Nevin Manimala

J Chem Theory Comput. 2022 Jun 3. doi: 10.1021/acs.jctc.2c00207. Online ahead of print.

ABSTRACT

Widely applicable, modified Green-Kubo expressions for the local diffusion coefficient (D_l) are obtained using linear response theory. In contrast to past definitions in use, these expressions are statistical mechanical results. Molecular simulations of systems with anisotropic diffusion and an inhomogeneous density profile confirm the validity of the results. Diffusion coefficients determined from different expressions in terms of currents and velocity correlations agree in the limit of large systems. Furthermore, they apply to arbitrarily small local regions, making them readily applicable to nanoscale and inhomogeneous systems where knowledge of D_l is important.

PMID:35657378 | DOI:10.1021/acs.jctc.2c00207

Int J Cancer. 2022 Jun 3. doi: 10.1002/ijc.34143. Online ahead of print.

ABSTRACT

Little is known about risk factors for progression of high-grade anal intraepithelial neoplasia (AIN) to anal squamous cell carcinoma (ASCC). In this large, population-based study, we assess the role of factors related to immune status for the risk of ASCC among individuals from the general population with a diagnosis of AIN3. Individuals diagnosed with AIN3 during 1985-2016 were identified in the Danish Pathology Registry and followed for subsequent development of ASCC. The study population was linked to the National Patient Registry, the Danish Prescription Registry, and the Danish HIV Cohort Study for information on autoimmune disease, genital warts, and HIV status. To study the progression rate, Cox regression models with hazard ratios (HR) and 95% confidence intervals (CI) were applied with time since AIN3 as the underlying time scale and with adjustment for age at AIN3 diagnosis, year of AIN3 diagnosis, and sex. The study population comprised 1,222 individuals with AIN3 contributing 12,824 person-years of follow-up. Ninety-seven individuals (7.9%) developed ASCC. Individuals registered with an autoimmune disease or genital warts before and/or after the AIN3 diagnosis had an increased rate of progression to ASCC compared with individuals without these conditions. People living with HIV had a higher progression rate than HIV-negative individuals (HR = 4.25; 95% CI: 1.87-9.65) with the highest progression rate among those with CD4 count <200 cells/μl. These associations may be caused by an interplay between HPV infection and immunosuppression.

PMID:35657350 | DOI:10.1002/ijc.34143

Int J Cancer. 2022 Jun 3. doi: 10.1002/ijc.34148. Online ahead of print.

ABSTRACT

Risk of colorectal cancer (CRC) increases in relatives of patients with CRC. The extent to which this is attributable to genetic predisposition or shared environment is unclear. We explored this question using nationwide cohorts from Denmark, Finland and Sweden. From 1977-2013, we identified 359,879 individuals with a CRC diagnosis and 2,258,870 of their relatives who we followed for CRC incidence. We calculated standardised incidence ratios (SIR) and 95% confidence intervals (CI) for CRC in individuals with an affected relative. We used nationwide household and pedigree data along with national SIR estimates to calculate risk ratios (RR) for the contribution of shared household environment, childhood environment, and genetic relationship to CRC risk in those with an affected relative. SIR of CRC was increased for individuals with an affected relative, across all countries and ages. For those with an affected parent, the SIR was 1.65 (95% CI: 1.61-1.69), 1.98 (95% CI: 1.87-2.09), for those with an affected sibling, and 2.14 (95% CI: 1.84-2.49) for those with an affected halfsibling. In those <65 years old, shared childhood (RR: 1.41, 95% CI: 1.26-1.57) and household (RR: 2.08, 95% CI: 1.25-3.46) environments were significantly greater contributors to familial risk of CRC than genetics (RR: 0.88, 95% CI: 0.53-1.46). This large-scale Nordic population-based study of excess risk of CRC among relatives of those with CRC addresses the difficult disentangling of shared environment from genetic predisposition in the heritability of CRC. We found shared environment to be the most important contributor to CRC risk.

