Nevin Manimala

Syst Biol. 2021 Dec 2:syab079. doi: 10.1093/sysbio/syab079. Online ahead of print.

ABSTRACT

Understanding variation in rates of evolution and morphological disparity is a goal of macroevolutionary research. In a phylogenetic comparative methods framework, we present three explicit models for linking the rate of evolution of a trait to the state of another evolving trait. This allows testing hypotheses about causal influences on rates of phenotypic evolution with phylogenetic comparative data. We develop a statistical framework for fitting the models with generalized least-squares regression and use this to discuss issues and limitations in the study of rates of evolution more generally. We show that the power to detect effects on rates of evolution is low in that even strong causal effects are unlikely to explain more than a few percent of observed variance in disparity. We illustrate the models and issues by testing if rates of beak-shape evolution in birds are influenced by brain size, as may be predicted from a Baldwin effect in which presumptively more behaviorally flexible large-brained species generate more novel selection on themselves leading to higher rates of evolution. From an analysis of morphometric data for 645 species, we find evidence that both macro- and microevolution of the beak are faster in birds with larger brains, but with the caveat that there are no consistent effects of relative brain size.[Baldwin effect; beak shape; behavioral drive; bird; brain size; disparity; phylogenetic comparative method; rate of evolution.].

PMID:34865153 | DOI:10.1093/sysbio/syab079

Nephrol Dial Transplant. 2021 Dec 4:gfab346. doi: 10.1093/ndt/gfab346. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with acute interstitial nephritis (AIN) can present without typical clinical features, leading to a delay in diagnosis and treatment. We therefore developed and validated a diagnostic model to identify patients at risk of AIN using variables from the electronic health record.

METHODS: In patients who underwent a kidney biopsy at Yale between 2013-2018, we tested the association of over 150 variables with AIN including demographics, comorbidities, vital signs, and laboratory tests (training set, 70%). We used least absolute shrinkage and selection operator (LASSO) methodology to select pre-biopsy features associated with AIN. We performed AUC analysis with internal (held-out test set, 30%) and external validation (Biopsy Biobank Cohort of Indiana). We tested change in model performance after addition of urine biomarkers in Yale AIN study.

RESULTS: We included 393 patients (AIN = 22%) in training set, 158(AIN = 27%) in test set, 1118(AIN = 11%) in validation set, and 265(AIN = 11%) in Yale AIN study. Variables in selected model included serum creatinine (adjusted odds ratio, 2.31(1.42-3.76)), blood urea nitrogen to creatinine ratio (0.40(0.20-0.78)), and urine dipstick specific gravity (0.95(0.91-0.99)) and protein (0.39(0.23-0.68)). This model showed an AUC of 0.73(0.64-0.81) in the test set, which was similar to the AUC in the external validation cohort [0.74(0.69-0.79)]. The AUC improved to 0.84(0.76-0.91) upon addition of urine interleukin-9 and TNF-α.

CONCLUSIONS: We developed and validated a statistical model that showed a modest AUC for AIN diagnosis, which improved upon addition of urine biomarkers. Future studies could evaluate this model and biomarkers to identify unrecognized cases of AIN.

PMID:34865148 | DOI:10.1093/ndt/gfab346

Nephrol Dial Transplant. 2021 Dec 3:gfab344. doi: 10.1093/ndt/gfab344. Online ahead of print.

ABSTRACT

BACKGROUND: Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been recognized as non-HLA antibodies associated with allograft rejection and poor allograft outcomes after kidney transplantation. The aim of this study was to assess the risk anti-AT1R-Abs pose for rejection and graft loss among kidney transplant populations.

METHODS: We systematically searched PubMed, EMBASE, and the Cochrane Library databases for relevant articles published from inception until June 2021 to identify all studies concerning the role AT1R-Abs play in the clinical outcome after kidney transplantation. Two reviewers independently identified studies, abstracted outcome data, and assessed the quality of the studies. The meta-analysis was summarized using the fixed-effects models or random-effects models, according to heterogeneity. The major outcomes included delayed graft function, acute rejection, graft loss, or patient death after transplantation.

RESULTS: Twenty-one eligible studies involving a total of 4,023 kidney transplantation recipients were included in the evaluation to identified. Meta-analysis results showed that the AT1R-Ab positive kidney transplant (KT) group had a greater incidence of antibody-mediated rejection (RR = 1.94, 95%CI: 1.61-2.33, P < 0.00001) and graft loss (RR = 2.37, 95%CI: 1.50-3.75, P = 0.0002) than did the AT1R-Abs negative KT group. There was no significant statistical difference in delayed graft function rate, T-cell mediated rejection, mixed rejection, acute cellular rejection, acute rejection, and patient death rate between AT1R-Ab positive KT and AT1R-Ab negative KT groups.

