bluuebunny/crossref_metadata_2025 huggingface dataset:
Recognizing obesity as a disease
Authors: Christensen Sandra
Published: January 2021

Obesity is a chronic, progressive, relapsing disease that impairs health and quality of life and shortens lifespan. Genetic and environmental factors contribute to its development and persistence. If left untreated, it worsens and leads to serious health consequences for those affected, as well as their offspring and future generations. Obesity complications drive many of the conditions that are seen routinely in clinical practice. By treating obesity first, many of these conditions improve or resolve. Given the seriousness of the disease, it is imperative that clinicians in primary and specialty care settings diagnose and treat or refer so that patients can receive appropriate treatment. Evidence-based treatment that is individualized and patient centered improves health and quality of life.
Cytologic and Histologic Aspects of High-Grade Transformation of Salivary Gland Carcinoma
Authors: Nakaguro Masato , Faquin William C. , Sadow Peter M.
Published: January 2021

High-grade transformation (HGT) is a process whereby low- to intermediate-grade carcinomas transform into high-grade, poorly differentiated, or undifferentiated carcinomas. In salivary gland tumor pathology, several terminologies, including dedifferentiation or hybrid tumor, have been adopted to describe tumors that do not fit into one distinct tumor type. As HGT confers a poor prognosis despite initial tumor type, the finding of HGT must be recognized for optimal patient management. Preoperative fine-needle aspiration biopsy is typically positive for malignancy, but the recognition of both low- and high-grade components is not always possible and, if only the latter present, may obscure the tumor subtype from which the HGT derives. Most HGTs occur in association with acinic cell carcinoma and adenoid cystic carcinoma, but have also been seen with epithelial-myoepithelial carcinoma, secretory carcinoma, and mucoepidermoid carcinoma.
Ancillary Testing of Salivary Gland Fine-Needle Aspiration Biopsy Material
Authors: Wong Kristine S. , Krane Jeffrey F.
Published: January 2021

Salivary gland tumors are often challenging to diagnose, particularly in cytologic material. Advances in our understanding of the molecular alterations in different salivary neoplasms have improved the ancillary testing tools available to resolve diagnostic uncertainty and refine clinical management options. Using a morphologically based approach focused on common basaloid and oncocytic/clear cell tumors, this review discusses the current role of immunohistochemical and fluorescence in situ hybridization–based testing as tools for diagnosing salivary gland tumors in fine-needle aspiration biopsy specimens.
Circumferential Lipobrachioplasty Is a Safe Procedure
Authors: Ahmad Mahfouz S. I.
Published: January 2021

Background:

Excess fat and skin in the upper arms have become troublesome with aging and especially after the advancement in methods of weight reduction. Arm contouring procedures can be divided into three groups: those dealing with skin redundancy, those dealing with the lipodystrophy, and a combination of both. This study tries to find an answer to the debate about the safety of simultaneous circumferential liposuction and brachioplasty.

Methods:

Sixty-two patients (49 women and 13 men) were operated on by simultaneous circumferential suction-assisted lipectomy followed by brachioplasty. Preoperative and postoperative arm circumferences and outcomes (including complications and patient satisfaction) were evaluated starting at least 6 months after the procedure.

Results:

Only two patients (3.2 percent) developed small areas of wound dehiscence that healed after repeated dressing and an extended period of compression garment use. One patient (1.6 percent) complained of hypertrophic scarring, which was managed by local compression and silicone sheets. The average reduction in mid arm circumference was 9 cm (range, 5 to 14 cm). Approximately 95.2 percent of the patients in the study are highly satisfied, and 4.8 percent reported a mild degree of satisfaction.

Conclusions:

Simultaneous circumferential arm liposuction followed by brachioplasty addresses both the lipodystrophy and arm ptosis in a single hospital admission. This combination does not increase the complication rate. The results are highly satisfactory to the patients. According to the results of this study, circumferential arm lipobrachioplasty is considered to be a safe, efficient, reliable, and feasible procedure.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Extending the Reach of Craniofacial Free Flaps Using the Descending Branch of the Lateral Circumflex Femoral Vessels
Authors: Frommer Sarah A. , Teal Lindsey N. , Myers René P. , Kelley Patrick K. , Henry Steven L.
Published: January 2021

Craniofacial free tissue transfer is sometimes complicated by insufficient pedicle length and/or paucity of recipient vessels. A saphenous vein graft can be used to reach the high-flow, large-caliber vessels of the neck, but because of the vein’s taper and thick wall, there is often a mismatch. Following the principle of like-for-like, the authors prefer the descending branch of the lateral circumflex femoral vessels to achieve a more anatomical pedicle extension for free tissue transfer in complex craniofacial reconstruction. The authors’ experience using the descending branch of the lateral circumflex femoral pedicle extender from 2010 to 2019 was reviewed. Indications, patient characteristics, reconstruction site, flap type, pedicle length, recipient vessels, and vascular complications were noted. The authors reviewed two strategies for implementation of the pedicle extender: in some cases, the flap was first transferred and allowed to perfuse on the descending branch of the lateral circumflex femoral vessels in the thigh, and then transferred to the recipient vessels (double-ischemia transfer); and in other cases, the flap and pedicle extender were transferred such that the flap underwent a single period of ischemia (single-ischemia transfer). The descending branch of the lateral circumflex femoral pedicle extender was used in 17 craniofacial cases. Indications included tumor, trauma, osteoradionecrosis, and congenital. Double-ischemia transfer was used in eight cases and single-ischemia transfer in nine. The longest pedicle extender in the series was 15 cm. Arterial thrombosis occurred in one case. This case series demonstrates that the descending branch of the lateral circumflex femoral pedicle extender is a viable option for complex craniofacial free tissue transfer cases. It provides ample length and excellent vessel match, following the like-for-like principle.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Three-Dimensional Analysis and Surgical Planning for Open Correction of Trigonocephaly
Authors: Maniskas Seija , Chandler Ludmila , Bruckman Karl , Pourtaheri Navid , DiLuna Michael , Steinbacher Derek M.
Published: January 2021