PMID:35657349 | DOI:10.1002/ijc.34148

ACS Appl Mater Interfaces. 2022 Jun 3. doi: 10.1021/acsami.2c05761. Online ahead of print.

ABSTRACT

Active pharmaceutical ingredients (APIs) typically consist of solid therapeutic particles that may acquire electrostatic charge during milling and grinding operations. This may result in the agglomeration of particles, thereby reducing the flowability and affecting the homogeneity of the drug formulation. Electrostatic charge build-up may also lead to fire explosions. To avoid charge build-up, APIs are often coated with polymers. In this paper, atomic layer deposition (ALD) using metal oxides such as Al₂O₃ and TiO₂ on APIs, namely, palbociclib and pazopanib HCl, has been utilized to demonstrate a uniform coating that results in a significant reduction in the surface charge of the drug particles. Kelvin probe force microscopy (KPFM) shows a 4-fold decrease in the surface contact potential of uncoated pazopanib HCl (2.3 V) to 0.52 and 0.82 V in TiO₂-and Al₂O₃-coated APIs, respectively. Also, the ζ potential indicated a 4-fold decrease in the surface charge on coating pazopanib HCl, i.e., from -32.9 mV to -7.51 and -8.51 mV in Al₂O₃ and TiO₂, respectively. Surface morphology, thermal stability, dissolution studies, and cytotoxicity of the drug particles after coating were also examined. Thermal analysis indicated no change in the melting temperature (T_m) after coating. ALD coating was found to be uniform and conformal as observed in images obtained from scanning electron microscopy (SEM) and scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDS). The rate of dissolution was found to be delayed by the coating, and thus ALD offers slower drug release. Coating APIs with TiO₂ and Al₂O3 did not induce statistically significant cytotoxicity compared to the uncoated samples. The results presented in this study demonstrate that ALD coating can be used to reduce surface charge build-up and enhance the bulk properties of the drug particles without affecting their physicochemical properties.

PMID:35656880 | DOI:10.1021/acsami.2c05761

Hand (N Y). 2022 Jun 3:15589447221093676. doi: 10.1177/15589447221093676. Online ahead of print.

ABSTRACT

BACKGROUND: Stenosing flexor tenosynovitis is commonly treated by injection of corticosteroids into the flexor tendon sheath. However, there is no consensus in the literature regarding the optimal technique, specifically when not utilizing ultrasound guidance. Here, we present a cadaver study in which 3 common techniques of flexor sheath injection were compared with regard to their accuracy and safety profiles.

METHODS: Fifteen fresh-frozen cadaver hands (60 digits) were evenly divided into 3 groups (20 digits per group). Digits in each group were injected with methylene blue dye using 1 of the 3 techniques (palmar-to-bone, palmar supra-tendinous, and mid-axial). The fingers were then dissected and were inspected for location of dye, as well as injury to tendon or digital nerves.

RESULTS: The mid-axial technique demonstrated the greatest accuracy with the highest rate of all intra-sheath injection, 15 of 20 digits (75%), while the palmar-to-bone technique produced the most combined intra- and extra-sheath injections, 13 of 20 digits, (65%) and the palmar supra-tendinous technique resulted in the most all extra-sheath injections, 9 of 20 digits (45%). The difference in rates of all intra-sheath injection was significant (P = .01). The mid-axial technique also produced the fewest intra-tendinous injections 0 of 20, although this result did not reach statistical significance (P = .15).

CONCLUSIONS: Compared to other common non-image guided flexor tendon sheath injection techniques, the mid-axial injection technique was found to be the most accurate in producing all intra-sheath injection and least likely to result in intra-tendinous injection.

PMID:35656857 | DOI:10.1177/15589447221093676

Hand (N Y). 2022 Jun 3:15589447221093671. doi: 10.1177/15589447221093671. Online ahead of print.

ABSTRACT

BACKGROUND: Upper-extremity limb loss has been associated with serious psychological sequelae. Despite advancements in surgical procedures and prostheses for upper limb amputees, it is critical to recognize the psychosocial component of these patients’ care. Although the role of psychological factors in outcomes is increasingly acknowledged, little is known about the prevalence of depression and post-traumatic stress disorder (PTSD) in the civilian population after traumatic upper-extremity amputation.

