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Background:Potentially preventable hospitalisations (PPHs) are a common occurrence. Knowing the factors associated with PPHs may allow high-risk patients to be identified and healthcare resources to be better allocated, and these factors may differ between urban and rural locations. Aim: To determine factors associated with PPHs in an Australian rural population. Method: A retrospective review of admitted patients' demographic and clinical data was used to describe and model the factors associated with PPHs, using an age- and sex-matched control group of non-admitted patients. Setting:A multi-site rural general practice, Tasmania. Participants: Patients aged >18 years residing in the Huon-Bruny Island region of Tasmania, who were active patients at a rural general practice and were admitted to a public hospital for a PPH between 1/7/2016 and 30/6/2019. Main outcome measures: Overnight admission to hospital for a PPH. Results: Predictors with a significant odds-ratio (OR) in the final model were being single/unmarried (OR 2.43, 95%CI 1.38-4.28), higher Charlson Comorbidity Index score (OR 1.40, 95%CI 1.13-1.74) and the number of general practice visits in the preceding 12 months (OR 1.09, 95%CI 1.05-1.14). Conclusion(s): This study found that being single and having a higher comorbidity burden were the strongest independent risk factors for PPHs in a rural population. Demographic and socioeconomic factors appeared to be as, if not more, important than medical factors and warrant attention when considering the design of programs to reduce PPH risk in rural communities. This article is protected by copyright. All rights reserved.

OBJECTIVE Previous studies have demonstrated the short-term radiographic and clinical benefits of circumferential minimally invasive surgery (cMIS) and hybrid (i.e., minimally invasive anterior or lateral interbody fusion with an open posterior approach) techniques to correct adult spinal deformity (ASD). However, it is not known if these benefits are maintained over longer periods of time. This study evaluated the 2- and 3-year outcomes of cMIS and hybrid correction of ASD. METHODS A multicenter database was retrospectively reviewed for patients undergoing cMIS or hybrid surgery for ASD. Patients were ≥ 18 years of age and had one of the following: maximum coronal Cobb angle (CC) ≥ 20°, sagittal vertical axis (SVA) > 5 cm, pelvic incidence–lumbar lordosis mismatch (PI-LL) ≥ 10°, or pelvic tilt (PT) > 20°. Radiographic parameters were evaluated at the latest follow-up. Clinical outcomes were compared at 2- and 3-year time points and adjusted for age, preoperative CC, levels operated, levels with interbody fusion, presence of L5–S1 anterior lumbar interbody fusion, and upper and lower instrumented vertebral level. RESULTS Overall, 197 (108 cMIS, 89 hybrid) patients were included with 187 (99 cMIS, 88 hybrid) and 111 (60 cMIS, 51 hybrid) patients evaluated at 2 and 3 years, respectively. The mean (± SD) follow-up duration for cMIS (39.0 ± 13.3 months, range 22–74 months) and hybrid correction (39.9 ± 16.8 months, range 22–94 months) were similar for both cohorts. Hybrid procedures corrected the CC greater than the cMIS technique (adjusted p = 0.022). There were no significant differences in postoperative SVA, PI-LL, PT, and sacral slope (SS). At 2 years, cMIS had lower Oswestry Disability Index (ODI) scores (adjusted p < 0.001), greater ODI change as a percentage of baseline (adjusted p = 0.006), less visual analog scale (VAS) back pain (adjusted p = 0.006), and greater VAS back pain change as a percentage of baseline (adjusted p = 0.001) compared to hybrid techniques. These differences were no longer significant at 3 years. At 3 years, but not 2 years, VAS leg pain was lower for cMIS compared to hybrid techniques (adjusted p = 0.032). Those undergoing cMIS had fewer overall complications compared to hybrid techniques (adjusted p = 0.006), but a higher odds of pseudarthrosis (adjusted p = 0.039). CONCLUSIONS In this review of a multicenter database for patients undergoing cMIS and hybrid surgery for ASD, hybrid procedures were associated with a greater CC improvement compared to cMIS techniques. cMIS was associated with superior ODI and back pain at 2 years, but this difference was no longer evident at 3 years. However, cMIS was associated with superior leg pain at 3 years. There were fewer complications following cMIS, with the exception of pseudarthrosis.

Background There is a need to improve prognostic accuracy for patients with cutaneous melanoma (CM). A 31-gene expression profile (31-GEP) test uses the molecular biology of primary tumors to identify individual patient metastatic risk. Objective Develop a nomogram incorporating 31-GEP with relevant clinical factors to improve prognostic accuracy. Methods In an IRB-approved study, 1,124 patients from nine Mohs micrographic surgery centers were prospectively enrolled, treated with Mohs micrographic surgery, and had 31-GEP testing. Data from 684 of those patients with at least one-year follow-up or a metastatic event were included in nomogram development to predict metastatic risk. Results Logistic regression modeling of 31-GEP results and T stage provided the simplest nomogram with the lowest Bayesian information criteria score. Validation in an archival cohort (n=901) demonstrated a significant linear correlation between observed and nomogram-predicted risk of metastasis. The resulting nomogram more accurately predicts the risk for CM metastasis than T stage or 31-GEP alone. Limitations The patient population is representative of Mohs micrographic surgery centers. Sentinel lymph node biopsy was not performed for most patients and could not be used in the nomogram. Conclusions 31-GEP and T stage can be integrated to gain clinically useful prognostic information from data obtained non-invasively.

AIMS Socioeconomic status (SES) is an important variable that impacts healthcare outcomes. However, grouped SES data is not always representative of all members and it is difficult to obtain individual level data. A validated individual housing-based measure termed HOUSES is available, but has not been studied in diabetes. We hypothesize that patients in the lowest HOUSES quartile are associated with worse diabetic control as measured by the D5. METHODS A retrospective cohort study of 5463 patients with diabetes in 5 patient centered medical home practices in southeast Minnesota was conducted. HOUSES is a validated, standardized housing-based SES measure constructed from publicly available county assessor's office data. Diabetic control was assessed by the D5 (HgbA1c < 8, BP < 140/90, statin use, nonsmoking status, and antiplatelet therapy). RESULTS In the lowest HOUSES quartile, more patients had an uncontrolled D5 (56.4%) than any of the other quartiles (49.2%, 49.8%, 49.6% respectively, p < 0.001). A multivariate analysis shows the adjusted odds of D5 control for patients in the 2nd, 3rd or 4th HOUSES quartiles as opposed to the 1st quartile are 1.28, 1.21, and 1.20, respectively. CONCLUSION Lower SES as represented by the first quartile of HOUSES index, is associated with lower odds of D5 control and thus worse diabetic outcomes. Using the HOUSES index to identify these individuals in a patient centered medical home might prove useful in deciding where to focus diabetic control efforts.

Background and Overview To date, only about 125 cases of juvenile or adult spongiotic gingivitis have been described in the literature, primarily from retrospective biopsy searches. Spongiotic gingivitis is a relatively new, often misdiagnosed, periodontal pathology that was originally attributed only to juveniles. This is the first case report to our knowledge on spongiotic gingivitis diagnosed in a middle-aged adult man and treated with a novel carbon dioxide (CO2) laser low-energy ablation therapy. Case Description A 56-year-old man sought treatment for a localized erythematous lesion on the facial gingiva of the maxillary left central incisor (tooth no. 9). Initial treatment was conventional excisional surgery and biopsy. Diagnosed as spongiotic gingivitis, it reoccurred in the same location within 4 months. It was then treated in 3 sessions using a novel 9,300-nm CO2 laser low-energy ablation set at 0.4 W and 1.25-mm cut width for an irradiance of 33.3 W/cm2 and energy density of 0.21 J/cm2. The lesion was significantly reduced and has shown no hyperplastic reoccurrence to date. Conclusions and Practical Implications This case report brings to dental professionals’ attention that acute spongiotic gingivitis may occur in older adults, not just juveniles. As such, spongiotic gingivitis may be underreported in adults with localized gingivitis, possibly attributed to toothpastes containing sodium laurel sulfate. 9,300-nm CO2 laser therapy may successfully treat lesions such as acute spongiotic gingivitis without the need for anesthesia or additional medications. This report may also encourage further research on treatment modalities, biopsy of lesions resembling this entity, and improved reporting of adult spongiotic gingivitis to better understand this unique gingival pathology.

