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Bacterial wound infection has emerged as a pivotal threat to human health worldwide, and the situation has worsened owing to the gradual increase in antibiotic-resistant bacteria caused by the improper use of antibiotics. To reduce the use of antibiotics and avoid the increase in antibiotic-resistant bacteria, researchers are increasingly paying attention to photodynamic therapy, which uses light to produce reactive oxygen species to kill bacteria. Treating bacteria-infected wounds by photodynamic therapy requires fixing the photosensitizer (PS) at the wound site and maintaining a certain level of wound humidity. Hydrogels are materials with a high water content and are well suited for fixing PSs at wound sites for antibacterial photodynamic therapy. Therefore, hydrogels are often loaded with PSs for treating bacteria-infected wounds via antibacterial photodynamic therapy. In this review, we systematically summarised the antibacterial mechanisms and applications of PS-loaded hydrogels for treating bacteria-infected wounds via photodynamic therapy. In addition, the recent studies and the research status progresses of novel antibacterial hydrogels are discussed. Finally, the challenges and future prospects of PS-loaded hydrogels are reviewed.
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Antibacterianos , Bandagens , Hidrogéis , Fármacos Fotossensibilizantes , Infecção dos Ferimentos , Humanos , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Hidrogéis/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Cicatrização/efeitos dos fármacos , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologiaRESUMO
BACKGROUND: Postoperative anastomotic leakage (PAL) is a serious complication of gastric cancer surgery. Although perioperative management has made considerable progress, anastomotic leakage (AL) cannot always be avoided. The purpose of this study is to evaluate whether intraoperative leak testing (IOLT) can reduce the incidence of PAL and other postoperative outcomes in gastric cancer surgery. MATERIALS AND METHODS: In this meta-analysis, we searched the PubMed, Embase, and Cochrane Library databases for clinical trials to assess the application of IOLT in gastric cancer surgery. All patients underwent laparoscopic radical gastrectomy for gastric cancer surgery. Studies comparing the postoperative outcomes of IOLT and no intraoperative leak testing (NIOLT) were included. Quality assessment, heterogeneity, risk of bias, and the level of evidence of the included studies were evaluated. PAL, anastomotic-related complications, 30-day mortality, and reoperation rates were compared between the IOLT and NIOLT group. RESULTS: Our literature search returned 721 results, from which six trials (a total of 1,666 patients) were included in our meta-analysis. Statistical heterogeneity was low. The primary outcome was PAL. IOLT reduced the incidence of PAL [2.09% vs 6.68%; (RR = 0.31, 95% Cl 0.19-0.53, P < 0.0001]. Anastomotic-related complications, which included bleeding, leakage, and stricture, were significantly higher in the NIOLT group than in the IOLT group [3.24% VS 10.85%; RR = 0.30, 95% Cl 0.18-0.53, P < 0.0001]. Moreover, IOLT was associated with lower reoperation rates [0.94% vs 6.83%; RR = 0.18, 95% CI 0.07-0.43, P = 0.0002]. CONCLUSION: Considering the observed lower incidence of postoperative anastomotic leakage (PAL), anastomotic-related complications, and reoperation rates, IOLT appears to be a promising option for gastric cancer surgery. It warrants further study before potential inclusion in future clinical guidelines.
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Fístula Anastomótica , Gastrectomia , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirurgia , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/prevenção & controle , Fístula Anastomótica/etiologia , Gastrectomia/métodos , Gastrectomia/efeitos adversos , Laparoscopia/métodos , Laparoscopia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/etiologia , Reoperação/estatística & dados numéricos , Resultado do Tratamento , IncidênciaRESUMO
A green and highly efficient one-pot method for α-diaryl-ß-alkynol derivatives in water at room temperature was developed using the cocatalysis of a Lewis acid and meso-tetraphenylporphyrin iron(III) chloride (FeTPPCl). The unprecedented transformation was promoted by a modulation of the charge properties of propargylic carbocation chemistry and the use of an in situ-generated oxonium ylide as a matching nucleophile. The reaction was performed in water at room temperature with a highly step-economic manipulation in good to excellent yields and with a broad substrate scope. Water also acts as the third reactant for the one-pot transformation. Notably, the FeTPPCl catalyst can be directly reused four times with a slight discount in yields.
