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Jen-Ta Shih,1,2 Tsu-Te Yeh,1 Pei-Hung Shen,1 Chih-Chien Wang,1 Sheng-Hao Wang,1 Wu-Chien Chien,3– 6 Chi-Hsiang Chung,3– 5 Chia-Chun Wu1 1Department of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei, Taiwan; 3School of Public Health, National Defense Medical Center, Taipei, Taiwan; 4Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 5Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan; 6Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, TaiwanCorrespondence: Chia-Chun WuDepartment of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Chenggong Road, Neihu Dist, Taipei City, 11472, TaiwanTel +886-953-086-492Fax +886-2-8792-7186Email orthopedicsintsgh@gmail.comPurpose: With recent advances in surgical techniques and instruments, orthopedic surgeons are better equipped to treat metastatic bone disease. There has also been considerable progress in the non-surgical treatment of cancers, specifically in improving the survival rate of patients with advanced cancer. However, it remains unclear whether surgical resection of a metastatic bone lesion poses additional risk to the survival of patients with advanced cancer.Patients and Methods: This study utilized data from the National Health Insurance Research Database (NHIRD) in Taiwan between 2000 and 2015. Patients aged ≥ 18 years, who had been recently diagnosed with bone metastases (BM), were enrolled and assigned to either the surgery or non-surgery groups. The demographic characteristics were analyzed, and the adjusted hazard ratios (aHR) of mortality were calculated using Cox regression analysis.Results: Of the 4,549,226 individuals in the inpatient database of the NHIRD, 83,536 patients with BM were enrolled in this study. Among them, 8802 underwent surgical resection for skeletal metastatic lesion and 66,098 did not. Altogether, 28,691 patients died, including 2798 (31.8%) in the surgery group and 25,893 (39.2%) in the non-surgery group. The aHR for mortality was 0.7-fold lower in the surgery group (p < 0.001).Conclusion: This study demonstrates that surgical resection of metastatic bone lesions did not pose any additional risk to survival outcomes. Thus, we believe that surgery, if indicated, could have a competitive role in the management of metastatic bone disease.Keywords: bone metastasis, surgical resection, mortality, bone resorption inhibitor

Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. [ABSTRACT FROM AUTHOR]

Bisphosphonates have been associated with a decreased risk of revision surgery after total joint arthroplasty of the hip or knee (TJA) because of their effects on decreased periprosthetic bone loss and prosthetic migration. However, the results in the early literature are inconsistent, and the influence of bisphosphonates on associated complications and subsequent TJA remains unknown. This study investigated the association between the use of bisphosphonates and the risk of adverse outcomes after primary TJA. This matched cohort study utilized the National Health Insurance Research Database in Taiwan to identify patients who underwent primary TJA over a 15-year period (January 2000-December 2015 inclusive). Study participants were further categorized into two groups, bisphosphonate users and nonusers, using propensity score matching. The Kaplan-Meier curve analysis and adjusted hazard ratios (aHRs) of revision surgery, adverse outcomes of primary surgery and subsequent TJA were calculated using Cox regression analysis. This study analyzed data from 6485 patients who underwent total hip arthroplasty (THA) and 20,920 patients who underwent total knee arthroplasty (TKA). The risk of revision hip and knee arthroplasty was significantly lower in the bisphosphonate users than in the nonusers (aHR, 0.54 and 0.53, respectively). Furthermore, the risk of a subsequent total joint arthroplasty, adverse events and all-cause mortality were also significantly reduced in the bisphosphonate users. This study, involving a large cohort of patients who underwent primary arthroplasties, revealed that bisphosphonate treatment may potentially reduce the risk of revision surgery and associated adverse outcomes. Furthermore, the use of bisphosphonates after TJA is also associated with a reduced need for subsequent arthroplasty.Research Registration Unique Identifying Number (UIN): ClinicalTrials.gov Identifier-NCT05623540 ( https://clinicaltrials.gov/show/NCT05623540 )., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

During investigations of invertebrate-associated fungi in Yunnan Province of China, a new species, Sporodiniella sinensis sp. nov., was collected. Morphologically, S. sinensis is similar to Sporodiniella umbellata ; however, it is distinguished from S. umbellata by its greater number of sporangiophore branches, longer sporangiophores, larger sporangiospores, and columellae. The novel species exhibits similarities of 91.62 % for internal transcribed spacer (ITS), 98.66-99.10 % for ribosomal small subunit (nrSSU), and 96.36-98.22 % for ribosomal large subunit (nrLSU) sequences, respectively, compared to S. umbellata . Furthermore, phylogenetic analyses based on combined sequences of ITS, nrLSU and nrSSU show that it forms a separate clade in Sporodiniella , and clusters closely with S. umbellata with high statistical support. The phylogenetic and morphological evidence support S. sinensis as a distinct species. Here, it is formally described and illustrated, and compared with other relatives.