Patients with human immunodeficiency virus (HIV) infection are at increased risk of cardiovascular disease, but studies on HIV as a risk factor for cardiac arrest in the general population are lacking. We aimed to examine the association of HIV infection with out-of-hospital cardiac arrests (OHCAs). We used the Office of Statewide Health Planning and Development data to evaluate HIV infection as a predictor of OHCA in all California emergency department encounters from 2005 to 2015, adjusting for age, gender, race, income, obesity, smoking, alcohol, substance abuse, hypertension (HTN), diabetes, coronary artery disease, congestive heart failure (CHF), atrial fibrillation, and chronic kidney disease (CKD). We also determined patient characteristics modifying these associations by including interaction terms in multivariable-adjusted models. In 18,542,761 patients (mean age 47 ± 20 years, 53% women, 43,849 with HIV) followed for a median 6.8 years, 133,983 new OHCA events occurred. Incidence rates in patients with HIV were higher than in patients without HIV (1.99 vs 1.16 OHCA events per 1,000-person-years follow-up). After multivariable adjustment, HIV was associated with a 2.5-fold higher risk of OHCA (hazard ratio 2.47, 95% confidence interval 2.29 to 2.66, p

OBJECTIVE Few studies have compared fractional curve correction after long fusion between transforaminal lumbar interbody fusion (TLIF) and anterior lumbar interbody fusion (ALIF) for adult symptomatic thoracolumbar/lumbar scoliosis (ASLS). The objective of this study was to compare fractional correction, health-related quality of life (HRQL), and complications associated with L4–S1 TLIF versus those of ALIF as an operative treatment of ASLS. METHODS The authors retrospectively analyzed a prospective multicenter adult spinal deformity database. Inclusion required a fractional curve ≥ 10°, a thoracolumbar/lumbar curve ≥ 30°, index TLIF or ALIF performed at L4–5 and/or L5–S1, and a minimum 2-year follow-up. TLIF and ALIF patients were propensity matched according to the number and type of interbody fusion at L4–S1. RESULTS Of 135 potentially eligible consecutive patients, 106 (78.5%) achieved the minimum 2-year follow-up (mean ± SD age 60.6 ± 9.3 years, 85% women, 44.3% underwent TLIF, and 55.7% underwent ALIF). Index operations had mean ± SD 12.2 ± 3.6 posterior levels, 86.6% of patients underwent iliac fixation, 67.0% underwent TLIF/ALIF at L4–5, and 84.0% underwent TLIF/ALIF at L5–S1. Compared with TLIF patients, ALIF patients had greater cage height (10.9 ± 2.1 mm for TLIF patients vs 14.5 ± 3.0 mm for ALIF patients, p = 0.001) and lordosis (6.3° ± 1.6° for TLIF patients vs 17.0° ± 9.9° for ALIF patients, p = 0.001) and longer operative duration (6.7 ± 1.5 hours for TLIF patients vs 8.9 ± 2.5 hours for ALIF patients, p < 0.001). In all patients, final alignment improved significantly in terms of the fractional curve (20.2° ± 7.0° to 6.9° ± 5.2°), maximum coronal Cobb angle (55.0° ± 14.8° to 23.9° ± 14.3°), C7 sagittal vertical axis (5.1 ± 6.2 cm to 2.3 ± 5.4 cm), pelvic tilt (24.6° ± 8.1° to 22.7° ± 9.5°), and lumbar lordosis (32.3° ± 18.8° to 51.4° ± 14.1°) (all p < 0.05). Matched analysis demonstrated comparable fractional correction (−13.6° ± 6.7° for TLIF patients vs −13.6° ± 8.1° for ALIF patients, p = 0.982). In all patients, final HRQL improved significantly in terms of Oswestry Disability Index (ODI) score (42.4 ± 16.3 to 24.2 ± 19.9), physical component summary (PCS) score of the 36-item Short-Form Health Survey (32.6 ± 9.3 to 41.3 ± 11.7), and Scoliosis Research Society–22r score (2.9 ± 0.6 to 3.7 ± 0.7) (all p < 0.05). Matched analysis demonstrated worse ODI (30.9 ± 21.1 for TLIF patients vs 17.9 ± 17.1 for ALIF patients, p = 0.017) and PCS (38.3 ± 12.0 for TLIF patients vs 45.3 ± 10.1 for ALIF patients, p = 0.020) scores for TLIF patients at the last follow-up (despite no differences in these parameters at baseline). The rates of total complications were similar (76.6% for TLIF patients vs 71.2% for ALIF patients, p = 0.530), but significantly more TLIF patients had rod fracture (28.6% of TLIF patients vs 7.1% of ALIF patients, p = 0.036). Multiple regression analysis demonstrated that a 1-mm increase in L4–5 TLIF cage height led to a 2.2° reduction in L4 coronal tilt (p = 0.011), and a 1° increase in L5–S1 ALIF cage lordosis led to a 0.4° increase in L5–S1 segmental lordosis (p = 0.045). CONCLUSIONS Operative treatment of ASLS with L4–S1 TLIF versus ALIF demonstrated comparable mean fractional curve correction (66.7% vs 64.8%), despite use of significantly larger, more lordotic ALIF cages. TLIF cage height had a significant impact on leveling L4 coronal tilt, whereas ALIF cage lordosis had a significant impact on restoration of lumbosacral lordosis. The advantages of TLIF may include reduced operative duration and hospitalization; however, associated HRQL was inferior and more rod fractures were detected in the TLIF patients included in this study.

Objective To determine the incidence of hospital readmission in a geriatric hip fracture population within 90 days. Methods Analysis of patients aged ≥60 years presenting with a fragility fracture of the hip from a prospective geriatric hip fracture program registry was performed. Demographics, diagnoses, treatments, complications, hospital events, and readmission for any cause within 30 and 90 days were collected. Readmission events were categorized as defined by Bundled Care Payment Initiative (BCPI)/Care for Joint Replacement payment model. Results The population included 305 patients. All-cause readmission at 30 and 90 days was 11.5% and 19.7%, respectively. Surgical site infection or prosthesis failure accounted for 2.6% of 90 days readmissions. Application of the BCPI rules identified 44 of 60 readmitted patients (73.3%) with causes attributable to the surgical event: medical (0.7%), hospital (12.1%), and mechanical (2.6%). Death within 30 days was the largest contributor to hospital-related events. Conclusions This study identified a 90-day readmission rate of nearly 20% in patients with geriatric fragility fractures. Application of the BCPI definitions currently used in the Care for Joint Replacement payment model will result in more readmissions being attributed to the index surgical event than classically considered. If bundled payment models remain the future, further investigation of this population's risk factors for readmission is needed in light of these findings. Level of evidence Prognostic and Epidemiological Level II. See Instructions for Authors for a complete description of levels of evidence.