METHODS: In this retrospective observational single-center study, adult patients evaluated for traumatic upper limb amputations from 2016 to 2019 completed the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, Visual Analogue Scale, the Center for Epidemiologic Studies Depression Scale, and the Primary Care PTSD Screen during visits. All data underwent descriptive statistical analysis.

RESULTS: Thirty-nine adult patients treated for upper-extremity traumatic amputation completed patient-reported outcomes (PROs) questionnaires. The median final follow-up time for our cohort was 17 months from amputation. Twenty patients (51%) screened positive for depression and 27 (69%) for PTSD during follow-up. The median time from amputation to first positive screening was 6.5 months for depression and 10 months for PTSD. The physical component score of Veterans RAND 12-Item Health Survey (VR-12) was significantly worse for patients with depression. The Median DASH and mental component score of VR-12 were significantly worse for patients with PTSD.

CONCLUSION: Upper-extremity limb loss has a significant impact on mental health, which in turn affects PROs. The high prevalence of depression and PTSD in traumatic upper-extremity amputees underscores the necessity for screening and multidisciplinary treatment.

PMID:35656852 | DOI:10.1177/15589447221093671

Pediatr Blood Cancer. 2022 Jun 2:e29801. doi: 10.1002/pbc.29801. Online ahead of print.

ABSTRACT

BACKGROUND: Brentuximab vedotin (BV) is an antibody drug-conjugated anti-CD30 approved for the treatment of adult classical Hodgkin’s lymphoma (HL), whereas it is considered as off-label indication in paediatrics. The aim of the study was to evaluate the safety and efficacy of BV to treat patients aged less than 18 years with refractory/relapsed HL.

MATERIALS AND METHODS: In this multicentre, retrospective study, 68 paediatric patients who received at least one dose of BV between November 2011 and August 2020 were enrolled. A median of nine doses of BV were administered as monotherapy (n = 31) or combined with other therapies (n = 37). BV was administrated alone as consolidation therapy after stem cell transplantation (SCT) in 12 patients, before SCT in 18 patients, whereas in 15 patients it was used before and after SCT as consolidation therapy. Median follow-up was 2.8 years (range: 0.6-8.9 years).

RESULTS: The best response was observed in the 86% of patients; the overall response rate was 66%. The 3-year progression-free survival was 58%, whereas the overall survival was 75%. No statistically significant differences between patients treated with BV monotherapy or combination were highlighted. In multivariate analysis, patients with non-nodular sclerosis HL and not transplanted had an increased risk of failure. Overall, 46% of patients had grade 3-4 adverse events that led to BV discontinuation in five of them.

CONCLUSION: In conclusion, our study confirms that BV was a safe and effective drug, able to induce complete remission, either as monotherapy or in association with standard therapy.

PMID:35656841 | DOI:10.1002/pbc.29801

Stroke. 2022 Jun 3:101161STROKEAHA122038662. doi: 10.1161/STROKEAHA.122.038662. Online ahead of print.

ABSTRACT

BACKGROUND: Hypertension is a risk factor of poor stroke outcomes and associated with antiplatelet resistance. This study aimed to explore the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in patients with different hypertension status, using randomized trial data from the CHANCE-2 trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II).

METHODS: A total of 6412 patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles were enrolled and randomized to either ticagrelor-aspirin or clopidogrel-aspirin group. Hypertension status were classified into no, newly diagnosed, and previously diagnosed hypertension according to medical history, blood pressure, and antihypertensive medications during hospitalization. The primary efficacy and safety outcomes were stroke recurrence and moderate to severe bleeding risk within 90-day follow-up.