CONCLUSIONS: Our study shows that the presence of anti-AT1R-Abs was associated with a significantly higher risk of antibody-mediated rejection and graft loss in kidney transplantation. Future studies are still needed to evaluate the importance of routine anti-AT1R monitoring and therapeutic targeting. These results shows that assessment of anti-AT1R-Abs would be helpful in determining immunologic risk and susceptibility to immunologic events for recipients.

PMID:34865146 | DOI:10.1093/ndt/gfab344

Nephrol Dial Transplant. 2021 Dec 2:gfab318. doi: 10.1093/ndt/gfab318. Online ahead of print.

ABSTRACT

BACKGROUND: Anaemia is common in chronic kidney disease (CKD), and assessment of the risks and benefits of new therapies is important.

METHODS: The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL, or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomised to daprodustat or darbepoetin alfa (1:1) in an open- label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28 to 52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials.

RESULTS: Overall, 3872 patients were randomised from 39 countries (median age 67 years, 56% female; 56% White, 27% Asian, and 10% Black). Median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and eGFR was 18 mL/min/1.73 m2. Among randomised patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin- angiotensin system blockers, 55% were taking statin and 49% oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials.

CONCLUSION: ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis.

PMID:34865143 | DOI:10.1093/ndt/gfab318

Mil Med. 2021 Dec 4:usab510. doi: 10.1093/milmed/usab510. Online ahead of print.

ABSTRACT

INTRODUCTION: Catchment populations have several uses. A method using catchment population to estimate the incidence of sporadic Creutzfeldt-Jakob disease (sCJD) is described.

MATERIALS AND METHODS: A cohort of nine consecutive patients diagnosed with sCJD, symptom onset spanning 26 months, were observed at a rural tertiary university medical center that has approximately 40,000 hospital discharges annually. An effective catchment population was determined using surrounding county utilization frequency that captured all nine sCJD patients and accounted for over 87% of discharges.

RESULTS: The effective sCJD hospital catchment population was 1.266 million, implying an annual sCJD incidence rate of 3.39 per million (95% CIs, 1.55-6.43), assuming a Poisson distribution for sCJD occurrence.

CONCLUSIONS: This annual incidence rate suggests that many sCJD patients are unrecognized and unreported. An advantage of this catchment population method is independence from death certificate accuracy, important in rare diseases that are both rapidly and invariably fatal. The relative absence of significant healthcare systems competition in this rural population enhances the reliability of this finding. The most likely explanation for the high sCJD incidence rate suggested by this study is enhanced clinical suspicion and improved diagnostic accuracy.

PMID:34865142 | DOI:10.1093/milmed/usab510

Nicotine Tob Res. 2021 Dec 3:ntab227. doi: 10.1093/ntr/ntab227. Online ahead of print.

ABSTRACT

BACKGROUND: Cigarette smoking continues to be a major health concern and remains the leading preventable cause of death in the U.S. Recent efforts have been made to determine the potential health and policy benefits of reducing nicotine in combustible cigarettes. The degree to which changes in blood nicotine relate to measures of the abuse liability of reduced-nicotine cigarettes is unknown. The current study examined the relation between blood nicotine and behavioral economic demand measures of cigarettes differing in nicotine content.

METHODS: Using a within-subject design, participants smoked a single cigarette during each experimental session. Cigarettes included the participant’s usual-brand cigarette and SPECTRUM investigational cigarette differing in nicotine level (mg of nicotine to g of tobacco; 15.8mg/g, 5.2mg/g, 2.4mg/g, 1.3mg/g, and 0.4mg/g). During each session, blood was collected at multiple timepoints and behavioral economic demand was assessed. Nonlinear mixed-effects models were used to estimate differences derived intensity (Q0) and change in elasticity (α).

RESULTS: Measures related to blood nicotine decreased in an orderly fashion related to nicotine level and significantly predicted change in elasticity (α), but not derived intensity. No differences in demand parameters between the usual brand and 15.8mg/g cigarettes were observed. However, αwas significantly higher (lower valuation) for 0.4mg/g than 15.8mg/g cigarettes.

CONCLUSIONS: The lowest nicotine level (0.4mg/g) corresponded with the lowest abuse liability (α) compared to the full-strength control (15.8mg/g), with the 1.3mg/g level also resulting in low abuse liability.