Two new termite-pathogenic species, Ophiocordycepsglobiperitheciata and O.longistipes , are described from Yunnan Province, China. Six-locus (ITS, nrSSU, nrLSU, tef-1α , rpb1 and rpb2 ) phylogenetic analyses in combination with morphological observations were employed to characterize these two species. Phylogenetically, O.globiperitheciata is most closely related to Hirsutellacryptosclerotium and O.communis , whereas O.longistipes shares a sister relationship with O.fusiformis . However, O.globiperitheciata differs from H.cryptosclerotium by parasitizing Blattodea and producing clavate, unbifurcated stromata. Ophiocordycepsglobiperitheciata is distinguished from O.communis by multiple stromata, shorter asci and ascospores. Ophiocordycepslongistipes differs from O.fusiformis in producing larger stromata, perithecia, asci and ascospores, as well as smaller citriform or oval conidia. Morphological descriptions of the two new species and a dichotomous key to the 19 termite-pathogenic Ophiocordyceps species are presented., Competing Interests: The authors have declared that no competing interests exist., (Qi Fan, Tao Yang, Hui Li, Xue-Mei Wang, He-Fa Liao, Pei-Hong Shen, Zhu-Liang Yang, Wen-Bo Zeng, Yuan-Bing Wang.)

The selective functionalization of trifluoromethyl groups through C-F cleavage poses a significant challenge due to the high bond energy of the C(sp 3 )-F bonds. Herein, we present dihydroacridine derivatives as photocatalysts that can functionalize the C-F bond of trifluoromethyl groups with various alkenes under mild conditions. Mechanistic studies and DFT calculations revealed that upon irradiation, the dihydroacridine derivatives exhibit high reducibility and function as photocatalysts for reductive defluorination. This process involves a sequential single-electron transfer mechanism. This research provides valuable insights into the properties of dihydroacridine derivatives as photocatalysts, highlighting the importance of maintaining a planar conformation and a large conjugated system for optimal catalytic activity. These findings facilitate the efficient catalytic reduction of inert chemical bonds.