Metopic craniosynostosis results in trigonocephaly, characterized by a triangular forehead with metopic ridge, bitemporal pinching, and narrow-set eyes with recessed lateral orbital rims. Surgical management is controversial but may include open expansion and vault remodeling, to enhance neurocognitive and aesthetic outcomes. This article and video vignette depict the diagnosis and treatment of metopic craniosynostosis, demonstrating the senior author’s open approach, three-dimensional virtual surgical planning, and technical steps.
Reverse Lymph Node Mapping Using Indocyanine Green Lymphography: A Step Forward in Minimizing Donor-Site Morbidity in Vascularized Lymph Node Transfer
Authors: Pons Gemma , Abdelfattah Usama , Sarria Jose , Duch Joan , Masia Jaume
Published: January 2021

Background:

Reverse lymphatic mapping before harvesting a lymph node flap is crucial to avoid donor-site lymphedema; however, the technique is complex and unavailable in many centers. The authors introduce radioisotope-free reverse lymphatic mapping using indocyanine green and Patent Blue dye.

Methods:

The authors conducted a prospective study in patients undergoing free vascularized groin lymph node transfer for postmastectomy upper extremity lymphedema. The day before surgery, 0.2 ml of technetium-99 was injected into the first and second web spaces of the ipsilateral foot. The following day, once the patient was anesthetized, indocyanine green was injected into the same web spaces of the same foot and Patent Blue dye was injected just proximal to the upper margin of the skin paddle of the lymph node flap. The main lymph nodes draining the limb were localized using indocyanine green lymphography and gamma probe.

Results:

Thirty-nine patients underwent vascularized groin lymph node transfer with or without deep inferior epigastric artery perforator flap breast reconstruction. Navigation of the main lower extremity draining inguinal lymph nodes using the gamma probe and indocyanine green lymphography was identical in all patients. The blue-stained lymphatics in the skin paddle drained to the superficial proximal inguinal lymph node and were targeted for transfer. No donor-site lymphedema was reported, and lymphatic drainage of the lower extremity was preserved in all cases.

Conclusions:

Reverse lymphatic mapping using indocyanine green lymphography provides identical results to those using technetium-99 isotope scanning. However, indocyanine green is preferable in terms of safety and reproducibility and also avoids the complexity and hazards of radioisotope mapping.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Therapeutic cardiac arrest as an adjunct to resuscitative endovascular balloon occlusion of the aorta: Bridging the gap from fatal hemorrhage to definitive surgical control in swine
Authors: Stigall Kyle S. , Neidert Leslie E. , Morgan Clifford G. , Hemond Peter J. , Brown Dallas R. , Salas Mary , Hathaway Emily N. , Tiller Michael M. , Cardin Sylvain , Glaser Jacob J.
Published: January 2021

BACKGROUND

Uncontrolled hemorrhage is the leading cause of potentially survivable combat casualty mortality, with 86.5% of cases resulting from noncompressible torso hemorrhage. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive technique used to stabilize patients with noncompressible torso hemorrhage; however, its application can take an average of 8 minutes to place. One therapeutic capable of bridging this gap is adenosine-lidocaine-magnesium (ALM), which at high doses induces a reversible cardioplegia. We hypothesize by using ALM as an adjunct to REBOA, the ALM-induced cardiac arrest will temporarily halt exsanguination and reduce blood loss, allowing for REBOA placement and control of bleeding.

METHODS

Male Yorkshire swine (60–80 kg) were randomly assigned to REBOA only or ALM-REBOA (n = 8/group). At baseline, uncontrolled hemorrhage was induced via a 1.5-cm right femoral arteriotomy, and hemorrhaged blood was quantified. One minute after injury (S1), ALM was administered, and 7 minutes later (T0), zone 1 REBOA inflation occurred. If cardiac arrest ensued, cardiac function either recovered spontaneously or advanced life support was initiated. At T30, surgical hemostasis was obtained, and REBOA was deflated. Animals were resuscitated until they were humanely euthanized at T90.

RESULTS

During field care phase, heart rate and end-tidal CO2 of the ALM-REBOA group were significantly lower than the REBOA only group. While mean arterial pressure significantly decreased from baseline, no significant differences between groups were observed throughout the field care phase. There was no significant difference in survival between the two groups (ALM-REBOA = 89% vs. REBOA only = 100%). Total blood loss was significantly decreased in the ALM-REBOA group (REBOA only = 24.32 ± 1.89 mL/kg vs. ALM-REBOA = 17.75 ± 2.04 mL/kg, p = 0.0499).