IMPLICATIONS: This is the first study examining the relative contributions of nicotine content in cigarettes and blood nicotine levels on the behavioral economic demand abuse liability of cigarettes ranging in nicotine content. Our results suggest blood nicotine and nicotine content both predict behavioral economic demand abuse liability. In addition, our results suggest a nicotine content of 1.3mg/g or lower may be effective at reducing cigarette uptake among first-time (naïve) smokers. Our results largely conform to previous findings suggesting a very low nicotine content cigarette maintains lower abuse liability than full-strength cigarettes.

PMID:34865118 | DOI:10.1093/ntr/ntab227

Mil Med. 2021 Dec 4:usab505. doi: 10.1093/milmed/usab505. Online ahead of print.

ABSTRACT

INTRODUCTION: Splinting is an essential component of treating many lower extremity musculoskeletal injuries; however, little development has been made in splinting technology. The purpose of this study is to evaluate the efficacy of current immobilization equipment for lower extremity fractures by testing a novel one-step spray-on foam splint (Fast Cast) against structural aluminum malleable (SAM) lower extremity musculoskeletal injuries and 6-inch ACE (3M Corp., Minneapolis, MN, USA) bandage splints.

MATERIALS AND METHODS: Six orthopedic surgical residents and two medical students participated in a prospective analysis of austere splinting techniques and equipment that utilized a cadaveric model with a distal third tibia-fibula shaft fracture. Each participant was observed and scored by three fellowship trained attending orthopedic surgeons. All scoring was independent using a 5-point Likert scale based on 10 splinting criteria (50 total points possible), including quality of radiographic reduction, time to completion, safety, and sustain longitudinal traction. The Likert scale is a set of questions that reflects the respondent’s degree of agreement or disagreement with a statement. Each of the 10 questions has a range of 1-5. A score of 50 means the splint performed perfectly. The lowest possible score is a 10. The participants utilized standard equipment that included SAM splints and 6-inch ACE wraps (3M Corp., Minneapolis, MN, USA) in their first attempt. A second immobilization attempt was done with a one-step spray-on foam splint (Fast Cast). After each splinting attempt, the reduction was verified with radiographic imaging. Data analysis was performed using standard descriptive statistics, Student’s t-tests, and inter-rater reliability was calculated using Cronbach’s alpha scores. This project is Institutional Review Board (IRB) exempt.

RESULTS: The one-step spray-on foam splinting technique was superior (P < .05) in all parameters of the Likert scale, yielding a mean overall score of 45.1 points (±3.8), safety 4.7 points, longitudinal traction 4.5 points, and time 136 seconds (±23). The SAM resulted in a mean overall score of 33.8 points (±7.3), safety 2.8 points, longitudinal traction 4.1 points, and time 170 seconds (±52). Radiographic rating was 4.1 points (±0.7) for the SAM splint and 4.5 (±0.6) for Fast Cast. The differences in time to completion and radiograph rating did not reach statistical significance (P = .12 and P = .07, respectively).

CONCLUSION: A one-step spray-on foam splinting technique demonstrated consistent superiority in reducing fracture motion, potential soft-tissue damage, and sustained longitudinal traction as compared to the standard technique.

PMID:34865117 | DOI:10.1093/milmed/usab505

Mil Med. 2021 Dec 4:usab468. doi: 10.1093/milmed/usab468. Online ahead of print.

ABSTRACT

INTRODUCTION: Recent epidemiological evidence shows that shoulder and upper-arm complaints impose a substantial burden on the armed forces of the United States and create significant challenges for all components of the physical fitness domain of total force fitness. Clinicians, epidemiologists, and health-services researchers interested in shoulder and upper-arm injuries and their functional limitations rarely have objective, validated criteria for rigorously evaluating diagnostic practices, prescribed treatments, or the outcomes of alternative approaches. We sought to establish and quantify patient volume, types of care, and costs within the Military Health System (MHS) in assessing and managing active duty members with nonoperative shoulder and upper-arm dysfunction.

MATERIALS AND METHODS: We performed a retrospective cohort study using data from the MHS Data Repository and MHS MART (M2) from fiscal year 2014 to identify active duty individuals with a diagnosis of shoulder and upper-arm injury or impairment defined by one of the International Classification of Disease Ninth Edition diagnosis codes that were selected to reflect nonoperative conditions such as fractures or infections. Statistical analyses include descriptive statistics on patient demographics and clinical visits, such as the range and frequency of diagnoses, number and types of appointments, and clinical procedure information following the diagnosis. We also examined treatment costs related to shoulder dysfunction and calculated the total cost to include medications, radiological, procedural, and laboratory test costs for all shoulder dysfunction visits in 2014 and the average cost for each visit. We further examined the category of each medication prescribed.