Background: Central compartment atopic disease (CCAD) is a recent, novel phenotype of chronic rhinosinusitis. Only a few studies have assessed olfactory function in patients with CCAD., Objectives: We aimed to investigate olfactory function changes after functional endoscopic sinus surgery (FESS) in patients with CCAD and proposed some surgical techniques to enhance the postoperative olfactory outcomes in such patients., Design: A retrospective cohort study., Methods: We collected data from 23 patients (8 men and 15 women) with CCAD who underwent FESS performed by a surgeon in Taiwan, between June 2018 and December 2021. The demographic data, olfactory function, and serum and tissue eosinophil percentages of the included patients were analyzed. The Top International Biotech Smell Identification Test (TIBSIT; Top International Biotech, Taipei, Taiwan) was used to assess olfactory function., Results: Of the 23 patients, most (95%) showed a positive reaction to aeroallergens, and 2 patients (8.7%) had asthma. Ten patients (43.5%) had peripheral eosinophilia, and 9 (39%) had eosinophilic nasal polyps. Moreover, the patients presented with variable olfactory dysfunction; the mean preoperative TIBSIT (pr-TIBSIT) score was 12.8 ± 2.3 (range: 0-43), whereas the mean postoperative TIBSIT (po-TIBSIT) score was 29.2 ± 1.9 (range: 16-44). The po-TIBSIT score was significantly better than the pre-TIBSIT score (paired t test, P  < .0001). The improvement in olfactory function was not significantly correlated with the patients' age, serum eosinophil percentages, and nasal polyp eosinophil counts., Conclusion: Our findings indicate that CCAD is significantly associated with olfactory dysfunction and that FESS can effectively improve olfactory function. To optimize postoperative olfactory outcomes, precise removal of polyps from the olfactory cleft without damaging the neuroepithelium is recommended. Our study provides valuable insights into the management of CCAD patients undergoing FESS and can guide surgical decision-making to achieve optimal olfactory function outcomes., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Osteoporosis is characterized by low bone mass, bone microarchitecture disruption, and collagen loss, leading to increased fracture risk. In the current study, collagen peptides were extracted from milkfish scales (MS) to develop potential therapeutic candidates for osteoporosis. MS was used to synthesize a crude extract of fish scales (FS), collagen liquid (COL), and hydroxyapatite powder (HA). COL samples were further categorized according to the peptide size of total COL (0.1 mg/mL), COL < 1 kDa (0.1 mg/mL), COL: 1-10 kDa (0.1 mg/mL), and COL > 10 kDa (0.1 mg/mL) to determine it. Semi-quantitative reverse transcription polymerase chain reaction (sqRT-PCR) and immunofluorescence labeling were used to assess the expression levels of specific mRNA and proteins in vitro. For in vivo studies, mice ovariectomy (OVX)-induced postmenopausal osteoporosis were developed, while the sham surgery (Sham) group was treated as a control. Collagen peptides (CP) from MS inhibited osteoclast differentiation in RAW264.7 cells following an insult with nuclear factor kappa-B ligand (RANKL). CP also enhanced osteoblast proliferation in MG-63 cells, possibly through downregulating NFATc1 and TRAP mRNA expression and upregulating ALP and OPG mRNA levels. Furthermore, COL1 kDa also inhibited bone density loss in osteoporotic mice. Taken together, CP may reduce RANKL-induced osteoclast activity while promoting osteoblast synthesis, and therefore may act as a potential therapeutic agent for the prevention and control of osteoporosis., Competing Interests: The authors report no conflict of interest in relation to the work., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Background: This study aimed to evaluate the impact of malnutrition on in-hospital outcomes in patients undergoing total hip arthroplasty (THA) for osteonecrosis of the femoral head (ONFH)., Methods: This population-based retrospective study extracted data of patients undergoing THA for ONFH in the US National Inpatient Sample between 2005 and 2018. Factors associated with in-hospital mortality, medical and surgical complications, unfavorable discharge, and prolonged hospital stay were determined by logistic regression analysis., Results: A total of 72,304 adults ≥18 years old with nontraumatic ONFH admitted for primary THA were included. Malnutrition was detected in 7152 (9.9%) patients using validated discharge codes. In-hospital mortality was 0.8% vs 0.1% for patients who were malnourished vs nonmalnourished. After adjusting for confounders, malnutrition was significantly associated with an increased risk of in-hospital death (adjusted odds ratio [aOR], 4.67; 95% CI, 2.43-8.97), medical complications (aOR, 1.49; 95% CI, 1.32-1.68), surgical complications (aOR, 1.78; 95% CI, 1.61-1.96), unfavorable discharge (aOR, 1.24; 95% CI, 1.11-1.39), and prolonged hospital stay (aOR, 1.90; 95% CI, 1.67-2.16) compared with adequate nutrition. Malnutrition was also associated with higher total hospital costs (adjusted β = $9620; 95% CI, 7.87-11.36). Furthermore, the association between malnutrition, any medical or surgical complications, and unfavorable discharge was stronger in patients younger than 50 years than those ≥50 years old., Conclusions: In US patients undergoing primary THA for ONFH, malnutrition increases the risk of unfavorable in-hospital outcomes. This patient subgroup may require special attention and better strategies to improve perioperative care., (© 2023 American Society for Parenteral and Enteral Nutrition.)

The Miyun Reservoir is the major source of surface drinking water in Beijing. However, the total nitrogen (TN) concentrations in the Miyun Reservoir and inflowing rivers have recently been increasing. In this study, the Mangniu River, a typical inflow river in the upper reaches of the Miyun Reservoir, was selected as the study area to investigate the spatial distribution and transformation of various nitrogen forms from the perspective of microbial community composition and predicting function, aimimg at providing a scientific reference for nitrogen pollution control of the Miyun Reservoir. The results indicated that except for TN, all the other physical and chemical water quality indicators in the upper reaches of the Miyun Reservoir met the Class II criteria of the environmental quality standards for surface water in China (GB 3838-2002). Additionally, NO 3 - -N was the primary constituent of TN, ranging from 77.7% to 92.9%. Banchengzi Reservoir has a certain self-purification ability because its high C/N ratio promotes denitrification. Significant differences in microbial community structure were observed between the water and sediments of Mangniu River along with spatial distribution. High NO 3 - -N concentration was the major environmental factor affecting the succession of microbial community structure. Many nitrification and denitrification microorganisms existed in Mengniu River, and the relative abundance of denitrification bacteria (DNB) was higher than that of nitrification bacteria, and that in the sediments was slightly higher than that in the water. Nitrosopumilus and Pseudomonas were the dominant nitrification and denitrification bacteria in Mengniuhe River, respectively. The results of phylogenetic investigation of communities by the reconstruction of unobserved states (PICRUSt2) showed that NO 3 - -N reduction module was the major nitrogen metabolism module, which primarily occurred in water. The abundance of the functional genes for nitrification (i.e., narGH ) was the highest in water, and the major functional gene involved in NO 3 - -N reduction was nirBD of DNRA, which was primarily present in the sediments; however, the main functional gene involved in denitrification was nirK .