CONCLUSION

Adenosine-lidocaine-magnesium is a novel therapeutic, which, when used with REBOA, can significantly decrease the amount of blood loss at initial presentation, without compromising survival. This study provides proof of concept for ALM and its ability to bridge the gap between patient presentation and REBOA placement.
β-Blockers for traumatic brain injury: A systematic review and meta-analysis
Authors: Ding Huaqiang , Liao Luoxing , Zheng Xiaomei , Wang Qisheng , Liu Zhi , Xu Guanghui , Li Xing , Liu Liang
Published: January 2021

BACKGROUND

Paroxysmal sympathetic hyperactivity (PSH) and catecholamine surge, which are associated with poor outcome, may be triggered by traumatic brain injury (TBI).

β Adrenergic receptor blockers (β-blockers), as potential therapeutic agents to prevent paroxysmal sympathetic hyperactivity and catecholamine surge, have been shown to improve survival after TBI. The principal aim of this study was to investigate the effect of β-blockers on outcomes in patients with TBI.

METHODS

For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and Cochrane Library databases from inception to September 25, 2020, for randomized controlled trials, nonrandomized controlled trials, and observational studies reporting the effect of β-blockers on the following outcomes after TBI: mortality, functional measures, and cardiopulmonary adverse effects of β-blockers (e.g., hypotension, bradycardia, and bronchospasm). With use of random-effects model, we calculated pooled estimates, confidence intervals (CIs), and odds ratios (ORs) of all outcomes.

RESULTS

Fifteen studies with 12,721 patients were included. Exposure to β-blockers after TBI was associated with a significant reduction in adjusted in-hospital mortality (OR, 0.39; 95% CI, 0.30–0.51; I
2 = 66.3%; p < 0.001). β-Blockers significantly improved the long-term (≥6 months) functional outcome (OR, 1.75; 95% CI, 1.09–2.80; I
2 = 0%; p = 0.02). Statistically significant difference was not seen for cardiopulmonary adverse events (OR, 0.91; 95% CI, 0.55–1.50; I
2 = 25.9%; p = 0.702).

CONCLUSION

This meta-analysis demonstrated that administration of β-blockers after TBI was safe and effective. Administration of β-blockers may therefore be suggested in the TBI care. However, more high-quality trials are needed to investigate the use of β-blockers in the management of TBI.

LEVEL OF EVIDENCE

Systematic review and meta-analysis, level III.
Human Metapneumovirus and Parainfluenza Virus Infections in Lung Transplant Recipients: The Effects on Lung Allograft and Clinical Outcomes
Authors: Permpalung Nitipong , Sait Afrah S. , Bazemore Katrina , Avery Robin K. , Mathew Joby , Shah Pali D.
Published: January 2021

Background.

Human metapneumovirus (HMPVi) and parainfluenza virus (PIVi) infections are common community-acquired infections in lung transplant recipients (LTRs), but data are extremely limited.

Methods.

A retrospective study including all LTRs at the Johns Hopkins Hospital during July 2010–June 2019 with positive HMPV and PIV polymerase chain reaction respiratory specimens was performed.

Results.

Thirty-one HMPV- and 53 PIV-infected LTRs were identified. LTRs with HMPVi and PIVi had similar baseline characteristics, infection parameters, treatment allocation, and allograft function outcomes. Among entire cohort, 31.6% had chronic allograft dysfunction (CLAD) stage progression within 1 y postinfections (29.2% versus 35.5% for PIVi versus HMPVi, respectively, P = 0.56). In forced expiratory volume in 1 s percent (FEV1%) trajectory analysis showed steadily decline of FEV1 across time among CLAD stage progressors from both viruses. FEV1% decline ≥10% at 90 d had adjusted hazard ratio for CLAD stage progression of 18.4 (4.98-67.76) and 4.6 (1.36-15.34) for PIVi and HMPVi, respectively. PIVi caused higher donor-specific antigen development (11.8% versus 3.2%, P = 0.18) and 1-y mortality (9.4% versus 0%, P = 0.11), compared with HMPVi, even though the results were not statistically significant. Ribavirin did not show protective effect, and mycophenolate discontinuation during infection did not increase risk of CLAD stage progression.

Conclusions.

One-third of HMPV- and PIV-infected LTRs developed CLAD stage progression within 1 y. The lack of early lung function recovery may predict long-term CLAD progression.
Longer Distance From Dialysis Facility to Transplant Center Is Associated With Lower Access to Kidney Transplantation
Authors: Whelan Adrian M. , Johansen Kirsten L. , McCulloch Charles E. , Adelmann Dieter , Niemann Claus U. , Roll Garrett R. , Siyahian Salpi , Grimes Barbara , Ku Elaine
Published: January 2021

Background.

Rates of kidney transplantation vary substantially across dialysis facilities in the United States. Whether distance between the dialysis facility and transplant center associates with variations in transplantation rates has not been examined.

Methods.

We performed a retrospective study of adults treated with dialysis between 2005 and 2015, according to the US Renal Data System. We examined the association between distance from dialysis facility to transplant center and time to kidney transplantation (primary outcome) and waitlist registration (secondary outcome) using Fine-Gray models. We also performed sensitivity analyses using the distance from each patient’s dialysis facility to the nearest transplant center as the predictor so that patients who were never registered on the waitlist (and therefore would not have a transplant center) could be included.

Results.