RESULTS: A total of 55,643 individuals met study criteria and accrued 193,455 shoulder-dysfunction-related clinical visits in fiscal year 2014. This cohort represents approximately 4.8% of the 1,155,183 active duty service members assigned to the United States and its territories during FY 2014. Most patients were male (85.32%), younger (85.25% were under 40 years old), and Caucasian/White (71.12%). The most common diagnosis code was 719.41 (pain in joint, shoulder region; 42.48%). The majority of the patients 42,750 (76.8%) had four or fewer medical visits during the study period and 12,893 (23.2%) had more than four visits. A total of 4,733 patients (8.5%) underwent arthrocentesis aspiration or injection. The total cost for all visits was $65,066,767.89. The average and median cost for each visit were $336.34 (standard deviation was $1,493.87) and $163.11 (range was from 0 to $84,183.88), respectively. Three out of four patients (75.3%) underwent radiological examinations, and 74.2% of these individuals had more than one radiological examination. Medications were prescribed to 50,610 (91.0%) patients with the three most common being IBUPROFEN (12.21%), NAPROXEN (8.51%), and OXYCODONE-ACETAMINOPHEN (5.04%), respectively.

CONCLUSIONS: Nearly 1 in 20 active duty military service members presented for nonoperative care of shoulder and/or upper-arm dysfunction during FY2014. Further examinations of the etiology and potential impact of shoulder/upper-arm dysfunction on force readiness are clearly warranted, as are additional studies directed at identifying best practices for preventing injury-related dysfunction and determining best practices for the treatment of shoulder dysfunction to optimize service member fitness and force readiness.

PMID:34865115 | DOI:10.1093/milmed/usab468

Eur J Dent. 2021 Dec 4. doi: 10.1055/s-0041-1736292. Online ahead of print.

ABSTRACT

OBJECTIVE: This article evaluates the success of prosthetic rehabilitation of thin wiry ridge and implants placed simultaneously in splitted ridge both clinically and radiographically.

MATERIALS AND METHODS: Twenty-one participants were enrolled of which 13 patients (8 females and 5 males) were suffering from maxillary ridge atrophy and 8 patients (5 females and 3 males) had mandibular ridge atrophy; a total of 42 implants were performed using the ridge expansion technique. The expansion was performed using the conventional disk technique, piezoelectric corticotomy, and self-threading expanders. Implants were placed and loaded with fixed partial denture after 4 months for the mandible and 6 months for the maxilla. Implant stability quotient (ISQ) was measured at T0 (implant placement) and TL (loading). Crestal bone levels were measured at different times: T0, TL, and T12 (12 months). Evaluation of prosthetic and surgical complications was carried out. Data were analyzed and compared using analysis of variance and paired t-tests at a significance level of 5%.

RESULTS: All implants met the criteria for success. All implants showed a higher mean bone loss from T0 to TL (1.259 ± 0.3020) than from TL to T12 (0.505 ± 0.163) with a statistically significant difference (p < 0.0001). ISQ values sharply increased at the time of loading (72.52 ± 2.734) than at implant insertion (44.5 ± 4.062) with a significant difference (p < 0.0001). Minor prosthetic and surgical complications were reported.

CONCLUSION: The results from this study support the efficacy of prosthetic rehabilitation of thin wiry ridge using split ridge technique and the success of implants placed simultaneously in splitted ridge.

PMID:34863083 | DOI:10.1055/s-0041-1736292

Eur J Dent. 2021 Dec 4. doi: 10.1055/s-0041-1735935. Online ahead of print.

ABSTRACT

OBJECTIVE: The primary focus of this clinical study was to analyze the probability of occurrence of instrument fracture after root canal preparation of primary molars with the help of Kedo-S Square pediatric rotary file.

MATERIALS AND METHODS: Three experienced specialists treated 100 primary maxillary and mandibular molars (335 root canals) using a standardized protocol over 2 months. Biomechanical preparations were carried out using Kedo-S Square file, as per the suggestions given by the manufacturer. Every instrument in Group A helped handle three clinical cases, while for groups B, C and D, they helped in handling 5, 9, and 12 cases, respectively. Making use of an operational microscope, the rotary files, after being pulled out from the canal, were observed. The values were tabulated, and descriptive statistics were performed.

RESULTS: There were two fractures (2%), of which 1 occurred in group C in the apical 1/3rd of distobuccal canal of maxillary molar, and the other occurred in group D in the apical 1/3rd of mesiobuccal canal of maxillary molar.

CONCLUSIONS: The fracture rate of Kedo-S Square rotary file is quite low. It is primarily in the buccal canals of the maxillary molars and the apical third of the root canal that the instrument has a greater probability of separation.

PMID:34863082 | DOI:10.1055/s-0041-1735935