Background: Dedifferentiated fat cells (DFATs) are highly homogeneous and multipotent compared with adipose-derived stromal cells (SCs). Infrapatellar fat pad (IFP)-SCs have advanced chondrogenic potency; however, whether IFP-DFATs could serve as better cell material remains unclear. Here, we aimed to examine the influence of age and body mass index (BMI) on the features of IFPs and IFP-derived cells (IFP-SCs and IFP-DFATs) with exploration of the clinical utilization of IFP-DFATs., Methods: We collected IFPs with isolation of paired IFP-SCs and IFP-DFATs from individuals aged 65 years and older with distinct body weights who underwent total knee replacement for osteoarthritis (OA). Flow cytometry was used to characterize the cellular immunophenotypes. Adipogenesis and chondrogenesis were performed in vitro . Real-time qPCR, western blotting, and Oil Red O or Alcian blue staining were performed to evaluate inflammation, adipogenesis, and chondrogenesis. RNA sequencing and Seahorse analyses were conducted to explore the underlying mechanisms., Results: We found that IFPs from old or normal-weight individuals with knee OA were pro-inflammatory, and that interleukin-6 (IL-6) signaling was associated with multiple immune-related molecules, whereas IFP-derived cells could escape the inflammatory properties. Aging plays an important role in diminishing the chondrogenic and adipogenic abilities of IFP-SCs; however, this effect was avoided in IFP-DFATs. Generally, IFP-DFATs presented a steady state of chondrogenesis (less influenced by age) and consistently enhanced adipogenesis compared to paired IFP-SCs in different age or BMI groups. RNA sequencing and Seahorse analysis suggested that the downregulation of eukaryotic initiation factor 2 (EIF2) signaling and enhanced mitochondrial function may contribute to the improved cellular biology of IFP-DFATs., Conclusions: Our data indicate that IFP-DFATs are superior cell material compared to IFP-SCs for cartilage differentiation and adipogenesis, particularly in advanced aging patients with knee OA., The Translational Potential of This Article: These results provide a novel concept and supportive evidence for the use of IFP-DFATs for cell therapy or tissue engineering in patients with knee OA. Using Ingenuity Pathway Analysis (IPA) of RNA-seq data and Seahorse analysis of mitochondrial metabolic parameters, we highlighted that some molecules, signaling pathways, and mitochondrial functions are likely to be jointly coordinated to determine the enhanced biological function in IFP-DFATs., Competing Interests: The authors declare that there is no conflict of interest., (© 2023 The Authors.)

Background/purpose: Complex arthroplasties for periacetabular metastatic lesions can result in complications including infection and prosthesis loosening owing to poor bone quality. A new surgical protocol has been developed as a joint-sparing surgery to avoid complications after arthroplasties. The main surgical steps are: (a) conservative and accurate tumor resection with aid of 3D printing model-assisted preoperative resection simulation and preparation of pre-contour plate, (b) reconstruction with structural bone graft through the sandwich technique for augmentation of subchondral bone., Methods: This retrospective study consisted of 6 patients (5 with metastatic bone tumors and one with multiple myeloma). The pelvic bone resection as defined by Enneking and Dunham were typed I + II in 2 patients and type II in 4 patients. The medical records, images, musculoskeletal tumor society (MSTS) score and visual analogue scale (VAS) were used for evaluation., Results: The mean operative time was 234 minutes, and the average surgical blood loss was 1408 mL. The mean follow-up period was 21 months. The mean VAS significantly decreased at postoperative 1-week and 1-year follow-up. There were no intraoperative or early postoperative complications. The median MSTS score during the final follow-up was 26 points (range, 14-28 points). Except for one case who experienced severe joint destruction, all the other five cases were classified as excellent or good (>15)., Conclusion: With precise tumor resection and reconstruction with sandwich procedure, the joint-sparing surgery can be performed in selected patients with metastatic periacetabular tumors., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

In recent years, advance care planning (ACP) promotion in Taiwan has expanded beyond clinical practice to the broader population. This study aims to investigate people's attitudes toward ACP and to identify factors influencing their signing of advance directives (ADs) and appointment of health care agents (HCAs)., Methods: We identified 2337 ACP participants from consultation records between 2019 and 2020. The relationships among the participants' characteristics, AD completion, and HCA appointment were investigated., Results: Of 2337 cases, 94.1% completed ADs and 87.8% were appointed HCAs. Welfare entitlement (OR = 0.47, p < 0.001), the place ACP progressed (OR = 0.08, p < 0.001), the participation of second-degree relatives (OR = 2.50, p < 0.001), and the intention of not being a family burden (OR = 1.65, p = 0.010) were significantly correlated with AD completion. The probability of appointing HCAs was higher in participants with family caregiving experience (OR = 1.42, p < 0.05), who were single (OR = 1.49, p < 0.05), and who expected a good death with dignity (OR = 1.65, p < 0.01)., Conclusions: Our research shows that adopting ACP discussion in Taiwan is feasible, which encourages ACP conversation and facilitates AD completion., Implications: Male and younger adults may need extra encouragement to discuss ACP matters with their families., Limitations: due to sampling restrictions, our data were chosen from an urban district to ensure the integrity of the results. Furthermore, interview data could be collected in future research to supplement the quantitative results.