OBJECTIVE Deterioration of global coronal alignment (GCA) may be associated with worse outcomes after adult spinal deformity (ASD) surgery. The impact of fusion length and upper instrumented vertebra (UIV) selection on patients with this complication is unclear. The authors’ objective was to compare outcomes between long sacropelvic fusion with upper-thoracic (UT) UIV and those with lower-thoracic (LT) UIV in patients with worsening GCA ≥ 1 cm. METHODS This was a retrospective analysis of a prospective multicenter database of consecutive ASD patients. Index operations involved instrumented fusion from sacropelvis to thoracic spine. Global coronal deterioration was defined as worsening GCA ≥ 1 cm from preoperation to 2-year follow-up. RESULTS Of 875 potentially eligible patients, 560 (64%) had complete 2-year follow-up data, of which 144 (25.7%) demonstrated worse GCA at 2-year postoperative follow-up (35.4% of UT patients vs 64.6% of LT patients). At baseline, UT patients were younger (61.6 ± 9.9 vs 64.5 ± 8.6 years, p = 0.008), a greater percentage of UT patients had osteoporosis (35.3% vs 16.1%, p = 0.009), and UT patients had worse scoliosis (51.9° ± 22.5° vs 32.5° ± 16.3°, p < 0.001). Index operations were comparable, except UT patients had longer fusions (16.4 ± 0.9 vs 9.7 ± 1.2 levels, p < 0.001) and operative duration (8.6 ± 3.2 vs 7.6 ± 3.0 hours, p = 0.023). At 2-year follow-up, global coronal deterioration averaged 2.7 ± 1.4 cm (1.9 to 4.6 cm, p < 0.001), scoliosis improved (39.3° ± 20.8° to 18.0° ± 14.8°, p < 0.001), and sagittal spinopelvic alignment improved significantly in all patients. UT patients maintained smaller positive C7 sagittal vertical axis (2.7 ± 5.7 vs 4.7 ± 5.7 cm, p = 0.014). Postoperative 2-year health-related quality of life (HRQL) significantly improved from baseline for all patients. HRQL comparisons demonstrated that UT patients had worse Scoliosis Research Society–22r (SRS-22r) Activity (3.2 ± 1.0 vs 3.6 ± 0.8, p = 0.040) and SRS-22r Satisfaction (3.9 ± 1.1 vs 4.3 ± 0.8, p = 0.021) scores. Also, fewer UT patients improved by ≥ 1 minimal clinically important difference in numerical rating scale scores for leg pain (41.3% vs 62.7%, p = 0.020). Comparable percentages of UT and LT patients had complications (208 total, including 53 reoperations, 77 major complications, and 78 minor complications), but the percentage of reoperated patients was higher among UT patients (35.3% vs 18.3%, p = 0.023). UT patients had higher reoperation rates of rod fracture (13.7% vs 2.2%, p = 0.006) and pseudarthrosis (7.8% vs 1.1%, p = 0.006) but not proximal junctional kyphosis (9.8% vs 8.6%, p = 0.810). CONCLUSIONS In ASD patients with worse 2-year GCA after long sacropelvic fusion, UT UIV was associated with worse 2-year HRQL compared with LT UIV. This may suggest that residual global coronal malalignment is clinically less tolerated in ASD patients with longer fusion to the proximal thoracic spine. These results may inform operative planning and improve patient counseling.

Herein, we report the design and synthesis of inhibitors of Mycobacterium tuberculosis (Mtb) phospho-MurNAc-pentapeptide translocase I (MurX), the first membrane-associated step of peptidoglycan synthesis, leveraging the privileged structure of the sansanmycin family of uridylpeptide natural products. A number of analogues bearing hydrophobic amide modifications to the pseudo-peptidic end of the natural product scaffold were generated that exhibited nanomolar inhibitory activity against Mtb MurX and potent activity against Mtb in vitro. We show that a lead analogue bearing an appended neopentylamide moiety possesses rapid antimycobacterial effects with a profile similar to the frontline tuberculosis drug isoniazid. This molecule was also capable of inhibiting Mtb growth in macrophages where mycobacteria reside in vivo and reduced mycobacterial burden in an in vivo zebrafish model of tuberculosis.

Objective The primary course of treatment for patients with low- to intermediate-risk tonsil cancer has evolved with a shift toward primary transoral robotic surgery (TORS) or radiation therapy (RT). While favorable outcomes have been reported after deintensification via unilateral TORS or RT (uniRT), comparisons of functional outcomes between these treatments are lacking. We compared clinical outcomes (Dynamic Imaging Grade of Swallowing Toxicity [DIGEST] and feeding tube [FT]) and patient-reported swallowing outcomes (MD Anderson Dysphagia Inventory [MDADI]) based on primary treatment strategy: TORS, uniRT, or bilateral RT (biRT). Study design Secondary analysis of prospective cohort. Setting Single institution. Methods The study sample comprised 135 patients with HPV/p16+ T1-T3, N0-2b (American Joint Committee on Cancer, seventh edition), N0-1 (eighth edition) squamous cell carcinoma of the tonsil were sampled from a prospective registry. Modified barium swallow studies graded per DIGEST, FT placement and duration, and MDADI were collected. Results Baseline DIGEST grade significantly differed among treatment groups, with higher dysphagia prevalence in the TORS group (34%) vs the biRT group (12%, P = .04). No significant group differences were found in DIGEST grade or dysphagia prevalence at subacute and longitudinal time points (P = .41). Mean MDADI scores were similar among groups at baseline (TORS, 92; uniRT, 93; biRT, 93; P = .90), subacute (TORS, 83; uniRT, 88; biRT, 82; P = .38) and late time points (TORS, 86; uniRT, 86; biRT, 87; P = .99). FT placement and duration significantly differed among primary treatment groups (FT [median days]: TORS, 89% [3]; uniRT, 8% [82]; biRT, 37% [104]; P Conclusion While TORS and uniRT offer optimal functional outcomes related to dysphagia, results suggest that no measurable clinician-graded or patient-reported differences in swallow outcomes exist among these primary treatment strategies and biRT. Aside from baseline differences that drive treatment selection, differences in FT rate and duration by primary treatment strategy likely reflect diverse toxicities beyond dysphagia.

Objectives/hypothesis Radiation-associated sarcomas of the head and neck (RASHN) are known but rare sequelae after radiation for squamous cell carcinoma. The purpose of this study was to characterize RASHN, estimate the risk of RASHN in head and neck squamous cell patients after therapeutic radiation, and compare their survival to that of patients with de novo sarcomas of the head and neck (dnSHN). Study design Retrospective database analysis. Methods RASHN and dnSHN cases were collected from the Surveillance, Epidemiology, and End Results Database to identify risk factors and calculate incidence and latency. Survival was compared between RASHN and dnSHN. Results The risk of RASHN was 20.0 per 100,000 person-years. The average latency period was 124.2 months (range 38-329). The cumulative incidence of RASHN at 20 years was 0.13%. Oral cavity and oropharynx primaries demonstrate increased risk. Five-year overall survival of RASHN was 22.4% compared to 64.5% for dnSHN. Conclusions RASHN are confirmed to be rare. RASHN have poor overall survival and worse survival compared to dnSHN. The impact of intensity-modulated radiation therapy protocols on this risk is unknown. Modifiable risk factors of smoking and alcohol consumption continue to dwarf radiation therapy as risk factors of second primary head and neck cancers. Level of evidence 3 Laryngoscope, 2021.

Background The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. Methods In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. Results One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. Conclusions The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Objective To characterize the safety of sildenafil in premature infants. Study design A phase I, open-label trial of sildenafil in premature infants receiving sildenafil per usual clinical care (cohort 1) or receiving a single IV dose of sildenafil (cohort 2). Safety was evaluated based on adverse events (AEs), transaminase levels, and mean arterial pressure monitoring. Results Twenty-four infants in cohort 1 (n = 25) received enteral sildenafil. In cohort 2, infants received a single IV sildenafil dose of 0.25 mg/kg (n = 7) or 0.125 mg/kg (n = 2). In cohort 2, there was one serious AE related to study drug involving hypotension associated with a faster infusion rate than specified by the protocol. There were no AEs related to elevated transaminases. Conclusion Sildenafil was well tolerated by the study population. Drug administration times and flush rates require careful attention to prevent infusion-related hypotension associated with faster infusions of IV sildenafil in premature infants. Clinical trial ClinicalTrials.gov Identifier: NCT01670136.