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A Pd-catalyzed multicomponent reaction was developed by trapping oxomium ylide with nitrosobenzene via Pd-promoted umpolung chemistry. The Pd catalyst plays two important roles: diazo compound decomposed catalyst and Lewis acid for the activation of nitrosobenzene. This strategy provides some insight into a new way for discovery of multicomponent methodology to construct complex molecules. The developed method also provides rapid access to a series of O-(2-oxy) hydroxylamine derivatives, which exhibit good anticancer activity in osteosarcoma cells.
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Oxigênio , Paládio , Catálise , Ácidos de LewisRESUMO
BACKGROUND: Gastric cancer (GC) is the third most common cause of cancer deaths worldwide. In the present study, we aimed to identify novel GC biomarkers by integrating isobaric tags of relative and absolute quantitation (iTRAQ) for aberrantly expressed proteins in GC patients. METHODS: Using stable isotope tags, we labeled an initial discovery group comprising four paired gastric cancer and adjacent gastric tissue samples, and subjected them to LC-ESI-MS/MS. We used a validation set comprising 129 paired gastric cancer and adjacent gastric tissues from patients and benign healthy controls to validate the candidate targets. RESULTS: We identified two proteins, NAD(P)-dependent steroid dehydrogenase-like (NSDHL) and neutral cholesterol ester hydrolase 1 (NCEH1), that were significantly overexpressed in GC tissues. The sensitivity and specificity of NSDHL were 80.6% and 74.4%, respectively, in GC compared with a sensitivity of 25.6% in adjacent tissues and 24% in benign healthy controls. The area under the ROC curve (AUC) for NSDHL was 0.810 for GC detection. Overexpression of NSDHL in GC was significantly correlated with local tumor invasion. The sensitivity and specificity of NCEH1 were 77.5% and 73.6%, respectively, in GC compared with a sensitivity of 26.4% in adjacent tissues and 20% in benign controls. The AUC for NSDHL was 0.792. Overexpression of NCEH1 was significantly associated with tumor histological classification and local invasion. Moreover, a combined analysis of NSDHL and NCEH1 achieved a sensitivity and specificity of 85.7% and 83%, respectively, and the AUC was 0.872. The combined analysis of NSDHL and NCEH1 was significantly correlated with histological grade and TNM â ¡-â £ staging. CONCLUSIONS: iTRAQ-labeled quantitative proteomics represents a powerful method to identify novel cancer biomarkers. The present study identified NSDHL and NCEH1 as useful biomarkers for screening, diagnosis, and prognosis of patients with gastric cancer.
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3-Hidroxiesteroide Desidrogenases/metabolismo , Biomarcadores Tumorais/análise , Esterol Esterase/metabolismo , Neoplasias Gástricas/diagnóstico , 3-Hidroxiesteroide Desidrogenases/análise , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células em Anel de Sinete/diagnóstico , Carcinoma de Células em Anel de Sinete/metabolismo , Carcinoma de Células em Anel de Sinete/patologia , Estudos de Casos e Controles , Detecção Precoce de Câncer , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteômica/métodos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray , Esterol Esterase/análise , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Espectrometria de Massas em TandemRESUMO
Both bioxindoles and continuous quaternary carbons play important roles in pharmaceutical scaffolds. However, few examples were developed to construct bioxindoles containing continuous quaternary carbons because of the steric hindrance effect. Here, a rhodium(II)-catalyzed three-component reaction of N,N-disubstituted anilines, 3-diazooxindoles, and isatin ketimines to deliver the 3-amino-3'-aryl-bioxindole compounds containing continuous quaternary carbons as products is developed. This transformation is proposed to proceed in a Mannich-type trapping of a zwitterion intermediate initiated from aromatic C-H bond functionalization. Several of these compounds exhibit good inhibitory activity against growth of osteosarcoma cell lines.
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A Rh(I)/Sc(III) co-catalyzed synthesis of highly valuable functionalized 1,4-diketone derivatives in good yields and with an excellent diastereoselectivity. The established method provides a rapid approach to structurally diverse 1,4-diketone scaffold in a very mild and rapid fashion from simple starting materials. Moreover, the protocol could be easily scaled up to gram-scale synthesis. An attempt to develop an asymmetric version of the Rh(I)/guanidine system was also explored, resulting in a moderate enantioselectivity (71% ee).