The Energy Recovery Ventilator (ERV) is proven efficient for residential ventilation applications. Yet, certain drawbacks, including a more confined space due to descended ceiling, a lengthy accompanying duct system, and over-ventilation issues that result in extensive energy consumption, need to be addressed. In this study, a novel Chain Recooling Energy Recovery Ventilator (CR-ERV) system is proposed to replace the typical ERV system design to solve the shortcomings above. By conducting an experiment on a three-bedroom condo in a hot and humid climate, it was found that compared to the natural ventilation strategy, the proposed system can help reduce the mean indoor carbon dioxide (CO 2 ) concentration from 976 to 677 ppm and PM 2.5 concentration from 6.4 to 4.1 μg/m 3 , representing a 29% and 34% reduction, respectively. From the regulatory perspective, only 64.4% of the natural-ventilated hours have a CO 2 concentration below the 1000 ppm limit per the local air quality Act. This fraction can be improved to 99% after adopting the proposed ventilation system. All these benefits come at the cost of a slight 2.3% increase in electricity consumption. In summary, the proposed system is proven efficient, and its implementation is fairly straightforward and economical; thus might be worth integrating into future residential building projects., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Medication errors can have severe consequences and threaten patient safety. The patient safety-related benefits of automated dispensing cabinets (ADCs) have been reported by several previous studies, including a reduction in medication errors in intensive care units (ICUs) and emergency departments. However, the benefits of ADCs need to be assessed, given the different healthcare practice models. This study aimed to compare the rates of medication errors, including prescription, dispensing, and administrative, before and after using ADCs in intensive care units. The prescription, dispensing, and administrative error data before and after the adoption of ADCs were retrospectively collected from the medication error report system. The severity of medication errors was classified according to the National Coordinating Council for Medication Error Reporting and Prevention guidelines. The study outcome was the rate of medication errors. After the adoption of ADCs in the intensive care units, the rates of prescription and dispensing errors reduced from 3.03 to 1.75 per 100,000 prescriptions and 3.87 to 0 per 100,000 dispensations, respectively. The administrative error rate decreased from 0.046 to 0.026%. The ADCs decreased National Coordinating Council for Medication Error Reporting and Prevention category B and D errors by 75% and category C errors by 43%. To improve medication safety, multidisciplinary collaboration and strategies, such as the use of automated dispensing cabinets, education, and training programs from a systems perspective, are warranted., (© 2023. The Author(s).)

Alcohol withdrawal is a clinically important consequence and potential driver of Alcohol Use Disorder. However, susceptibility to withdrawal symptoms, ranging from craving and anxiety to seizures and delirium, varies greatly. Selectively bred Withdrawal Seizure-Prone (WSP) and Seizure-Resistant (WSR) mice are an animal model of differential susceptibility to withdrawal and phenotypes with which withdrawal severity correlates. To identify innate drivers of alcohol withdrawal severity, we performed a multi-omic study of the WSP and WSR lines and F2 mice derived from them, using genomic, genetic, and transcriptomic analyses. Genes implicated in seizures and epilepsy were over-represented among those that segregated between WSP and WSR mice and that displayed differential expression in F2 mice high and low in withdrawal. Quantitative trait locus (QTL) analysis of ethanol withdrawal convulsions identified several genome-wide significant loci and pointed to genes that modulate potassium channel function and neural excitability. Perturbations of expression of genes involved in synaptic transmission, including GABAergic and glutamatergic genes, were prominent in prefrontal cortex transcriptome. Expression QTL (eQTL) analysis fine mapped genes within the peak ethanol withdrawal QTL regions. Genetic association analysis in human subjects provided converging evidence for the involvement of those genes in severity of alcohol withdrawal and dependence. Our results reveal a polygenic network and neural signaling pathways contributing to ethanol withdrawal seizures and related phenotypes that overlap with genes modulating epilepsy and neuronal excitability., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: A salient effect of addictive drugs is to hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Reduced dopamine type 2 receptor availability in the striatum is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences etiologic for this disorder. Here, we sought to identify gene expression changes attributable to innate low expression of the Drd2 gene in the striatum and specific to striatal indirect medium spiny neurons (iMSNs)., Methods: Cre-conditional, translating ribosome affinity purification (TRAP) was used to purify and analyze the translatome (ribosome-bound messenger RNA) of iMSNs from mice with low/heterozygous or wild-type Drd2 expression in iMSNs. Complementary electrophysiological recordings and gene expression analysis of postmortem brain tissue from human cocaine users were performed., Results: Innate low expression of Drd2 in iMSNs led to differential expression of genes involved in GABA (gamma-aminobutyric acid) and cAMP (cyclic adenosine monophosphate) signaling, neural growth, lipid metabolism, neural excitability, and inflammation. Creb1 was identified as a likely upstream regulator, among others. In human brain, expression of FXYD2 , a modulatory subunit of the Na/K pump, was negatively correlated with DRD2 messenger RNA expression. In iMSN-TRAP- Drd2 HET mice, increased Cartpt and reduced S100a10 (p11) expression recapitulated previous observations in cocaine paradigms. Electrophysiology experiments supported a higher GABA tone in iMSN- Drd2 HET mice., Conclusions: This study provides strong molecular evidence that, in addiction, inhibition by the indirect pathway is constitutively enhanced through neural growth and increased GABA signaling., (© 2022 The Authors.)