BACKGROUND Patients' self-reports suggest that acute alcohol consumption may trigger a discrete atrial fibrillation (AF) event. OBJECTIVE To objectively ascertain whether alcohol consumption heightens risk for an AF episode. DESIGN A prospective, case-crossover analysis. SETTING Ambulatory persons in their natural environments. PARTICIPANTS Consenting patients with paroxysmal AF. MEASUREMENTS Participants were fitted with a continuous electrocardiogram (ECG) monitor and an ankle-worn transdermal ethanol sensor for 4 weeks. Real-time documentation of each alcoholic drink consumed was self-recorded using a button on the ECG recording device. Fingerstick blood tests for phosphatidylethanol (PEth) were used to corroborate ascertainments of drinking events. RESULTS Of 100 participants (mean age, 64 years [SD, 15]; 79% male; 85% White), 56 had at least 1 episode of AF. Results of PEth testing correlated with the number of real-time recorded drinks and with events detected by the transdermal alcohol sensor. An AF episode was associated with 2-fold higher odds of 1 alcoholic drink (odds ratio [OR], 2.02 [95% CI, 1.38 to 3.17]) and greater than 3-fold higher odds of at least 2 drinks (OR, 3.58 [CI, 1.63 to 7.89]) in the preceding 4 hours. Episodes of AF were also associated with higher odds of peak blood alcohol concentration (OR, 1.38 [CI, 1.04 to 1.83] per 0.1% increase in blood alcohol concentration) and the total area under the curve of alcohol exposure (OR, 1.14 [CI, 1.06 to 1.22] per 4.7% increase in alcohol exposure) inferred from the transdermal ethanol sensor in the preceding 12 hours. LIMITATION Confounding by other time-varying exposures that may accompany alcohol consumption cannot be excluded, and the findings from the current study of patients with AF consuming alcohol may not apply to the general population. CONCLUSION Individual AF episodes were associated with higher odds of recent alcohol consumption, providing objective evidence that a modifiable behavior may influence the probability that a discrete AF event will occur. PRIMARY FUNDING SOURCE National Institute on Alcohol Abuse and Alcoholism.

Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms. In patients with PBD-ZSD, pathogenic variants in the PEX family of genes disrupt normal peroxisomal function, impairing α- and β-oxidation of very-long-chain fatty acids and synthesis of bile acids, resulting in increased levels of toxic bile acid intermediates and multisystem organ damage. The spectrum of severity in PBD-ZSD is variable, with some patients dying in the first year of life, while others live into adulthood. Symptoms of mild PBD-ZSD include various combinations of developmental delay, craniofacial dysmorphic features, visual impairment, sensorineural hearing loss, liver disease, and adrenal insufficiency. Disease progression in mild PBD-ZSD is generally slow, and may include extended periods of stability in some cases. The presence and extent to which symptoms occur in mild PBD-ZSD represents a diagnostic challenge that can cause delays in diagnosis with potential significant implications related to disease monitoring and treatment. There is some support for the pharmacologic therapies of Lorenzo's oil, docosohexanoic acid, and batyl alcohol in altering symptoms; however, systematic long-term studies are lacking. Cholic acid (CA) therapy has demonstrated treatment efficacy in patients with PBD-ZSD, including decreased toxic bile acid intermediates, transaminase levels, and liver inflammation, with improvement in growth parameters. However, these responses are most apparent in patients diagnosed and treated at a young age. Advanced liver disease may limit the efficacy of CA, underscoring the need to diagnose and treat these patients before significant liver damage and other related complications occur. Here we discuss the signs and symptoms of PBD-ZSD in patients with mild disease, standard diagnostic tools, factors affecting disease management, and available pharmacological interventions.

Objective To conduct a comprehensive search for evidence with regard to whether central sensitization after an injury can act as a persistent autonomous pain generator after the inducing injury has healed. Methods We searched Medline on PubMed and the Cochrane Library, screening 3,572 abstracts, from which 937 full-text articles were obtained, with 186 of these discarded as irrelevant to the question being posed. The remaining 751 articles were studied for evidence. Results Fourteen publications were judged to provide weak evidence for the hypothesis of central sensitization as a persisting autonomous pain generator, but none addressed the question directly. No strong evidence for the affirmative answer was found. Sixty-one publications were judged to provide weak evidence for a negative answer, and ten were judged to provide strong evidence. Unexpectedly, serious weaknesses were discovered in the literature underpinning the validity of the clinical diagnosis of central sensitization in humans: 1) inappropriate extrapolation, in many publications, of laboratory animal data to humans; 2) failure to demonstrate the absence of peripheral pain generators that might be perpetuating central sensitization; and 3) many factors now shown to confound what is being measured by quantitative sensory testing, conditioned pain modulation, and the Central Sensitization Inventory. Conclusions We found no evidence proving that central sensitization can persist as an autonomous pain generator after the initiating injury has healed. Our review has also shown that the evidential basis for the diagnosis of central sensitization in individual patients is seriously in question.

Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.

The iconic Tasmanian devil (Sarcophilus harrisii) is endangered due to the transmissible cancer Devil Facial Tumour Disease (DFTD), of which there are two genetically independent subtypes (DFT1 and DFT2). While DFT1 and DFT2 can be differentially diagnosed using tumour biopsies, there is an urgent need to develop less-invasive biomarkers that can detect DFTD and distinguish between subtypes. Extracellular vesicles (EVs), the nano-sized membrane-enclosed vesicles present in most biofluids, represent a valuable resource for biomarker discovery. Here, we characterized the proteome of EVs from cultured DFTD cells using data-independent acquisition–mass spectrometry and an in-house spectral library of > 1500 proteins. EVs from both DFT1 and DFT2 cell lines expressed higher levels of proteins associated with focal adhesion functions. Furthermore, hallmark proteins of epithelial–mesenchymal transition were enriched in DFT2 EVs relative to DFT1 EVs. These findings were validated in EVs derived from serum samples, revealing that the mesenchymal marker tenascin-C was also enriched in EVs derived from the serum of devils infected with DFT2 relative to those infected with DFT1 and healthy controls. This first EV-based investigation of DFTD increases our understanding of the cancers’ EVs and their possible involvement in DFTD progression, such as metastasis. Finally, we demonstrated the potential of EVs to differentiate between DFT1 and DFT2, highlighting their potential use as less-invasive liquid biopsies for the Tasmanian devil.

Objective: Concerns have been raised over the appropriateness of dosing of direct-acting oral anticoagulants (DOACs) in clinical practice. We investigated this issue in patients who were initiated on a DOAC in Australian general practices. Methods:This was a retrospective study among patients newly diagnosed with atrial fibrillation (AF) who were prescribed DOACs, using data obtained from 417 general practice sites across Australia over 8 years (2011–2019). Direct-acting oral anticoagulant dosing was compared with published recommendations, in relation to age and kidney function. Results: A total of 11,251 patients (mean age, 72.8 y; 46.8% female) newly diagnosed with AF were prescribed a DOAC. Of these, 2667 patients (23.7%) had a recorded prescription of a potentially inappropriate DOAC dosage, of whom 2304 (86.4%) and 283 (10.6%) were prescribed lower and higher than the recommended dosage, respectively. The remaining 80 patients (3.0%) were initiated on DOACs when contraindicated based on renal function. Overall, the proportion of patients who seemed to be initiated on a potentially inappropriate DOAC dose decreased from 38.3% (95% confidence interval, 26.1%–51.8%) in 2012 to 22.7% (95% confidence interval, 19.8%–26.0%; P < 0.001) in 2019. By 2019, 19.4%, 20.3%, and 9.3% of the patients with a recorded prescription of apixaban, rivaroxaban, and dabigatran, respectively, received a lower-than-guideline-recommended dose. The patients were more likely to be prescribed a potentially inappropriate dosage if they were elderly with multiple comorbidities. Conclusions: Potential inappropriate DOAC dosing is a problem in the prevention of stroke associated with AF. Nearly 1 in 5 patients received a lower-than-guideline-recommended dose, indicating a need for strategies to raise awareness among prescribers.