Assuntos
Cetonas/química , Ródio/química , Escândio/química , Compostos de Amônio/química , Compostos de Anilina/química , Catálise , Indóis/químicaRESUMO
1,2,5-Triol derivatives with vicinal chiral centers have been synthesized from simple starting materials by one-pot method in good yields and with an excellent enantioselectivity. This process was promoted by a chiral secondary amine and iridium(I) cocatalyzed three-component reaction of aryldiazoacetates and alcohols with enals as electrophiles followed by a reduction with NaBH4. Iridium(I)-associated oxonium ylide intermediates were efficiently generated and successfully trapped by the amine-activated enals via a selective 1,4-addition manner, generating enantioselective three-component coupling products.
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A highly diasetereoselective Mannich-type multicomponent reaction was developed to rapidly construct alkynylamide-substituted α,ß-diamino acid derivatives from simple starting materials under mild conditions in moderate to good yields for hit hunting. Most of the resulting products 4 exhibited good anticancer activity in HCT116, BEL7402, and SMMC7721 cells.
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Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an ideal target for treatment of type II diabetes and obesity. However, no druggable PTP1B inhibitor has been established and there is still an urgent demand for the development of structurally novel PTPIB inhibitor. Herein, we reported core-structurally novel PTP1B inhibitors with low micromole-ranged inhibitory activity by one-pot reaction from simple starting materials. Further studies demonstrated some of these active compounds had a specific selectivity over other PTPs. The structure and activity relationship was also described. The best active and selective compound 5e inhibited PTP1B activity with an IC50 of 4.53µM. Molecular docking analysis further demonstrated that compound 5e bound to the active pocket of PTP1B. The results might provide some insights for further development of new drugs for type II diabetes and obesity.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indóis/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Descoberta de Drogas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , OxindóisRESUMO
An elegant synergistic catalytic system comprising a ruthenium complex with a chiral Brønsted acid was developed for a four-component Mannich/cascade aza-Michael reaction. The ruthenium-associated ammonium ylides successfully trapped with in situ generated imines indicates a stepwise process of proton transfer in the ruthenium-catalyzed carbenoid N-H insertion reaction. The different decomposition abilities of various ruthenium complexes towards diazo compounds were well explained by the calculated thermodynamic data. The transformation features a mild, rapid, and efficient method for the synthesis of enantiomerically pure 1,3,4-tetrasubstituted tetrahydroquinolines bearing a quaternary stereogenic carbon center from simple starting precursors in moderate yields with high diastereo- and enantioselectivity.
Assuntos
Rutênio/química , Tetra-Hidroisoquinolinas/síntese química , Catálise , Complexos de Coordenação/química , Estereoisomerismo , Tetra-Hidroisoquinolinas/químicaRESUMO
A first example of 1,4-conjugate addition of ß,γ-unsaturated N-sulfonylimines via the oxonium ylides trapping process was developed. This method afforded a novel and efficient access for the high regio- and diastereoselective construction of α-hydroxyl-δ-amino esters derivatives, which exhibit inhibitory activity on PTP1B and SIRT1 enzymes in vitro. The synthetic potentials and the biological activity of the resulting products were well demonstrated to be promising for drug discovery.
Assuntos
Inibidores Enzimáticos/farmacologia , Iminas/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sirtuína 1/antagonistas & inibidores , Sulfonas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ésteres , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Sirtuína 1/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The chiral Rh(I)-diene-catalyzed asymmetric three-component reaction of aryldiazoacetates, aromatic amines, and ß-nitroacrylates was achieved to obtain γ-nitro-α-amino-succinates in good yields and with high diastereo- and enantioselectivity. This reaction is proposed to proceed through the enantioselective trapping of Rh(I)-associated ammonium ylides by nitroacrylates. This new transformation represents the first example of Rh(I)-carbene-induced ylide transformation.
Assuntos
Acrilatos/química , Compostos de Amônio/química , Metano/análogos & derivados , Ródio/química , Catálise , Metano/química , Estrutura Molecular , EstereoisomerismoRESUMO
A visible-light-induced highly efficient C(sp3)-H amination of ethers with amides and azoles has been presented under mild conditions via a nitrogen- and carbon-centered radical coupling process. This protocol successfully utilizes 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and tert-butyl nitrite (TBN) as cocatalysts to deliver the aminated products of ethers under aerobic conditions. Notably, the developed reaction features the corresponding products in good yields (up to 93%) with a wide substrate scope. The mechanistic study indicates that C-N bond formation proceeds via a direct radical cross-coupling process. Preliminary biological activity analysis indicates that the resulting products have good and selective inhibitory activity on osteosarcoma (OS) cell lines and are promising for use as hits for drug discovery.
