of the Asian Journal of Urology(AJU)on the most recent advances in this field.

Review of deep learning and artificial intelligence models in fetal brain magnetic resonance imaging

Central nervous system abnormalities in fetuses are fairly common,happening in 0.1%to 0.2%of live births and in 3%to 6%of stillbirths.So initial detection and categorization of fetal Brain abnormalities are critical.Manually detecting and segmenting fetal brain magnetic resonance imaging(MRI)could be timeconsuming,and susceptible to interpreter experience.Artificial intelligence(AI)algorithms and machine learning approaches have a high potential for assisting in the early detection of these problems,improving the diagnosis process and follow-up procedures.The use of AI and machine learning techniques in fetal brain MRI was the subject of this narrative review paper.Using AI,anatomic fetal brain MRI processing has investigated models to predict specific landmarks and segmentation automatically.All gestation age weeks(17-38 wk)and different AI models(mainly Convolutional Neural Network and U-Net)have been used.Some models'accuracy achieved 95%and more.AI could help preprocess and postprocess fetal images and reconstruct images.Also,AI can be used for gestational age prediction(with one-week accuracy),fetal brain extraction,fetal brain segmentation,and placenta detection.Some fetal brain linear measurements,such as Cerebral and Bone Biparietal Diameter,have been suggested.Classification of brain pathology was studied using diagonal quadratic discriminates analysis,Knearest neighbor,random forest,naive Bayes,and radial basis function neural network classifiers.Deep learning methods will become more powerful as more large-scale,labeled datasets become available.Having shared fetal brain MRI datasets is crucial because there aren not many fetal brain pictures available.Also,physicians should be aware of AI's function in fetal brain MRI,particularly neuroradiologists,general radiologists,and perinatologists.

A systematic review of robot-assisted partial nephrectomy outcomes for advanced indications:Large tumors(cT2-T3),solitary kidney,completely endophytic,hilar,recurrent,and multiple renal tumors

Objective:Robot-assisted partial nephrectomy(RAPN)has become widely used for treatment of renal cell carcinoma and it is expanding in the field of complex renal masses.The aim of this systematic review was to analyze outcomes of RAPN for completely endophytic renal masses,large tumors(cT2-T3),renal cell carcinoma in solitary kidney,recurrent tumors,completely endophytic and hilar masses,and simultaneous and multiple tumors.Methods:A comprehensive search in the PubMed,Scopus,Web of Science,and Cochrane Central Register of Controlled Trials databases was performed in December 2022 for English language papers.The primary endpoint was to evaluate the role of RAPN in the setting of each category of complex renal masses considered.The secondary endpoint was to evaluate the surgical and functional outcomes.Results:After screening 1250 records,43 full-text manuscripts were selected,comprising over 8500 patients.Twelve and thirteen studies reported data for endophytic and hilar renal masses,respectively.Five and three studies reported outcomes for cT2-T3 and solitary kidney patients,respectively.Four studies focused on redo-RAPN for recurrent tumors.Two studies investigated simultaneous bilateral renal masses and five reports focused on multiple tumor excision in ipsilateral kidney.Conclusion:Over the past decade,evidence supporting the use of RAPN for the most challenging nephron-sparing surgery indications has continuously grown.Although limitations remain including study design and lack of detailed long-term functional and oncological outcomes,the adoption of RAPN for the included advanced indications is associated with favorable surgical outcomes with good preservation of renal function without compromising the oncological result.Certainly,a higher likelihood of complication might be expected when facing extremely challenging cases.However,none of these indications should be considered per se an exclusion criterion for performing RAPN.Ultimately,a risk-adapted approach should be employed.

Changes in physical activity and sleep following the COVID-19 pandemic on a university campus:Perception versus reality

It has been hypothesized that key lifestyle behaviors of physical activity and sleep worsened in response to the Coronavirus disease(COVID-19)pandemic.However,there have been inconsistencies in findings of changes in these key lifestyle behaviors across populations likely due to the wide variety of assessment methods.The purpose of the study was to compare physical activity and sleep before and after the COVID-19 pandemic using accelerometers and self-reported behaviors.A longitudinal follow-up was conducted on students,faculty,and staff at a university campus in the United States.In the periods before March 2020(covering the academic years of 2018–2019 or 2019–2020)and again in April–June 2021,participants completed surveys to evaluate their physical activity and sleep behaviors and wore an accelerometer.A total of 44 participants completed the survey at both timepoints and 32 completed accelerometer assessment at both timepoints.Fifty-seven percent of participants reported a perceived decline in physical activity,while 30%reported a worsening in sleep.From selfreported data,overall physical activity did not change,but there was a decrease in active transport(p<0.001)and increase in domestic physical activity(p?0.012).Sleep quality decreased as evidenced by an increase in Pittsburgh Sleep Quality Index scores(p?0.045).There were no changes in accelerometer measured physical activity or sleep.There were no changes in physical or mental health.While perceptions of physical activity declined from prior to the COVID-19 pandemic,there were no changes in device-measured physical activity,and changes in self-reported physical activity differed by domain.

Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Chiari畸形Ⅰ合并神经源性吞咽功能障碍的临床特征（英文）

目的:成年Chiari畸形Ⅰ型(chiari malformation typeⅠ,CMⅠ)患者中神经源性吞咽障碍的发生率并不少见,临床上罕有关于食管高分辨率测压(high-resolution manometry,HRM)技术对CMⅠ患者吞咽功能的精确评价的报道。本研究拟通过HRM量化评价CMⅠ患者吞咽功能,初步探讨影响吞咽功能的可能相关因素及其机制。方法:共纳入北京大学第三医院2010年1月至2015年7月收治的42例经临床和MRI检查、确诊不合并寰枢椎脱位的CMⅠ患者,将患者分为吞咽障碍组20例和不合并吞咽障碍组22例。所有患者均接受HRM检查,收集所有患者的临床、影像学资料和HRM评价参数,并做统计学分析。结果:(1)合并吞咽障碍的女性CMⅠ患者比例明显高于不合并吞咽障碍组(14/20 vs.8/22,P=0.029),吞咽障碍组后组颅神经损伤的其他症状(包括声音嘶哑、咽部感觉减退、患侧面部感觉减退及汗液分泌减少等)发生率明显高于不合并吞咽障碍对照组(15/20 vs.5/22,P=0.01)。(2)HRM显示吞咽障碍组食管上括约肌(upper esophageal sphincter,UES)松弛比高于对照组(75.3%vs.63.1%,P=0.023),UES上缘亦高于对照组(17.2 cm vs.15.7 cm,P=0.005)。(3)吞咽障碍组MRI影像上延髓或上颈部的脊髓空洞比例明显高于对照组(17/20 vs.7/22,P=0.001)。结论:CMⅠ患者的吞咽障碍经常与后组颅神经损伤、共济失调和阳性锥体束征相关,HRM显示平均UES松弛比例的差异亦有可能与延髓或上颈髓的脊髓空洞症有关,CMⅠ中的吞咽障碍的机制可能是由于神经源性咽肌运动障碍所导致,吞咽障碍病因学检查应包括CMⅠ畸形鉴别诊断。

胚胎期脂多糖暴露可通过钟样受体4引起出生后多巴胺能神经元减少

目的观察钟样受体4(TLR-4)在胚胎期脂多糖(LPS)暴露引起的出生后个体脑内多巴胺(DA)能神经元减少中的作用。方法 TLR-4突变型C57BL/10ScNCr小鼠和野生型C57BL/10ScSn小鼠各15只,在妊娠期第10.5天给小鼠腹腔注射LPS或肽聚糖(PDG),出生后4月龄时收集大脑组织标本(n=5),通过免疫组织化学染色和体视学技术定量DA能神经元和小胶质细胞数量,高效液相色谱法测定DA及其代谢物水平,免疫荧光法结合流式细胞术测定TNF-α和IL-1β蛋白水平。结果出生前接触过LPS的4月龄C57BL/10ScSn小鼠,与注射生理盐水的对照小鼠比较,黑质DA能神经元减少(25.3±2.1)%,纹状体DA含量降低(33.5±5.0)%,黑质小胶质细胞数量增加(294±24)%,黑质和纹状体TNF-α和IL-1β蛋白水平也明显增高;但是出生前接触过LPS的TLR-4突变型C57BL/10ScNCr小鼠脑内无相应变化。出生前接触过TLR-2配体PDG的4月龄C57BL/10ScNCr和C57BL/10ScSn小鼠均出现脑内DA能神经元减少和免疫炎症改变。结论胚胎期接触LPS可通过TLR-4引起出生后个体脑内DA能神经元减少。

锌指E盒结合蛋白1在骨发育和骨肿瘤发生中的作用

锌指E盒结合蛋白1(Zeb 1)为Zeb基因家族一员,是胚胎发育、细胞分化、肿瘤发生等生理病理过程必不可少的转录因子;有实验证据表明Zeb 1与骨发育和骨肿瘤发生发展密切相关。本文结合Zeb 1结构和功能,从生理性骨发育和病理性恶性骨肿瘤发生发展的角度系统论述Zeb 1相关调控机制,并做进一步的研究展望。