This study aimed to evaluate the different clinical results and factors associated with cartilage defects in military draftees who underwent different treatments after anterior cruciate ligament (ACL) rupture. Overall, 105 patients who had sustained ACL rupture were military draftees who underwent a conscription examination for physical status assessment from January 2012 to December 2020. Patients were divided into three groups: conservative treatment after ACL rupture, status post-anterior cruciate ligament reconstruction (ACLR), but graft rupture, and status post-ACLR with graft intact. Inter-group comparisons and statistical analyses were performed for age, body mass index (BMI), thigh circumference difference, side-to-side difference in anterior knee translation by KT-2000, meniscus tear, and cartilage defect. Multivariate logistic regression analysis was used to determine the factors associated with cartilage defects. The multivariable regression model showed that BMI (odds ratio OR: 1.303; 95% CI: 1.016-1.672; p = 0.037), thigh circumference difference (OR: 1.403; 95% CI: 1.003-1.084; p = 0.034), tear of lateral meniscus (LM) and medial meniscus (MM) (OR: 13.773; 95% CI: 1.354-140.09; p = 0.027), and graft rupture group (OR: 5.191; 95% CI: 1.388-19.419; p = 0.014) increased the risk of cartilage defects. There was no correlation between cartilage defects and age, KT-2000 difference, tear of LM or MM, or graft intact group. Progression of osteoarthritis was concerned after ACL rupture, and this study identified several factors of post-ACLR graft rupture, greater thigh circumference difference, BMI, and meniscus tear of both LM and MM affecting cartilage defects, which represent early degenerative osteoarthritis changes of the knee. The results of this study should be customized for rehabilitation and military training, especially in military draftees with ACL injuries.

Pelvic and acetabular fractures are challenging for orthopedic surgeons, but 3D printing has many benefits in treating these fractures and has been applied worldwide. This study aimed to determine whether 3D printing can shorten the length of hospital stay (LHS) in nongeriatric male adult patients with these fractures. This is a single-center retrospective study of 167 nongeriatric male adult participants from August 2009 to December 2021. Participants were divided into two groups based on whether they received 3D printing assistance. Subgroup analyses were performed. Pearson’s correlation and multivariable linear regression models were used to analyze the LHS and the parameters. Results showed that 3D printing-assisted surgery did not affect LHS in the analyzed patients. The LHS was positively correlated with the Injury Severity Score (ISS). Initial hemoglobin levels were negatively associated with LHS in patients aged 18−40 and non-major trauma (ISS < 16) patients. In 40−60-year-old and non-major trauma patients, the duration from fracture to admission was significantly associated with LHS. This study indicates that 3D-assisted technology for pelvic or acetabular fracture surgery for nongeriatric male adults does not influence the LHS. More importantly, the initial evaluation of patients in the hospital was the main predictor of the LHS.