Parent-youth intimacy protects adolescents from adjustment problems, including weight concerns, low self-esteem, and depressive symptoms. This study aimed to identify when in development parent-youth intimacy emerges as a protective factor, how this protective effect changes in its strength across adolescence, and whether there are differences in intimacy-adjustment linkages depending on parent and youth gender. The sample was 388 predominately White American adolescents (50.8% female; ages 12-20 years, M = 15.2, SD = 1.63 at Time 1) from 202 families. Time-varying effect models revealed that associations between intimacy and adjustment problems were dynamic and differed by parent and youth gender and across adjustment problems. Father-youth intimacy was associated with fewer weight concerns across most of adolescence for girls and boys, and these effects were strongest in mid- and late adolescence, respectively. Mother-youth intimacy was associated with boys' but not girls' weight concerns, and only in early adolescence. Father-youth intimacy was associated with fewer depressive symptoms for boys and girls across most of adolescence, whereas mother-youth intimacy was associated with fewer depressive symptoms in mid-adolescence. However, the association between intimacy and depressive symptoms was strongest during mid-adolescence for mother- and father-youth intimacy. Finally, father-youth intimacy was associated with higher self-esteem from early through mid-adolescence for boys and girls, whereas mother-youth intimacy was associated with higher self-esteem across most of adolescence for girls and during early and late adolescence for boys. Findings have implications for the timing and targets of family interventions and highlight parents' unique and shared roles in adolescents' adjustment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE.Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system.Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P .001) than those without acute abnormalities.Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.ClinicalTrials.gov: NCT02811263.

PURPOSE: There are limited prospective data on predictors of patient-reported outcomes (PROs) after whole-breast irradiation (WBI) plus a boost. We sought to characterize longitudinal PROs and cosmesis in a randomized trial comparing conventionally fractionated (CF) versus hypofractionated (HF) WBI. METHODS AND MATERIALS: From 2011 to 2014, women aged ≥40 years with Tis-T2 N0-N1a M0 breast cancer who underwent a lumpectomy with negative margins were randomized to CF-WBI (50 Gray [Gy]/25 fractions plus boost) versus HF-WBI (42.56 Gy/16 fractions plus boost). At baseline (pre-radiation), at 6 months, and yearly thereafter through 5 years, PROs included the Breast Cancer Treatment Outcome Scale (BCTOS), Functional Assessment of Cancer Therapy−Breast (FACTB), and Body Image Scale; cosmesis was reported by the treating physician using Radiation Therapy Oncology Group cosmesis values. Multivariable mixed-effects growth curve models evaluated associations of the treatment arm and patient factors with outcomes and tested for relevant interactions with the treatment arm. RESULTS: A total of 287 patients were randomized, completing a total of 14,801 PRO assessments. The median age was 60 years, 37% of patients had a bra cup size ≥D, 44% were obese, and 30% received chemotherapy. Through 5 years, there were no significant differences in PROs or cosmesis by treatment arm. A bra cup size ≥D was associated with worse BCTOS cosmesis (P < .001), BCTOS pain (P = .001), FACT-B Trial Outcome Index (P = .03), FACT-B Emotional Well-being (P = .03), and Body Image Scale (P = .003) scores. Physician-rated cosmesis was worse in patients who were overweight (P = .02) or obese (P < .001). No patient subsets experienced better PROs or cosmesis with CF-WBI. CONCLUSIONS: Both CF-WBI and HF-WBI confer similar longitudinal PROs and physician-rated cosmesis through 5 years of follow-up, with no relevant subsets that fared better with CF-WBI. This evidence supports broad adoption of hypofractionation with boost, including in patients receiving chemotherapy and in a population with a high prevalence of obesity. The associations of large breast size and obesity with adverse outcomes across multiple domains highlight the opportunity to engage at-risk patients in lifestyle intervention strategies, as well as to consider alternative radiation treatment regimens.

Aedes notoscriptus (Skuse), the Australian backyard mosquito, is a pestiferous daytime-biting species native to Australia and the surrounding southwestern Pacific region. It is suspected to play a role in the transmission of several arboviruses and is considered a competent vector of dog heartworm, Dirofilaria immitis (Leidy). This highly adaptable mosquito thrives in natural and artificial water-holding containers in both forested and urbanized areas, from tropical to temperate climates, and has benefitted from a close association with humans, increasing in abundance within its native range. It invaded and successfully established in New Zealand as well as in previously unoccupied temperate and arid regions of Australia. Ae. notoscriptus was discovered in Los Angeles County, CA, in 2014, marking the first time this species had been found outside the southwestern Pacific region. By the end of 2019, immature and adult mosquitoes had been collected from 364 unique locations within 44 cities spanning three southern California counties. The discovery, establishment, and rapid spread of this species in urban areas may signal the global movement and advent of a new invasive container-inhabiting species. The biting nuisance, public health, and veterinary health implications associated with the invasion of southern California by this mosquito are discussed.

BACKGROUND The anterior cruciate ligament quality of life (ACL-QOL) score is a disease-specific patient-reported outcome measure that assesses patients with ACL deficient and reconstructed knees. The ACL-QOL has demonstrated validity, responsiveness, and reliability in adult populations but has yet to be specifically evaluated in adolescent patients. The purpose of this study was to assess the validity, responsiveness, and reliability of the ACL-QOL in an adolescent population. METHODS Between 2010 and 2015, questionnaires from 294 consecutive adolescent patients consented for an ACL reconstruction were collected from an orthopaedic sport medicine clinic. The ACL-QOL was administered preoperatively, and at 6, 12, and 24 months following primary ACL reconstruction. To assess content validity, the Cronbach α and floor and ceiling effects were measured. Question reading level was measured with an online tool (https://readable.com/). Responsiveness was assessed with a 1-way analysis of variance to compare the preoperative and postoperative time periods. A test-retest strategy with completion of the ACL-QOL twice within 3 weeks was used to assess reliability using an intraclass correlation coefficient (ICC 2,k) and the SEM. RESULTS The ACL-QOL demonstrated high content validity with a Cronbach αbetween 0.93 and 0.97, with no evidence of floor or ceiling effects at any study time point. The mean readability grade level was calculated to be 6.9, along with a readability score of 68. The ACL-QOL scores revealed a statistically significant improvement over time (P

Background The pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus. Methods The brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants’ history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation. Results Of the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ2 = 7.1, p = 0.008, df = 1) and depression (χ2 = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5–6.4, χ2 = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3–5.0, χ2 = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra. Conclusion These results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.

Pseudoprogression, defined as the radiographic false appearance of disease progression, is not frequently observed in patients with malignant peripheral nerve sheath tumor (MPNST). We report on a case of a patient with neurofibromatosis type 1 (NF1) MPNST pseudoprogression that presented as suspected local recurrence 9.5 years after last treatment. The patient underwent surgical resection following growth of a mass on sequential MRI imaging; surgical pathology, however, showed skeletal muscle with atrophy, fibroadipose tissue, and fat necrosis, without any evidence of tumor. As MPNST survival rates increase, physicians should consider pseudoprogression as a potential presentation after prior treatment.

Events causing acute stress to the health care system, such as the COVID-19 pandemic, place clinical decisions under increased scrutiny. The priority and timing of surgical procedures are critically evaluated under these conditions, yet the optimal timing of procedures is a key consideration in any clinical setting. There is currently no single article consolidating a large body of current evidence on timing of nerve surgery. MEDLINE and EMBASE databases were systematically reviewed for clinical data on nerve repair and reconstruction to define the current understanding of timing and other factors affecting outcomes. Special attention was given to sensory, mixed/motor, nerve compression syndromes, and nerve pain. The data presented in this review may assist surgeons in making sound, evidence-based clinical decisions regarding timing of nerve surgery.