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Osteosarcoma (OS) is a rare malignant tumor that has predominantly affected children and adolescents in the past 50 years. The genomes of OS tumors exhibit a high degree of complexity, which leads to the great challenge of target identification for anti-OS. To date, no efficient therapeutic target for the treatment of OS has been validated in clinical practice. In our previous drug hunting for the treatment of OS by phenotypic screening, we found that thiazolone derivate (R)-8i was an effective and selective inhibitor against OS in MNNG/HOS cells and in vivo. However, the mechanism of action and specific molecular targets of (R)-8i remain unclear. In this study, we design and synthesize the photo-cross-linking probes based on the lead compound (R)-8i and identify DDX5 as a potential target protein using an activity-based protein profiling strategy. Further experiments including Western blot, shRNA knockdown experiments, cell colony formation, wound healing assays, and cellular thermal shift assays support that (R)-8i binds to DDX5 and induces its degradation, which affect cell proliferation and migration through the PI3K-AKT-mTOR signaling pathway. The research shows that DDX5 is a potential therapeutic target for the treatment of OS.
Assuntos
Proliferação de Células , RNA Helicases DEAD-box , Osteossarcoma , Tiazóis , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Movimento Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Chemotherapy combining with surgical treatment has been the main strategy for osteosarcoma treatment in clinical. Due to unclear pathogenesis and unidentified drug targets, significant progress has not been made in the development of targeted drugs for osteosarcoma during the past 50 years. Our previous discovery reported compound R-8i with a high potency for the treatment of osteosarcoma by phenotypic screening. However, both the metabolic stability and bioavailability of R-8i are poor (T1/2 = 5.36 min, mouse liver microsome; and bioavailability in vivo F = 52.1 %, intraperitoneal administration) which limits it use for further drug development. Here, we described an extensive structure-activity relationship study of thiazolidine-4-one sulfone inhibitors from R-8i, which led to the discovery of compound 68. Compound 68 had a potent cellular activity with an IC50 value of 0.217 µM, much higher half-life (T1/2 = 73.8 min, mouse liver microsome) and an excellent pharmacokinetic profile (in vivo bioavailability F = 115 %, intraperitoneal administration). Compound 68 also showed good antitumor effects and low toxicity in a xenograft model (44.6 % inhibition osteosarcoma growth in BALB/c mice). These results suggest that compound 68 is a potential drug candidate for the treatment of osteosarcoma.
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Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Humanos , Camundongos , Animais , Preparações Farmacêuticas , Relação Estrutura-Atividade , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Neoplasias Ósseas/tratamento farmacológico , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular TumoralRESUMO
The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to human. Since there are still no effective treatment options against the new emerging variants of SARS-CoV-2, it is necessary to devote a continuous endeavor for more targeted drugs and the preparation for the next pandemic. Salvia miltiorrhiza and its active ingredients possess wide antiviral activities, including against SARS-CoV-2. Danshensu, as one of the most important active ingredients in Salvia miltiorrhiza, has been reported to inhibit the entry of SARS-CoV-2 into ACE2 (angiotensin-converting enzyme 2)-overexpressed HEK-293T cells and Vero-E6 cells. However, there is a paucity of information regarding its detailed target and mechanism against SARS-CoV-2. Here, we present Danshensu as a covalent inhibitor of 3-chymotrypsin-like protease (3CLpro) against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. Further molecular docking, site-directed mutagenesis, circular dichroism (CD) and fluorescence spectra revealed that Danshensu covalently binds to C145 of SARS-CoV-2 3CLpro, meanwhile forming the hydrogen bonds with S144, H163 and E166 in the S1 site. Structure-based optimization of Danshensu led to the discovery of the promising compounds with good inhibitory activity and microsomal stability in vitro. Due to Danshensu inhibiting lung inflammation in the mouse model, we found that Danshensu derivatives also showed better anti-inflammatory activity than Danshensu in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Thus, our study provides not only the clue of the efficacy of Salvia miltiorrhiza against SARS-CoV-2, but also a detailed mechanistic insight into the covalent mode of action of Danshensu for design of covalent inhibitors against SARS-CoV-2 3CLpro, highlighting its potential as a bifunctional molecule with antivirus and anti-inflammation.