In total, 178 885 waitlisted patients were included for our primary analysis. As distance between dialysis facility and transplant center increased, lower hazard of transplantation (subhazard ratio [HR], 0.92; 95% confidence interval [CI], 0.91-0.94, if distance was 10 to <50 miles; sub-HR, 0.90; 95% CI, 0.88-0.92, if distance ≥50 miles compared with <10 miles) was noted. We also found a weak association between longer distance and hazard of waitlist registration (sub-HR, 0.96; 95% CI, 0.94-0.97, if distance was ≥50 miles versus <10 miles). Findings were similar in sensitivity analyses using distance between dialysis facility and the nearest transplant center (N = 1 149 721).

Conclusions.

Patients receiving dialysis in facilities located further away from transplant centers have lower hazard of kidney transplantation. Developing strategies to address barriers to transplantation in patients receiving dialysis at facilities located far away from a transplant center may help improve disparities in transplantation rates.
Hyponatremia Is Associated With Increased Mortality in Children on the Waiting List for Liver Transplantation
Authors: Bezinover Dmitri , Nahouraii Lauren , Sviatchenko Alexandr , Wang Ming , Kimatian Steven , Saner Fuat H. , Stine Jonathan G.
Published: January 2021

Background.

Our aim was to determine whether hyponatremia is associated with waiting list or posttransplantation mortality in children having liver transplantation (LT).

Methods.

A retrospective analysis of the united network for organ sharing/organ procurement transplantation network database on pediatric LT performed between 1988 and 2016 was conducted. Hyponatremia was defined as a serum sodium of 130 mEq/L or below. Subjects were divided into 2 age groups: I (0–6 y old) and II (7–18 y old). Patient survival before and after LT, as well as graft survival, were compared in patients with and without hyponatremia. Multivariable Cox proportional hazards models were constructed for perioperative mortality.

Results.

Data from 6606 children were available for analysis of waiting list mortality, and 4478 for postoperative mortality. The prevalence of hyponatremia at the time of registration was 2.8% and 3.7% at the time of LT. Waiting list mortality in patients with hyponatremia was significantly higher in group I (P < 0.001) but not in group II (P = 0.09). In group I, the relative risk of mortality adjusted to pediatric end-stage liver disease score was significantly associated with hyponatremia (P < 0.001). A sodium level below 130 mEq/L (hazard ration [HR] = 1.7), younger age (group I) (HR = 2.01), and need for dialysis (HR = 2.3) were independent predictors for increased waiting list mortality. There was no difference in overall postoperative patient or graft survival related to hyponatremia.

Conclusions.

Hyponatremia is associated with increased waiting list mortality for pediatric LT candidates, particularly in younger children. Future studies examining incorporation of age-specific serum sodium levels into organ allocation policies in children seems warranted based on our findings.
Pancreatic Islet Changes in Human Whole Organ Pancreas Explants: What Can Be Learned From Explanted Samples?
Authors: Dumbill Richard , Laurenson-Schafer Hannah , Sharples Edward J. , Barnes James , Mittal Shruti , Friend Peter J. , Clark Anne
Published: January 2021

Background.

Whole pancreas transplantation (Tx) is a successful treatment for type 1 diabetes resulting in independence from antidiabetic therapies. Transplant-related factors contributing to pancreatic islet failure are largely unknown; both recurring insulitis and pancreatitis have been implicated. The aim was to determine if cellular changes in islets and exocrine tissue are evident early in Tx, which could contribute to eventual graft failure using well-preserved tissue of grafts explanted from largely normoglycemic recipients.

Methods.

Histological specimens of explants (n = 31), Tx duration 1 day–8 years (median 29 d), cold ischemia time 7.2–17.3 hours (median 11.1 h), donor age 13–54 years (median 38 y) were examined; sections were labeled for inflammation, islet amyloidosis, and tissue fibrosis, and morphometry performed on immunolabeled insulin and glucagon positive islet cells. Data were related to clinical details of donor, recipient, and features of Tx.

Results.

Islet inflammation consistent with recurrent insulitis was not seen in any sample. Insulin-labeled islet cell proportion decreased with donor age (P < 0.05) and cold ischemia (P < 0.01) in explants from 26 normoglycemic patients; glucagon-labeled area proportion increased with cold ischemia (P < 0.05). Clinical pancreatitis was the explant reason in 12 of 28 normoglycemic cases. Exocrine fibrotic area/pancreas was variable (0.7%–55%) and unrelated to clinical/pathological features. Islet amyloid was present in 3 normoglycemic cases (donor ages 58, 42, and 31 y; Tx duration 8 y, 31 and 33 d, respectively). In 1 patient receiving antidiabetic therapy, the insulin-labeled area was reduced but with no evidence of islet inflammation.

Conclusions.

Explant histological changes after short-term Tx are similar to those seen in type 2 diabetes and occur in the absence of immunologic rejection without causing hyperglycemia. This suggests that factors associated with Tx affect islet stability; persistent deterioration of islet integrity and exocrine tissue fibrosis could impact on sustainability of islet function.
Clinical Outcomes of Perioperative Desensitization in Heart Transplant Recipients
Authors: Plazak Michael E. , Gale Stormi E. , Reed Brent N. , Hammad Sara , Ton Van-Khue , Kaczorowski David J. , Madathil Ronson J. , Ravichandran Bharath
Published: January 2021

Background.