RESULTS: Ticagrelor-aspirin was associated with reduced risk of new stroke in patients without hypertension (32 [4.8%] versus 60 [7.2%]; hazard ratio, 0.55 [95% CI, 0.35-0.86]), but not in those with a newly diagnosed hypertension (20 [5.3%] versus 36 [9.1%]; hazard ratio 0.59 [95% CI, 0.33-1.07]), or those with a previously diagnosed hypertension (139 [7.0%] versus 147 [7.4%]; hazard ratio, 0.93 [95% CI, 0.74-1.18]) compared with clopidogrel-aspirin (P=0.04 for interaction). The risk of bleeding for ticagrelor-aspirin was not associated with hypertension status (0.1% versus 0.4%; 0.3% versus 0.5%, 0.4% versus 0.3%, P=0.50 for interaction). All the efficacy and safety outcomes between treatments did not differ by blood pressure levels on admission.

CONCLUSIONS: In the CHANCE-2 trial, patients without hypertension received a significantly greater benefit from ticagrelor- aspirin than those with previous hypertension after minor stroke or transient ischemic attack, and a similar benefit trend was observed in those with newly diagnosed hypertension.

REGISTRATION: URL: http://www.

CLINICALTRIALS: gov; Unique identifier: NCT04078737.

PMID:35656824 | DOI:10.1161/STROKEAHA.122.038662

Ann Otol Rhinol Laryngol. 2022 Jun 3:34894221098802. doi: 10.1177/00034894221098802. Online ahead of print.

ABSTRACT

OBJECTIVES: Hypopharyngeal and laryngeal cancers are aggressive and usually diagnosed at advanced stage with esophagus invasion. Total pharyngolaryngoesophagectomy with gastric pull-up reconstruction has been a common surgery for these cancers but long-term outcomes are still questionable. This study aimed to investigate short-term and long-term outcomes of patients who underwent this surgery.

METHODS: Patients with hypopharyngeal or laryngeal cancer invading cervical esophagus who underwent total pharyngolaryngoesphagectomy with gastric pull-up between 2012 and 2016 was included and followed up until 2021. Short-term outcomes were complications and long-term outcomes were overall survival (OS) and disease-free survival (DFS).

RESULTS: Fifty patients were included with a mean age of 60.3 years and 94% were male. Pyriform fossa was the most common primary site of tumor (50%), followed by posterior hypopharyngeal wall (18%) and postcricoid region (18%). Mean operating time, postoperative oral intake and hospital stay was 363.1 ± 43.6 minutes, 8.8 ± 3.6 days and 14.2 ± 3.0 days respectively. Complications occurred in 15 patients (30%) without any in-hospital death. During the follow-up period, 17 patients had recurrence and 35 patients died. Median (95% confidence interval [CI]) OS and DFS time were 30 (21-37) and 30 (19-36) months. Five-year OS and DFS probability (95% CI) were 22.6% (12.8-39.7) and 22.7% (12.9-39.8).

CONCLUSIONS: Total pharyngolaryngoesophagectomy with gastric pull-up is feasible and safe. However, even with curative surgery and multimodal treatment, advanced pharyngeal or laryngeal cancer with cervical esophagus invasion still has poor survival outcome.

PMID:35656819 | DOI:10.1177/00034894221098802

J Biopharm Stat. 2022 Jun 3:1-18. doi: 10.1080/10543406.2022.2058524. Online ahead of print.

ABSTRACT

This research focuses on the bias and type I error control issues when the marginal structural models (MSMs) are applied to evaluate the causal survival benefits of active intervention versus control in randomized clinical trials (RCTs) with treatment switching after disease progression. When MSMs are applied in the RCT setting, the question of interest, model specifications, strategies for type I error control, bias reduction, etc. differ somewhat from those for observational studies. This manuscript discusses the approaches used to accommodate these differences. Through Monte Carlo simulations and a case study, our research demonstrates that, with sufficient attention paid to issues applicable to RCTs in particular, MSMs may perform better than the inverse probability of censoring weighting (IPCW) method in analyzing the survival endpoint in RCTs with treatment switching because more information is used by the MSM.

PMID:35656809 | DOI:10.1080/10543406.2022.2058524