Iron loading has been consistently reported in those with alcohol use disorder (AUD), but its effect on the clinical course of the disease is not yet fully understood. Here, we conducted a cohort study to examine whether peripheral iron measures, genetic variation in HFE rs1799945 and their interaction differed between 594 inpatient participants with alcohol use disorder (AUD) undergoing detoxification and 472 healthy controls (HC). We also assessed whether HFE rs1799945 was associated with elevated peripheral iron and can serve as a predictor of withdrawal severity. AUD patients showed significantly higher serum transferrin saturation than HC. Within the AUD group, transferrin saturation significantly predicted withdrawal symptoms (CIWA-Ar) and cumulative dose of benzodiazepine treatment during the first week of detoxification, which is an indicator of withdrawal severity. HFE rs1799945 minor allele carriers showed elevated transferrin saturation compared to non-carriers, both in AUD and healthy controls. Exploratory analyses indicated that, within the AUD cohort, HFE rs1799945 predicted CIWA withdrawal scores, and this relationship was significantly mediated by transferrin saturation. We provide evidence that serum transferrin saturation predicts alcohol withdrawal severity in AUD. Moreover, our findings replicated previous studies on elevated serum transferrin saturation in AUD and an involvement of HFE rs1799945 in serum transferrin saturation levels in both AUD and healthy controls. Future studies may use transferrin saturation measures as predictors for treatment or potentially treat iron overload to ameliorate withdrawal symptoms., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Background: In Australia, because of inequity in dental service accessibility and affordability, patients can see general medical practitioners (GPs) for acute dental conditions., Methods: This cross-sectional study consisted of surveys distributed to the board registered GPs practising in Australia. The main outcome measures included statistical analysis of GPs managing different dental emergency scenarios and their confidence and expectations in managing dental emergencies., Results: A total of 425 GPs participated in the study. The sample primarily consisted of GPs practising in metropolitan clinics (n = 315). Most participants reported that they would refer to the dentist for mobilized tooth (n = 402). There was a negative correlation between GPs with 5-29 years of experience and traumatized tooth management (P < 0.05). GPs aged between 40 and 49 years were more inclined to treat patients with mobilized teeth [Multivariate (MV): 0.42(0.09-0.74)]. However, GPs with 0-5 years of experience were less likely to manage patients with dental abscess [MV: -0.52(-0.80 to -0.24)]., Conclusion: Most GPs referred dental emergencies to dentists. GP management of dental emergencies were predominantly palliative. Therefore, opportunities for collaborative practice models amongst GPs and dentists may be needed to bridge the gap in the regional and remote locations., (© 2021 Australian Dental Association.)

Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid (HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1β to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1β increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1β-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1β culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.

Proteolytic fragments of fibronectin can have catabolic effects on cartilage, menisci, and synovium. Previous studies have reported that Toll-like receptor (TLR) signaling pathways might be associated with joint inflammation and joint destruction. Platelet-rich plasma (PRP) is increasingly being used to treat a range of joint conditions; however, it has yet to be determined whether PRP influences fibronectin fragment (FN-f) procatabolic activity and TLRs. In this study, human primary culture cells were treated with 30 kDa FN-f with/without PRP co-incubation, and then analyzed using real-time PCR to determine gene expression levels in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts. Protein levels were evaluated by Western immunoblotting. This study observed an increase in the protein expression of matrix metalloproteinases (MMPs), Toll-like receptor 2 (TLR2), nitric oxide synthase 2 (NOS2), prostaglandin-endoperoxide synthase (PTGS2), and cyclooxygenase 2 (COX2) in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts following insult with 30 kDa FN-f. Upregulation of these genes was significantly attenuated by PRP treatment. TLR2 and matrix metalloproteinase 13 (MMP-13) were also significantly attenuated by cotreatment with 30 kDa FN-f + PRP + TLR2 inhibitor. PRP treatment was shown to attenuate the 30 kDa FN-f-induced MMP-13 expression associated with the decreased expression of TLR2 in osteoarthritic chondrocytes and synovial fibroblasts. PRP treatment was also shown to attenuate procatabolic activity associated with MMP-13 expression via the TLR2 signaling pathway.

Background: Bones are the third most common site of metastasis, although bone metastasis (BM) incidence varies widely. This study investigated the incidence of BM in the most common cancers in Taiwan to present the recent treatment landscape in patients with organ-specific cancers., Methods: Data from the National Health Insurance Research Database of Taiwan were used to identify adult patients diagnosed with organ-specific cancers between January 1, 2000 and December 31, 2015. Kaplan-Meier analysis was used to quantify cumulative BM incidence at follow-up. BM incidences associated with different cancers were calculated comprehensively and stratified by sex, age group and follow-up periods, and age- and sex-adjusted hazard ratios (HRs) of BM were calculated using multivariate Cox regression analysis., Results: Among 938 776 participants (mean follow-up, 9.2 years), liver (19.6%), colorectal (17.1%) and lung (15.1%) cancers were most commonly associated with BM. The mean interval between a primary cancer diagnosis and BM was 2 years. BM incidence varied widely among cancers; lung cancer (3213 per 10 5 person-years) was associated with the highest BM risk, followed by oesophageal, prostate and breast cancer. HRs of BM were significantly higher for lung cancer (HR = 8.1) than for other cancers., Conclusion: The estimated BM incidence provided insight into oncological clinical practice trends in the Asia-Pacific region. BM incidence may vary among populations. Understanding the principles of clinical evaluation in patients with cancer of unknown primary origin can facilitate appropriate treatment recommendations., (© 2021 John Wiley & Sons Ltd.)