Sensitization remains a barrier to heart transplantation (HT). Perioperative desensitization strategies have been described; however, a paucity of evidence exists to demonstrate efficacy and safety in HT.

Methods.

This single-center, retrospective study consisted of adults who received an HT. Perioperative desensitization was initiated if virtual crossmatch or flow-cytometry crossmatch was positive. Therapy consisted of plasmapheresis, intravenous immunoglobulin, and rabbit antithymocyte globulin. Historical controls received standard immunosuppression or induction. The primary endpoint was survival at 12 mo. Secondary endpoints included freedom from acute rejection, cardiac allograft vasculopathy (CAV), and infectious complications.

Results.

Of the 104 patients included, 48 received no induction, 46 received induction, and 10 underwent perioperative desensitization. No differences were observed in the primary endpoint at 12 mo (90.0% versus 97.9%, P = 0.25 for desensitization versus no-induction; 90.0% versus 100%, P = 0.72 for desensitization versus induction). Rates of acute rejection were lower with induction and desensitization compared with no-induction. There were no significant differences in CAV between the groups. Infectious complications were also similar among the groups (10.0% versus 16.7%, P = 0.62 for desensitization versus no-induction; 10.0% versus 30.4%, P = 0.34 for desensitization versus induction).

Conclusions.

This study suggests that a perioperative desensitization strategy triggered by positive virtual crossmatch or flow-cytometry crossmatch allows for successful transplantation of sensitized HT recipients and results in acceptable rates of survival, rejection, CAV, and infection at 12 mo.
Impact of Subclinical Borderline Inflammation on Kidney Transplant Outcomes
Authors: Seifert Michael E. , Agarwal Gaurav , Bernard Miriam , Kasik Ellen , Raza S. Sikandar , Fatima Huma , Gaston Robert S. , Hauptfeld-Dolejsek Vera , Julian Bruce A. , Kew Clifton E. , Kumar Vineeta , Mehta Shikha , Ong Song , Rosenblum Frida , Towns Graham , Mannon Roslyn B.
Published: January 2021

Background.

Surveillance biopsies permit early detection of subclinical inflammation before clinical dysfunction, but the impact of detecting early subclinical phenotypes remains unclear.

Methods.

We conducted a single-center retrospective cohort study of 441 consecutive kidney transplant recipients between 2015 and 2018 with surveillance biopsies at 6 months post-transplant. We tested the hypothesis that early subclinical inflammation (subclinical borderline changes, T cell-mediated rejection, or microvascular injury) is associated with increased incidence of a composite endpoint including acute rejection and allograft failure.

Results.

Using contemporaneous Banff criteria, we detected subclinical inflammation in 31%, with the majority (75%) having a subclinical borderline phenotype (at least minimal inflammation with mild tubulitis [>i0t1]). Overall, subclinical inflammation was independently associated with the composite endpoint (adjusted hazard ratio, 2.88; 1.11-7.51; P = 0.03). The subgroup with subclinical borderline inflammation, predominantly those meeting the Banff 2019 i1t1 threshold, was independently associated with 5-fold increased hazard for the composite endpoint (P = 0.02). Those with concurrent subclinical inflammation and subclinical chronic allograft injury had worse outcomes. The effect of treating subclinical inflammation was difficult to ascertain in small heterogeneous subgroups.

Conclusions.

Subclinical acute and chronic inflammation are common at 6 months post-transplant in kidney recipients with stable allograft function. The subclinical borderline phenotype with both tubulitis and interstitial inflammation was independently associated with poor long-term outcomes. Further studies are needed to elucidate the role of surveillance biopsies for management of allograft inflammation in kidney transplantation.
Hydroxychloroquine and azithromycin: As a double edge sword for COVID-19?
Authors: Eftekhar Seyed Parsa , Kazemi Sohrab , Barary Mohammad , Javanian Mostafa , Ebrahimpour Soheil , Ziaei Naghmeh
Published: January 2021

Background

Hydroxychloroquine with or without azithromycin was one of the common therapies at the beginning of the COVID-19 pandemic. They can prolong QT interval, cause Torsade de pointes, and lead to sudden cardiac death. We aimed to assess QT interval prolongation and its risk factors in patients who received hydroxychloroquine with or without azithromycin.

Methods

This was a retrospective cohort study. 172 patients with COVID-19 included, hospitalized at hospitals of Babol University of Medical Sciences between March 5, 2020, and April 3, 2020. Patients were divided into two groups: hydroxychloroquine alone and hydroxychloroquine with azithromycin. Electrocardiograms were used for outcome assessment.

Results

83.1% of patients received hydroxychloroquine plus azithromycin vs 16.9% of patients who received only hydroxychloroquine. The mean age of patients was 59.2 ± 15.4. The mean of post-treatment QTc interval in the monotherapy group was shorter than the mean of post-treatment QTc interval in the combination therapy group but it had no significant statistical difference (462.5 ± 43.1 milliseconds vs 464.3 ± 59.1 milliseconds;P= 0.488). Generally, 22.1% of patients had a prolonged QTc interval after treatment. Male gender, or baseline QTc ≥ 450 milliseconds, or high-risk Tisdale score increased the likelihood of prolonged QTc interval. Due to QTc prolongation, 14 patients did not continue therapy after 4 days.