OBJECTIVE Circumferential minimally invasive spine surgery (cMIS) for adult scoliosis has become more advanced and powerful, but direct comparison with traditional open correction using prospectively collected data is limited. The authors performed a retrospective review of prospectively collected, multicenter adult spinal deformity data. The authors directly compared cMIS for adult scoliosis with open correction in propensity-matched cohorts using health-related quality-of-life (HRQOL) measures and surgical parameters. METHODS Data from a prospective, multicenter adult spinal deformity database were retrospectively reviewed. Inclusion criteria were age > 18 years, minimum 1-year follow-up, and one of the following characteristics: pelvic tilt (PT) > 25°, pelvic incidence minus lumbar lordosis (PI-LL) > 10°, Cobb angle > 20°, or sagittal vertical axis (SVA) > 5 cm. Patients were categorized as undergoing cMIS (percutaneous screws with minimally invasive anterior interbody fusion) or open correction (traditional open deformity correction). Propensity matching was used to create two equal groups and to control for age, BMI, preoperative PI-LL, pelvic incidence (PI), T1 pelvic angle (T1PA), SVA, PT, and number of posterior levels fused. RESULTS A total of 154 patients (77 underwent open procedures and 77 underwent cMIS) were included after matching for age, BMI, PI-LL (mean 15° vs 17°, respectively), PI (54° vs 54°), T1PA (21° vs 22°), and mean number of levels fused (6.3 vs 6). Patients who underwent three-column osteotomy were excluded. Follow-up was 1 year for all patients. Postoperative Oswestry Disability Index (ODI) (p = 0.50), Scoliosis Research Society–total (p = 0.45), and EQ-5D (p = 0.33) scores were not different between cMIS and open patients. Maximum Cobb angles were similar for open and cMIS patients at baseline (25.9° vs 26.3°, p = 0.85) and at 1 year postoperation (15.0° vs 17.5°, p = 0.17). In total, 58.3% of open patients and 64.4% of cMIS patients (p = 0.31) reached the minimal clinically important difference (MCID) in ODI at 1 year. At 1 year, no differences were observed in terms of PI-LL (p = 0.71), SVA (p = 0.46), PT (p = 0.9), or Cobb angle (p = 0.20). Open patients had greater estimated blood loss compared with cMIS patients (1.36 L vs 0.524 L, p < 0.05) and fewer levels of interbody fusion (1.87 vs 3.46, p < 0.05), but shorter operative times (356 minutes vs 452 minutes, p = 0.003). Revision surgery rates between the two cohorts were similar (p = 0.97). CONCLUSIONS When cMIS was compared with open adult scoliosis correction with propensity matching, HRQOL improvement, spinopelvic parameters, revision surgery rates, and proportions of patients who reached MCID were similar between cohorts. However, well-selected cMIS patients had less blood loss, comparable results, and longer operative times in comparison with open patients.

Several methodologies have been proposed to determine ideal ASD sagittal spinopelvic alignment (SRS–Schwab classification) global alignment and proportion (GAP) score, patient age-adjusted alignment). A recent study revealed the ability and limitations of these methodologies to predict PJK. The aim of the study was to develop a new approach, inspired by SRS classification, GAP score, and age-alignment to improve the evaluation of the sagittal plane. A multi-center ASD database was retrospectively evaluated for surgically treated ASD patients with complete fusion of the lumbar spine, and minimum 2 year follow-up. The Sagittal age-adjusted score (SAAS) methodology was created by assigning numerical values to the difference between each patient’s postoperative sagittal alignment and ideal alignment defined by previously reported age generational norms for PI-LL, PT, and TPA. Postoperative HRQOL and PJK severity between each SAAS categories were evaluated. 409 of 667 (61.3%) patients meeting inclusion criteria were evaluated. At 2 year SAAS score showed that 27.0% of the patients were under-corrected, 51.7% over-corrected, and 21.3% matched their age-adjusted target. SAAS score increased as PJK worsened (from SAAS = 0.2 for no-PJK, to 4.0 for PJF, p

Cancer is the second leading cause of death and there is an urgent need to improve cancer management. We have developed an innovative cancer therapy named Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) by combining gold nanostars (GNS)-mediated photothermal ablation with checkpoint inhibitor immunotherapy. Our previous studies have demonstrated that SYMPHONY photoimmunotherapy not only treats the primary tumor but also dramatically amplifies anticancer immune responses in synergy with checkpoint blockade immunotherapy to treat remote and unresectable cancer metastasis. The SYMPHONY treatment also induces a ‘cancer vaccine’ effect leading to immunologic memory and prevents cancer recurrence in murine animal models. This manuscript provides an overview of our research activities on the SYMPHONY therapy with plasmonic GNS for cancer treatment.

A characteristic aspect of the robust, systemic inflammatory state in sickle cell disease is dysfunction of endothelial nitric oxide synthase (eNOS). We identify ten aberrant endothelial cell inputs, present in the specific sickle context, that are known to have the ability to cause eNOS dysfunction. These are: endothelial arginase depletion, asymmetric dimethylarginine, complement activation, endothelial glycocalyx degradation, free fatty acids, inflammatory mediators, microparticles, oxidized low density lipoproteins, reactive oxygen species, and Toll-like receptor 4 signaling ligands. The effect of true eNOS dysfunction on clinical testing using flow-mediated dilation can be simulated by two known examples of endothelial dysfunction mimicry (hemoglobin consumption of NO; and oxidation of smooth muscle cell soluble guanylate cyclase). This lends ambiguity to interpretation of such clinical testing. The presence of these multiple perturbing factors argues that a therapeutic approach targeting only a single injurious endothelial input (or either example of mimicry) would not be sufficiently efficacious. This would seem to argue for identifying therapeutics that directly protect eNOS function or application of multiple therapeutic approaches. This article is protected by copyright. All rights reserved.

Mycobacterium tuberculosis remains a leading cause of death for which new drugs are needed. The identification of drug targets has been advanced by high-throughput and targeted genetic deletion strategies. Each though has limitations including the inability to distinguish between levels of vulnerability, lethality and scalability as a molecular tool. Using mycobacterial CRISPR interference in combination with phenotypic screening we have overcome these individual issues to investigate essentiality, vulnerability and lethality for 96 target genes from a diverse array of cellular pathways, many of which are potential antibiotic targets. Essential genes involved in cell wall synthesis and central cellular functions were equally vulnerable and often had bactericidal consequences. Conversely, essential genes involved in metabolism, oxidative phosphorylation or amino acid synthesis were less vulnerable to inhibition and frequently bacteriostatic. In conclusion, this study provides novel insights into mycobacterial genetics and biology that will help to prioritise potential drug targets.

BACKGROUND AND AIMS Hepatoblastoma (HBL) is a devastating pediatric liver cancer with multiple treatment options, but it ultimately requires surgery for a cure. The most malicious form of HBL is a chemo-resistant aggressive tumor that is characterized by rapid growth, metastases, and poor response to treatment. Very little is known of the mechanisms of aggressive HBL, and recent focuses have been on developing alternative treatment strategies. In this study, we examined the role of human chromosomal regions, called aggressive liver cancer domains (ALCDs), in liver cancer and evaluated the mechanisms that activate ALCDs in aggressive HBL. RESULTS We found that ALCDs are critical regions of the human genome that are located on all human chromosomes, preferentially in intronic regions of the oncogenes and other cancer-associated genes. In aggressive HBL and in patients with Hepatocellular (HCC), JNK1/2 phosphorylates p53 at Ser6, which leads to the ph-S6-p53 interacting with and delivering the poly(adenosine diphosphate ribose) polymerase 1 (PARP1)/Ku70 complexes on the oncogenes containing ALCDs. The ph-S6-p53-PARP1 complexes open chromatin around ALCDs and activate multiple oncogenic pathways. We found that the inhibition of PARP1 in patient-derived xenografts (PDXs) from aggressive HBL by the Food and Drug Administration (FDA)-approved inhibitor olaparib (Ola) significantly inhibits tumor growth. Additionally, this is associated with the reduction of the ph-S6-p53/PARP1 complexes and subsequent inhibition of ALCD-dependent oncogenes. Studies in cultured cancer cells confirmed that the Ola-mediated inhibition of the ph-S6-p53-PARP1-ALCD axis inhibits proliferation of cancer cells. CONCLUSIONS In this study, we showed that aggressive HBL is moderated by ALCDs, which are activated by the ph-S6-p53/PARP1 pathway. By using the PARP1 inhibitor Ola, we suppressed tumor growth in HBL-PDX models, which demonstrated its utility in future clinical models.