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COVID-19 , Lactatos , SARS-CoV-2 , Animais , Camundongos , Humanos , Simulação de Acoplamento Molecular , Proteínas não Estruturais Virais/química , Antivirais/química , Peptídeo Hidrolases/farmacologia , Inibidores de Proteases/farmacologiaRESUMO
A regioselective electrochemical C-H amination method to synthesize N2-substituted 1,2,3-triazole using easily accessible ethers has been developed. Various substituents, including heterocycles, have a good tolerance, and 24 examples were obtained in moderate to good yields. Control experiments and DFT calculation investigations demonstrate that the electrochemical synthesis undergoes a N-tosyl 1,2,3-triazole radical cation process promoted by the single-electron transfer of the lone pair electrons of the aromatic N-heterocycle, and the desulfonation is responsible for the high N2-regioselectivity.
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BACKGROUND Siewert type II adenocarcinoma of the esophagogastric junction is located at the boundary of the distal esophagus and gastric cardia, and surgical resection is currently performed using open or laparoscopic methods. This report presents 2 cases of laparoscopic resection of Siewert type II adenocarcinoma of the esophagogastric junction using a transhiatal approach, complicated by hemopericardium. CASE REPORT We present 2 patients diagnosed with Siewert type II esophagogastric junction cancer. A 67-year-old man had intermittent dull pain in the epigastrium without apparent cause for 10 months. A 69-year-old man had persistent dull pain in the middle and upper abdomen for more than 3 months and acid reflux after eating. Gastroscopy with pathological examination confirmed the diagnoses. The patients underwent laparoscopic transhiatal total gastrectomy according to the Japanese Gastric Cancer Treatment Guidelines 2018 (5th edition). Pathological analysis classified the cancers as T3N1M0 and T2N0M0, respectively. The patients' cases were complicated with hemopericardium 18 h and 23 h after surgery, respectively. The shared clinical symptoms of the patients included tachycardia and low blood pressure. Cardiovascular color Doppler ultrasound and computed tomography (CT) were used to identify the hemopericardium. Following emergent ultrasound-guided pericardiocentesis and drainage, the vital signs of the patients improved. Both patients recovered well, and no other complications occurred. CONCLUSIONS Hemopericardium is a life-threatening complication for patients with esophageal-gastric junction cancer who undergo transhiatal laparoscopic surgery. Quick detection and intervention for postoperative hemopericardium following laparoscopic transhiatal total gastrectomy are important. Ultrasound-guided pericardiocentesis and drainage is effective for the treatment of postoperative hemopericardium.
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Adenocarcinoma , Neoplasias Esofágicas , Laparoscopia , Derrame Pericárdico , Neoplasias Gástricas , Masculino , Humanos , Idoso , Pré-Escolar , Derrame Pericárdico/etiologia , Derrame Pericárdico/cirurgia , Junção Esofagogástrica/cirurgia , Junção Esofagogástrica/patologia , Adenocarcinoma/complicações , Adenocarcinoma/cirurgia , Adenocarcinoma/patologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Laparoscopia/métodos , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , DorRESUMO
Objective: To investigate the incidence of falls in elderly aged 65 years and above among outpatients and inpatients, and to analyze its related factors and identify prevention strategies. Methods: A retrospective analysis was conducted on 451 patients aged 65 years and above who received comprehensive geriatric assessment in outpatients and inpatients from the Department of Geriatrics in the Second Xiangya Hospital from March 2021 to March 2022. According to whether there had been at least one fall in the past year, the patients were divided into a fall group and a non-fall group. Data were collected from the We-Chat applet of comprehensive geriatric assessment. A t test and chi-square test were performed to compare the difference between the two groups. Logistic regression analysis was then conducted to identify factors associated with falls. Results: (1) The incidence of falls among the outpatient and inpatient was 28.8%. (2) The rate of light, moderate, and heavy dependence on daily living ability and decreased mobile balance ability were higher in the fall group than those in the non-fall group. The average calf circumference in the fall group was significantly lower than that in the non-fall group. (3) The prevalence of diabetes and eye diseases in the fall group was significantly higher than that in the non-fall group. (4) The percentage of insomnia and suspicious insomnia cases in the fall group was higher than that in the non-fall group. The mean scores for dysphagia, frailty, and incontinence were higher and the mean malnutrition score was lower in the fall group than in the non-fall group. (5) Multiple logistic regression analysis showed that frailty, insomnia, and malnutrition were independent influencing factors of fall (OR = 1.955, 1.652, 10.719, P = 0.044, 0.041, 0.025, respectively). Conclusions: The incidence of falls among outpatients and inpatients aged 65 years and above is high. Frailty, insomnia, and malnutrition are the main factors influencing falls in these patients.