Conclusion

Hospitalized patients treated with hydroxychloroquine with or without azithromycin, had no significant difference in prolongation of QT interval and outcome. But the number of patients with prolonged QT intervals in this study emphasizes careful cardiac monitoring during therapy; especially in high-risk patients.
Natural Progression of Routine Laboratory Markers following Spinal Trauma: A Longitudinal, Multi-Cohort Study
Authors: Bourguignon Lucie , Vo Anh Khoa , Tong Bobo , Geisler Fred , Mach Orpheus , Maier Doris , Kramer John L.K. , Grassner Lukas , Jutzeler Catherine R.
Published: January 2021

Objective

To track and quantify the natural course of hematological markers over the first year following spinal cord injury.

Methods

Data on hematological markers, demographics, and injury characteristics were extracted from medical records of a clinical trial (Sygen) and an ongoing observational cohort study (Murnau Study). The primary outcomes were concentration/levels/amount of commonly collected hematological markers at multiple time-points. Two-way ANOVA and mixed-effects regression techniques were used to account for the longitudinal data and adjust for potential confounders. Trajectories of hematological markers contained in both data sources were compared using the slope of progression.

Results

At baseline (≤ 2 weeks post-injury), most hematological markers were at pathological levels, but returned to normal values over the course of six to twelve months post-injury. The baseline levels and longitudinal trajectories were dependent on injury severity. More complete injuries were associated with more pathological values (e.g. hematocrit, ANOVA test; Chisq = 77.10, df = 3, adjusted p-value<0.001, and Chisq = 94.67, df = 3, adjusted p-value<0.001, in the Sygen and Murnau studies, respectively). Comparing the two databases revealed some differences in the hematological markers, which are likely attributable to differences in study design, sample size, and standard of care.

Conclusions

Due to trauma-induced physiological perturbations, hematological markers undergo marked changes over the course of recovery, from initial pathological levels that normalize within a year. The findings from this study are important as they provide a benchmark for clinical decision making and prospective clinical trials. All results can be interactively explored on the Haemosurveillance website (https://jutzelec.shinyapps.io/Haemosurveillance/).

Code availability

https://github.com/jutzca/Systemic-effects-of-Spinal-Cord-Injury
University students and staff able to maintain low daily contact numbers during various COVID-19 guideline periods
Authors: Trickey Adam , Nixon Emily , Christensen Hannah , Finn Adam , Thomas Amy , Relton Caroline , Montgomery Clara , Hemani Gibran , Metz Jane , Walker Josephine G. , Turner Katy , Kwiatkowska Rachel , Sauchelli Sarah , Danon Leon , Brooks-Pollock Ellen
Published: January 2021

Introduction

UK universities re-opened in September 2020, despite the on-going coronavirus epidemic. During the first term, various national social distancing measures were introduced, including banning groups of >6 people and the second lockdown in November. COVID-19 can spread rapidly in university-settings, and students’ adherence to social distancing measures is critical for controlling transmission.

Methods

We measured university staff and student contact patterns via an online, longitudinal survey capturing self-reported contacts on the previous day. We investigated the change in contacts associated with COVID-19 guidance periods: post-first lockdown (23/06/2020-03/07/2020), relaxed guidance period (04/07/2020-13/09/2020), “rule-of-six” period (14/09/2020-04/11/2020), and the second lockdown (05/11/2020-25/11/2020).

Results

722 staff (4199 responses) (mean household size: 2.6) and 738 students (1906 responses) (mean household size: 4.5) were included in the study. Contact number decreased with age. Staff in single-person households reported fewer contacts than individuals in 2-and 3-person households, and individuals in 4-and 5-person households reported more contacts.

For staff, daily contacts were higher in the relaxed guidance and “rule-of-six” periods (means: 3.2 and 3.5, respectively; medians: 3) than the post-first lockdown and second lockdown periods (means: 4.5 and 5.4, respectively; medians: 2). Few students responded until 05/10/2020, after which the median student contacts was 2 and the mean was 5.7, until the second lockdown when it dropped to 3.1.

Discussion

University staff and students responded to national guidance by altering their social contacts. The response in staff and students was similar, suggesting that students are able to adhere to social distancing guidance while at university.
Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24
Authors: Karunamuni Roshan A. , Huynh-Le Minh-Phuong , Fan Chun C. , Thompson Wesley , Lui Asona , Martinez Maria Elena , Rose Brent S. , Mahal Brandon , Eeles Rosalind A. , Kote-Jarai Zsofia , Muir Kenneth , Lophatananon Artitaya ,   UKGPCS collaborators, Tangen Catherine M. , Goodman Phyllis J. , Thompson Ian M. , Blot William J. , Zheng Wei , Kibel Adam S. , Drake Bettina F. , Cussenot Olivier , Cancel-Tassin Géraldine , Menegaux Florence , Truong Thérèse , Park Jong Y. , Lin Hui-Yi , Taylor Jack A. , Bensen Jeannette T. , Mohler James L. , Fontham Elizabeth T.H. , Multigner Luc , Blanchet Pascal , Brureau Laurent , Romana Marc , Leach Robin J. , John Esther M. , Fowke Jay H. , Bush William S. , Aldrich Melinda C. , Crawford Dana C. , Cullen Jennifer , Petrovics Gyorgy , Parent Marie-Élise , Hu Jennifer J. , Sanderson Maureen , Mills Ian G. , Andreassen Ole A. , Dale Anders M. , Seibert Tyler M. ,   The PRACTICAL Consortium
Published: January 2021