Background Opioid misuse is a widespread public health problem, and opioids are often prescribed in the dental environment. These recommendations provide alternatives to opioids to reduce or eliminate dental procedure–related acute pain. Methods A multidisciplinary working group developed these clinical recommendations to specifically address procedure-related acute pain. These recommendations, which are based on published peer-reviewed research and guidelines, include therapies used before, during, and after dental procedures. When evidence is not definitive, the best practices, which are based on experts’ consensus, are included. The recommendations are not intended to be exhaustive. Results These recommendations are a summary of the evidence and best practices for opioid alternatives to treat acute pain related to dental procedures. Conclusions Dental providers should prioritize opioid stewardship when managing procedure-related pain with strategies such as thorough preprocedure pain assessment, minimally invasive techniques, preemptive analgesia, intraprocedure pain management, and appropriately selected postprocedure pharmacologic therapy. Practical Implications These recommendations are a concise resource for clinical providers. It is important to address patients’ procedure-related pain, using nonopioids whenever possible. Alternatives are outlined, allowing providers to make informed decisions.

Tungiasis (sand flea disease) is an epidermal parasitic skin disease occurring in resource-limited communities. There is no standard treatment for tungiasis, and available treatment options are scarce. To our knowledge, this is the first systematic review aimed to assess randomised controlled trials (RCTs) investigating interventions for tungiasis. We systematically searched databases including MEDLINE (EBSCOhost), CENTRAL, CINAHL, PubMed, Web of Science, SciELO, LILACS and Embase (Scopus) for RCTs in any language, from inception of the databases until June 12, 2021. RCTs exploring preventive and therapeutic interventions for tungiasis were eligible. We used the revised Cochrane Collaboration's risk of bias tool to assess the risk of bias and Jadad scale to quantify the methodological quality of the RCTs. Of the 1839 identified records, only eight RCTs involving 808 participants were included, and several methodological deficiencies were identified in most of the trials. Trial interventions included: oral drugs niridazole and ivermectin and topical interventions of ivermectin lotion, metrifonate lotion, thiabendazole lotion, thiabendazole ointment, dimeticones (NYDA), and a neem seed and coconut oils-based mixture for treatment and coconut oil-based lotion (Zanzarin) for prevention. The coconut oil-based lotion for prevention and dimeticones for treatment of tungiasis have displayed the most promise. Most of the RCTs included in this study had low methodological quality. There is a clear unmet need for high-quality RCTs examining safe and effective prevention and treatment alternatives of tungiasis in endemic settings.

BackgroundWe aimed to address the paucity of information describing the treatable burden of disease associated with severe aortic stenosis (AS) within Australia’s ageing population.MethodsA contemporary model of the population prevalence of symptomatic, severe AS and treatment pathways in Europe and North America was applied to the 2019 Australian population aged ≥ 55 years (7 million people) on an age-specific basis. Applying Australian-specific data, these estimates were used to further calculate the total number of associated deaths and incident cases of severe AS per annum.ResultsBased on an overall point prevalence of 1.48 % among those aged ≥ 55 years, we estimate that a minimum of 97,000 Australians are living with severe AS. With a 2-fold increased risk of mortality without undergoing aortic valve replacement (AVR), more than half of these individuals (∼56,000) will die within 5-years. From a clinical management perspective, among those with concurrent symptoms (68.3 %, 66,500 [95 % CI 59,000–74,000] cases) more than half (58.4 %, 38,800 [95 % CI 35,700 − 42,000] cases) would be potentially considered for surgical AVR (SAVR) - comprising 2,400, 5,400 and 31,000 cases assessed as high-, medium- or low peri-operative mortality risk, respectively. A further 17,000/27,700 (41.6 % [95 % CI 11,600 − 22,600]) of such individuals would be potentially considered to a transthoracic AVR (TAVR). During the subsequent 5-year period (2020–2024), each year, we estimate an additional 9,300 Australians aged ≥ 60 years will subsequently develop severe AS (6,300 of whom will experience concurrent symptoms). Of these symptomatic cases, an estimated 3,700 and 1,600 cases/annum, will be potentially suitable for SAVR and TAVR, respectively.ConclusionsThese data suggest there is likely to be a substantive burden of individuals living with severe AS in Australia. Many of these cases may not have been diagnosed and/or received appropriate treatment (based on the evidence-based application of SAVR and TAVR) to reduce their high-risk of subsequent mortality.

The current study had the aim to assess whether temperamental traits mediate the relationship between time of puberty and eating disorder (ED) severity using a sample of 292 outpatients with EDs [68 with Anorexia Nervosa Restrictive Type (AN-R), 101 with Anorexia Nervosa Binge Purging Type (AN-BP), 72 with Bulimia Nervosa (BN) and 51 with Other Specified Feeding and Eating Disorder (OSFED)]. Age of puberty, the severity of EDs, and temperamental traits were assessed through Demographic and Medical History Form, Eating Disorder Examination 17.0d (EDE-17.0d) and Temperament and Character Inventory-Revised (TCI-R), with a focus on the temperament scales: novelty seeking (TCI-NS), harm avoidance (TCI-HA), reward dependence (TCI-RD) and persistence (TCI-P). One-way ANOVA, correlation, and mediating analyses through structural equation modeling were performed to test the relationship between variables under investigation and assess if the four temperamental traits act as mediators in the relationship between time of puberty and ED severity. The results show a full mediating effect of the temperamental sub-scales on the relationship between puberty and EDE-17. In particular, TCI-R HA showed a complementary mediation on the relationship between age of puberty and EDE-17.0d, meaning that age of puberty increases the level of TCI-R HA, which in turn increases the severity of ED, confirming that this temperamental trait plays an important role in the development of ED after puberty. To conclude, temperamental traits seem to play a full mediating role in the relationship between puberty and ED severity, but more research is needed.

INTRODUCTION Some patients have late recurrence after acutely successful radiofrequency catheter ablation (RFCA) of premature ventricular complexes (PVCs). The aim of this study was to evaluate predictors of long-term success following acutely successful PVC RFCA. METHODS We identified consecutive patients at our institution with frequent PVCs undergoing RFCA and reviewed procedural data and medical records. Acute success was defined as elimination of targeted PVCs for at least 30-min after RFCA. Long-term success was defined as absence of targeted PVCs during all follow-up visits and PVC-burden

Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Patients and Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2–40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8–6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.

Background Hepatoblastoma is the most common primary pediatric liver malignancy. Indocyanine green (ICG) has been described as an adjunct to resection in small series. Its utility remains undefined in larger cohorts. Methods Records for 29 patients diagnosed with hepatoblastoma who received ICG prior to surgical resection from 2017 to 2020 at a single institution were retrospectively reviewed. The primary outcome was correlation between intraoperative ICG‐avidity and histologic presence of hepatoblastoma. A secondary outcome included the histologic margin designation for resected liver specimens. Results ICG sensitivity was 91% for 120 resected thoracic specimens from 21 patients. Specificity was 57%. In 10% of operations, HB‐positive specimens were resected solely on ICG‐avidity. In an additional 40% of cases, ICG assisted in localizing a preoperatively diagnosed lesion. ICG sensitivity during thoracotomy and thoracoscopic surgery was 95 and 74%, respectively; primary and relapsed disease demonstrated sensitivity of 94 and 73%, respectively. Sensitivity was 92% for 25 resected liver specimens from nine patients with all parenchymal margins grossly negative for disease. Four multifocal lesions were identified with two resected solely by ICG‐avidity. Conclusions ICG is a sensitive adjunct for identifying local and metastatic hepatoblastoma, including lesions not visualized on preoperative imaging, and delineating margins during liver resection. False positives limit specificity; however, there were no adverse outcomes from additional resections. We noted that thoracoscopic surgery can be completed safely in patients with less significant disease burden, and conversion to thoracotomy, if necessary, is straightforward., ICG is a sensitive adjunct for identifying local and metastatic hepatoblastoma, including lesions not visualized on preoperative imaging, and delineating margins during liver resection. With its use, thoracoscopic surgery can be completed safely in patients with less significant disease burden with conversion to thoracotomy, if necessary.