2007年美国骨科医师年会脊柱分会场纪要

2007年2月14-18日，美国骨科医师年会（AAOS）在加利福尼亚州圣地亚哥的国际会议中心召开。参加本次会议代表来自北美洲、欧洲、亚洲、澳洲、中南美洲等共约4万余人。现将脊柱外科分会场主题作一简要总结汇报，与同道分享。

Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots:Stress,intestinal hyperpermeability and inflammation

Mast cells (MC) are pivotal elements in several physiological and immunological functions of the gastro- intestinal (GI) tract. MC translate the stress signals that has been transmitted through brain gut axis into release of proinflammatory mediators that can cause stimulation of nerve endings that could affect afferent nerve terminals and change their perception, affect intestinal motility, increase intestinal hyperpermeability and, in susceptible individuals, modulate the inflammation. Thus, it is not surprising that MC are an important element in the pathogenesis of inflammatory bowel disease and non inflammatory GI disorders such as IBS and mast cell enterocolitis.

Surgery for Peyronie＇s disease

Peymnie＇s disease （PD） is most simply referred to as a fibrotic wound-healing disorder of the tunica albuginea. It is both a physically and psychologically devastating disorder that causes penile deformity, curvature, hinging, narrowing and shortening, which may compromise sexual function. Although a variety of non-surgical treatments have been suggested, none to date offer a reliable and effective correction of the penile deformity. As a result, surgery remains the gold standard treatment option, offering the most rapid and reliable treatment which will be the focus of this article. We review the preoperative evaluation, surgical algorithm, graft materials and postoperative management of PD. Outcomes for tunical shortening, tunical lengthening and penile prosthesis placement for penile straightening are reviewed. Tunica albuginea plication is the preferred method of straightening for men with adequate rigidity and less severe disease defined as curvature less than 70° without narrowing/hinging. Men who have more severe, complex deformity, but maintain strong preoperative erectile function should be considered candidates for straightening with plaque incision or partial excision and grafting. Finally, for those men who have inadequate rigidity and PD, penile prosthesis placement with straightening is the best approach to address both problems.

Cirrhotic ascites review: Pathophysiology, diagnosis and management

Ascites is a pathologic accumulation of peritoneal fluidcommonly observed in decompensated cirrhotic states. Its causes are multi-factorial, but principally involve significant volume and hormonal dysregulation in the setting of portal hypertension. The diagnosis of ascites is considered in cirrhotic patients given a constellation of clinical and laboratory findings, and ultimately confirmed, with insight into etiology, by imaging and paracentesis procedures. Treatment for ascites is multimodal including dietary sodium restriction, pharmacologic therapies, diagnostic and therapeutic paracentesis, and in certain cases transjugular intra-hepatic portosystemic shunt. Ascites is associated with numerous complications including spontaneous bacterial peritonitis, hepato-hydrothorax and hepatorenal syndrome. Given the complex nature of ascites and associatedcomplications, it is not surprising that it heralds increased morbidity and mortality in cirrhotic patients and increased cost-utilization upon the health-care system. This review will detail the pathophysiology of cirrhotic ascites, common complications derived from it, and pertinent treatment modalities.

Radiation exposure and reduction in the operating room: Perspectives and future directions in spine surgery

Intraoperative imaging is vital for accurate placement of instrumentation in spine surgery. However, the use of biplanar fluoroscopy and other intraoperative imaging modalities is associated with the risk of significant radiation exposure in the patient, surgeon, and surgical staff. Radiation exposure in the form of ionizing radiation can lead to cellular damage via the induction of DNA lesions and the production of reactive oxygen species. These effects often result in cell death or genomic instability, leading to various radiation-associated pathologies including an increased risk of malignancy. In attempts to reduce radiation-associated health risks, radiation safety has become an important topic in the medical field. All practitioners, regardless of practice setting, can practice radiation safety techniques including shielding and distance to reduce radiation exposure. Additionally, optimization of fluoroscopic settings and techniques can be used as an effective method of radiation dose reduction. New imaging modalities and spinal navigation systems have also been developed in an effort to replace conventional fluoroscopy and reduce radiation doses. These modalities include Isocentric Three-Dimensional C-Arms, O-Arms, and intraoperative magnetic resonance imaging. While this influx of new technology has advanced radiation safety within the field of spine surgery, more work is still required to overcome specific limitations involving increased costs and inadequate training.