We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Genotypic data were obtained from PRACTICAL consortium for 6,253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with performance of PHS46+African. A calibration factor (CF) was formulated using estimated Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our dataset with 1000 Genomes, we identified statistically significant associations between continental and calibration groupings. In conclusion, we identified PCs within 8q24 SNP window that were strongly associated with performance of PHS46+African. Further research to improve clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry
Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers
Authors: Chen Guangbo , Deutsch Gail , Schulert Grant , Zheng Hong , Jang SoRi , Trapnell Bruce , Lee Pui , Macaubas Claudia , Ho Katherine , Schneider Corinne , Saper Vivian E. , de Jesus Adriana Almeida , Krasnow Mark , Grom Alexei , Goldbach-Mansky Raphaela , Khatri Purvesh , Mellins Elizabeth D , Canna Scott W.
Published: January 2021

Objectives

Recent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease, characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but sJIA-PAP patients also commonly experience features of drug reaction such as atypical rashes and eosinophilia. We sought to investigate immunopathology and identify biomarkers in sJIA, MAS, and sJIA-PAP.

Methods

We used SOMAscan to measure >1300 analytes in sera from healthy controls and patients with sJIA, MAS, sJIA-PAP and other related diseases. We verified selected findings by ELISA and lung immunostaining. Because the proteome of a sample may reflect multiple states (sJIA, MAS, sJIA-PAP), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.

Results

Proteome alterations in active sJIA and MAS overlapped substantially, including known sJIA biomarkers like SAA and S100A9, and novel elevations of heat shock proteins and glycolytic enzymes. IL-18 was elevated in all sJIA groups, particularly MAS and sJIA-PAP. We also identified an MAS-independent sJIA-PAP signature notable for elevated ICAM5, MMP7, and allergic/eosinophilic chemokines, which were all previously associated with lung damage. Immunohistochemistry localized ICAM5 and MMP7 in sJIA-PAP lung. ICAM5’s ability to distinguish sJIA-PAP from sJIA/MAS was independently validated.

Conclusions

Serum proteins support an sJIA-to-MAS continuum, help distinguish sJIA, sJIA/MAS, and sJIA-PAP, and suggest etiologic hypotheses. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP.
Impact of COVID-19 Pandemic on Inpatient Rehabilitation and the Original Infection Control Measures for Rehabilitation Team
Authors: Igawa Yukimasa , Sugimoto Takahiro , Horimoto Hiromasa , Moriya Yusuke , Okada Masaki , Yamada Yasuyuki
Published: January 2021

Objective

This study aimed to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on inpatient rehabilitation, and to determine the effectiveness of the original infection control measures implemented for the rehabilitation team.

Methods

In this single-center, retrospective, observational study, we calculated multiple rehabilitation indices of patients discharged from our rehabilitation ward between February 28 and May 25, 2020 when Hokkaido was initially affected by COVID-19, and compared them with those calculated during the same period in 2019. Fisher’s exact test and the Mann-Whitney U test were used for statistical analysis. We also verified the impact of implementing the original infection control measures for the rehabilitation team on preventing nosocomial infections.

Results

A total of 93 patients (47 of 2020 group, 46 of 2019 group) were included. The median age was 87 and 88 years, respectively, with no differences in age, sex, and main disease between the groups. Training time per day in the ward in 2020 was significantly lower than that in 2019 (p = 0.013). No significant differences were found in the qualitative evaluation indices of Functional Independence Measure (FIM) score at admission, FIM gain, length of ward stay, FIM efficiency, and rate of discharge to home. None of the patients or staff members had confirmed COVID-19 during the study period.

Conclusions

Early COVID-19 pandemic in Hokkaido affected the quantitative index for inpatient rehabilitation but not the qualitative indices. No symptomatic nosocomial COVID-19 infections were observed with our infection control measures.
Weighted burden analysis in 200 000 exome-sequenced UK Biobank subjects characterises effects of rare genetic variants on BMI
Authors: Curtis David
Published: January 2021

Introduction

A number of genes have been identified in which rare variants can cause obesity. Here we analyse a sample of exome sequenced subjects from UK Biobank using BMI as a phenotype.

Methods

There were 199,807 exome sequenced subjects for whom BMI was recorded. Weighted burden analysis of rare, functional variants was carried out, incorporating population principal components and sex as covariates. For selected genes, additional analyses were carried out to clarify the contribution of different categories of variant. Statistical significance was summarised as the signed log 10 of the p value (SLP), given a positive sign if the weighted burden score was positively correlated with BMI.

Results

Two genes were exome-wide significant,MC4R(SLP = 15.79) andPCSK1(SLP = 6.61). InMC4R, disruptive variants were associated with an increase in BMI of 2.72 units and probably damaging nonsynonymous variants with an increase of 2.02 units. InPCSK1, disruptive variants were associated with a BMI increase of 2.29 and protein-altering variants with an increase of 0.34. Results for other genes were not formally significant after correction for multiple testing, althoughSIRT1, ZBED6andNPC2were noted to be of potential interest.

Conclusion

Because the UK Biobank consists of a self-selected sample of relatively healthy volunteers, the effect sizes noted may be underestimates. The results demonstrate the effects of very rare variants on BMI and suggest that other genes and variants will be definitively implicated when the sequence data for additional subjects becomes available.