Purpose To report clinical outcomes in terms of disease control and toxicity in patients with major salivary gland cancers (SGCs) treated with proton beam therapy. Materials and Methods Clinical and dosimetric characteristics of patients with SGCs treated from August 2011 to February 2020 on an observational, prospective, single-institution protocol were abstracted. Local control and overall survival were calculated by the Kaplan-Meier method. During radiation, weekly assessments of toxicity were obtained, and for patients with ≥ 90 days of follow-up, late toxicity was assessed. Results Seventy-two patients were identified. Median age was 54 years (range, 23-87 years). Sixty-three patients (88%) received postoperative therapy, and nine patients (12%) were treated definitively. Twenty-six patients (36%) received concurrent chemotherapy. Nine patients (12%) had received prior radiation. All (99%) but one patient received unilateral treatment with a median dose of 64 GyRBE (relative biological effectiveness) (interquartile range [IQR], 60-66), and 53 patients (74%) received intensity-modulated proton therapy with either single-field or multifield optimization. The median follow-up time was 30 months. Two-year local control and overall survival rates were 96% (95% confidence interval [CI] 85%-99%) and 89% (95% CI 76%-95%], respectively. Radiation dermatitis was the predominant grade-3 toxicity (seen in 21% [n = 15] of the patients), and grade ≥ 2 mucositis was rare (14%; n = 10 patients). No late-grade ≥ 3 toxicities were reported. Conclusion Proton beam therapy for treatment of major SGCs manifests in low rates of acute mucosal toxicity. In addition, the current data suggest a high rate of local control and minimal late toxicity.

Purpose We compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT). Patients and Methods In 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores. Results Patient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years (P = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years (P = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance (P = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up (P Conclusion In patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment.

Depression and anxiety are highly prevalent and have major adverse effects on function and quality of life in Parkinson's disease (PD). Optimal management requires that motor symptoms and psychiatric symptoms be simultaneously addressed. While there is fairly robust evidence for the treatment of motor symptoms, there are no completed randomized controlled trials to guide pharmacological treatment of anxiety in PD and no nonpharmacologic interventions have proven efficacious. Several high-quality trials for depression in PD suggest a number of antidepressants and cognitive behavioral therapy may help, but there is no data on rates of recurrence, comparative efficacy, or augmentation strategies. In order to address the gaps in knowledge, the authors provide a summary of the current evidence for treating depression and anxiety in PD and offer an algorithm that extends beyond the current literature based on clinical experience working in a multidisciplinary specialty center.

Background Coronary artery bypass grafting with cardiopulmonary bypass (CPB) induces an inflammatory reaction that is associated with postoperative complications. Influenza vaccination has been shown to decrease cardiovascular morbidity in patients with cardiovascular disease, possibly via its anti-inflammatory properties. We hypothesize that influenza vaccination would attenuate the inflammatory reaction after CPB. Methods Thirty patients undergoing coronary artery bypass grafting were blindly randomized to receive the influenza vaccine (group I, n = 15) or a placebo (group II, n = 15) preoperatively. Serum samples of proinflammatory mediators (interleukin-6, interleukin-8, tumor necrosis factor, C-reactive protein) as well as the anti-inflammatory interleukin-10 were collected at different time points perioperatively. Assessment of myocardial dysfunction was investigated by measuring hemodynamic data, echocardiographic data, and troponin levels. Other clinical outcomes were collected prospectively. Results Proinflammatory cytokine levels were significantly reduced in the treatment group vs the placebo group (interleukin-6 [157.4 pg/dL vs 256 pg/dL, P = .043], interleukin-8 [65.03 pg/dL vs 118.56 pg/dL, P = .025], and tumor necrosis factor [12.05 pg/dL vs 20.8 pg/dL, P = .003]). These differences were observed at the end of CPB and persisted for 2 days postoperatively. Interestingly, the level of the anti-inflammatory marker interleukin-10 was significantly higher in group I (83.3 pg/dL vs 15.15 pg/dL, P = .008). Evidence of improved myocardial protection was observed in group I, as reflected by troponin measurements postoperatively (6020.2 pg/dL vs 12,098.01 pg/dL, P = .052). Conclusions Influenza vaccination attenuates the inflammatory response to CPB as reflected by a reduction in the level of troponin and proinflammatory mediators and an increase in the anti-inflammatory cytokine interleukin-10.

BACKGROUND Multiple registries have reported that >40% of high-risk atrial fibrillation patients are not taking oral anticoagulants. The purpose of our study was to determine the presence or absence of active atrial fibrillation and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 y, Diabetes mellitus, prior Stroke [or transient ischemic attack or thromboembolism], Vascular disease, Age 65-74 y, Sex category) risk factors to accurately identify high-risk atrial fibrillation (CHA2DS2-VASc ≥2) patients requiring oral anticoagulants and the magnitude of the anticoagulant treatment gap. METHODS We retrospectively adjudicated 6514 patients with atrial fibrillation documented by at least one of: billing diagnosis, electronic medical record encounter diagnosis, electronic medical record problem list, or electrocardiogram interpretation. RESULTS After review, 4555/6514 (69.9%) had active atrial fibrillation, while 1201 had no documented history of atrial fibrillation and 758 had a history of atrial fibrillation that was no longer active. After removing the 1201 patients without a confirmed atrial fibrillation diagnosis, oral anticoagulant use in high-risk patients increased to 71.1% (P < .0001 compared with 62.9% at baseline). Oral anticoagulant use increased to 79.7% when the 758 inactive atrial fibrillation patients were also eliminated from the analysis (P < .0001 compared with baseline). In the active high-risk atrial fibrillation group, there was no significant difference in the use of oral anticoagulants between men (80.7%) and women (78.8%) with a CHA2DS2-VASc ≥2, or in women with a CHA2DS2-VASc ≥3 (79.9%). CONCLUSIONS Current registries and health system health records with unadjudicated diagnoses over-report the number of high-risk atrial fibrillation patients not taking oral anticoagulants. Expert adjudication identifies a smaller treatment gap than previously described.

BackgroundPatients with symptomatic cervical deformity (CD) requiring surgical correction often present with hyperkyphosis (HK), although patients with hyperlordotic curves may require surgery as well. Few studies have investigated differences in CD corrective surgery with regard to HK and hyperlordosis (HL).ObjectiveThe objective of the study is to evaluate patterns in treatment for CD patients with baseline (BL) HK and HL and understand how extreme curvature of the spine may influence surgical outcomes.Materials and methodsOperative CD patients with BL and 1-year (1Y) radiographic data were included in the study. Patients were stratified based on BL C2-C7 lordosis (CL) angle: those >1 standard deviation (SD) from the mean (-6.96 ± 21.47°) were hyperlordotic (>14.51°) or hyperkyphotic (

Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by pathogenic biallelic variants in the ETHE1 gene. The phenotype of this disease has been attributed to deficiency in the mitochondrial sulfur dioxygenase leading to many downstream effects. Ethylmalonic encephalopathy classically presents with developmental regression, petechiae, acrocyanosis, and chronic diarrhea. The neurologic phenotype includes hypotonia, spastic diplegia, ataxia, and developmental delay. As more patients with this condition are described, the neurologic phenotype continues to expand. Although strokelike episodes or metabolic strokes have been studied in other mitochondrial disorders, they have not been thoroughly reported in this disorder. Herein, we describe 3 patients with ethylmalonic encephalopathy who presented clinically with strokelike episodes and strokelike abnormalities on brain magnetic resonance imaging in the setting of acute illness, and the long-term sequelae with evolution into cystic changes in one of these subjects.