This research has been conducted using the UK Biobank Resource.
Association of pre-pandemic high-density lipoprotein cholesterol with risk of COVID-19 hospitalisation and death: the UK Biobank cohort study
Authors: Lassale Camille , Hamer Mark , Hernáez Álvaro , Gale Catharine R. , Batty G. David
Published: January 2021

Objective

There is growing evidence of, and biological plausibility for, elevated levels of high-density lipoprotein cholesterol (HDL-C), being related to lower rates of severe infection. Accordingly, we tested whether pre-pandemic HDL-C within the normal range is associated with subsequent COVID-19 hospitalisations and death.

Approach

We analysed data on 317,306 participants from UK Biobank, a prospective cohort study, baseline data for which were collected between 2006 and 2010. Follow-up for COVID-19 was via hospitalisation records and a national mortality registry.

Results

After controlling for a series of confounding factors which included health behaviours, inflammatory markers, and socio-economic status, higher levels of HDL-C were related to a lower risk of later hospitalisation for COVID-19. The effect was linear (p-value for trend 0.001) such that a 0.2 mmol/L increase in HDL-C was associated with a corresponding 9% reduction in risk (odds ratio; 95% confidence interval: 0.91; 0.86, 0.96). A very similar pattern of association was apparent when COVID-19 mortality was the outcome of interest (odds ratio per 0.2 mmol/l increase in HDL-C: 0.90; 0.81, 1.00); again, a stepwise effect was evident (p-value for trend 0.03).

Conclusions

These novel results for HDL-C and COVID-19 events warrant testing in other studies.
Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder
Authors: Courraud Jeremie , Chater-Diehl Eric , Durand Benjamin , Vincent Marie , del Mar Muniz Moreno Maria , Boujelbene Imène , Drouot Nathalie , Genschik Loréline , Schaefer Elise , Nizon Mathilde , Gerard Bénédicte , Abramowicz Marc , Cogné Benjamin , Bronicki Lucas , Burglen Lydie , Barth Magalie , Charles Perrine , Colin Estelle , Coubes Christine , David Albert , Delobel Bruno , Demurger Florence , Passemard Sandrine , Denommé Anne-Sophie , Faivre Laurence , Feger Claire , Fradin Mélanie , Francannet Christine , Genevieve David , Goldenberg Alice , Guerrot Anne-Marie , Isidor Bertrand , Johannesen Katrine M. , Keren Boris , Kibæk Maria , Kuentz Paul , Mathieu-Dramard Michele , Demeer Bénédicte , Metreau Julia , Møller Rikke Steensbjerre , Moutton Sébastien , Pasquier Laurent , Pilekær Sørensen Kristina , Perrin Laurence , Renaud Mathilde , Saugier Pascale , Svane Joane , Thevenon Julien , Them Frederic Tran Mau , Tronhjem Cathrine Elisabeth , Vitobello Antonio , Layet Valerie , Birling Marie-Christine , Drunat Severine , Bayat Allan , Dubourg Christèle , Chehadeh Salima El , Fagerberg Christina , Mignot Cyril , Guipponi Michel , Bienvenu Thierry , Herault Yann , Thompson Julie , Willems Marjolaine , Mandel Jean-Louis , Weksberg Rosanna , Piton Amélie
Published: January 2021

ABBSTRACT

DYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboringDYRK1Avariants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specificDYRK1Aclinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii)in vitrooverexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurringde novo.
Adjustment for energy intake in nutritional research: a causal inference perspective
Authors: Tomova Georgia D , Arnold Kellyn F , Gilthorpe Mark S , Tennant Peter WG
Published: January 2021

Background

Four models are commonly used to adjust for energy intake when estimating the causal effect of a dietary component on an outcome; (1) the ‘standard model’ adjusts for total energy intake, (2) the ‘energy partition model’ adjusts for remaining energy intake, (3) the ‘nutrient density model’ rescales the exposure as a proportion of total energy, and (4) the ‘residual model’ indirectly adjusts for total energy by using a residual. It remains underappreciated that each approach evaluates a different estimand and only partially accounts for proxy confounding by common dietary causes.

Objective

To clarify the implied causal estimand and interpretation of each model and evaluate their performance in reducing dietary confounding.

Design

Semi-parametric directed acyclic graphs and Monte Carlo simulations were used to identify the estimands and interpretations implied by each model and explore their performance in the absence or presence of dietary confounding.

Results

The ‘standard model’ and the mathematically identical ‘residual model’ estimate theaverage relative causal effect(i.e., a ‘substitution’ effect) but provide biased estimates even in the absence of confounding. The ‘energy partition model’ estimates thetotal causal effectbut only provides unbiased estimates in the absence of confounding or when all other nutrients have equal effects on the outcome. The ‘nutrient density model’ has an obscure interpretation but attempts to estimate the average relative causal effect rescaled as a proportion of total energy intake. Accurate estimates of both the total and average relative causal effects may instead be estimated by simultaneously adjusting for all dietary components, an approach we term the ‘all-components model’.

Conclusion

Lack of awareness of the estimand differences and accuracy of the four modelling approaches may explain some of the apparent heterogeneity among existing nutritional studies and raise serious questions regarding the validity of meta-analyses where different estimands have been inappropriately pooled.