Background: The Taiwan Smell Identification Test (TWSIT) was developed and successfully administered in Taiwanese population since 2015. However, for sanitation reason, the original liquid-jar form of this test is not appropriate. The commercialized TWSIT was then re-designed as "scratch-and-sniff" version: the TIBSIT (Top International Biotech, Taipei, Taiwan). This project aims to investigate the normative value of TIBSIT in different age groups and genders., Methods: Volunteers aged 20 to 80 with no subjective smell loss were recruited in a rhinology clinic. The participants were given full instructions on using the TIBSIT., Results: Two hundred and nine healthy subjects (female: male =107: 102) were enrolled into this study. The median TIBSIT score in female and male subjects is 47 and 46, respectively. Subjects were further divided into three age groups: (A) 20∼34 years (n = 77), (B) 35∼54 years (n = 77), and (C) 55∼80 years (n = 55). The TIBSIT scores at the tenth percentile value at each age group of male patients are 43, 42 and 37; while the scores at the tenth percentile value at each age group of female patients are 42, 42 and 41. TIBSIT score was significantly and inversely correlated with age (Spearman rho = - 0.20, p  = 0.004.)., Conclusion: We established the normative values of the new TIBSIT in different age groups in Taiwan. Future nation-wide screening is needed for more sophisticated norms establishment., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

The long pentraxin 3 (PTX3) is a prototypic molecule for recognizing pathogens. Liver X receptors (LXRs), belonging to nuclear receptors (NRs) for cholesterol metabolism through heterodimerizing with other NRs, were recently reported to participate in inflammation. However, their roles in chronic rhinosinusitis without nasal polyps (CRSsNP) are unclear. Therefore, this study was sought to explore roles of LXRs in chronic rhinosinusitis (CRS) sinonasal tissues and derived fibroblasts. Immunohistochemistry indicated that LXRα and β expression and lipid/fat deposition were differentially expressed in the control and CRSsNP nasal mucosa. GW7647 (a peroxisome proliferator activated receptor α (PPARα) agonist) and GW3965 (a dual agonist for LXRα and β) significantly caused PTX3 induction in the fibroblast cells. GW3965 induced PTX3 mRNA and protein expression, and the induction substantially led to PTX3 secretion. Meanwhile, an endogenous agonist-cholesterol had a similar enhancing effect on the induction of PTX3 protein. LXR siRNA knockdown to lower LXRα or β expression significantly compromised PTX3 induction. Interestingly, GW3965 also induced phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) activation and its inhibition reduced PTX3 expression. Collectively, we demonstrated here for the first time that CRSsNP nasal mucosa differentially expresses LXRα and β and deposits lipids/fats that may contain cholesterol metabolites to activate LXRs. Activation of LXRs leads to PTX3 production in sinonasal mucosa-derived fibroblasts. Our previous study showed PTX3 overexpression in the nasal cavity of CRSsNP, whereas this study highlights that cholesterol metabolites and LXR activation regulate PTX3 production and may contribute to antimicrobial activity and tissue repair during CRSsNP progression.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r g ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r gs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors., (© 2020 Society for the Study of Addiction.)

Microporous materials exhibit fast CO 2 adsorption rate with possible sacrificed capacity, while CO 2 chemisorption on metal oxides is remarkable but kinetics and reactive area are critical. In order to adopt the advantages of both microporous sorbent zeolitic imidazolate framework (ZIF) and metal oxide (MO), in this research, magnesium oxide (MgO) and zinc oxide (ZnO) were doped to ZIF-8 (MO@ZIF) using infiltration and calcination processes. The powder X-ray diffraction patterns showed retained ZIF-8 integrity after MO addition. Broad MgO peaks implied well-dispersed nanoparticles, while sharp ZnO diffractions indicated oxide agglomeration, supported by the field emission transmission electron microscope images. ZIF pore size was expanded due to confined MgO without sacrificing the framework porosity. Because of nanoconfinement, the MgO@ZIF-8 room temperature CO 2 adsorption, as well as the adsorption rate constant in pseudo-second order model, were two-fold higher than expectation. In addition, the decarbonation temperature in MgO@ZIF-8 was reduced by 40 degrees. In general, it was found that metal oxide nanoconfinement in microporous zeolitic imidazolate frameworks performed improved CO 2 uptake, facilitated adsorption kinetics at ambient temperature, and lowered regeneration temperature to release CO 2 ., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The clavicle hook plate has been commonly used to treat distal clavicle fractures and acromioclavicular (AC) joint dislocations; however, midshaft clavicle fracture at the medial end of the hook plate remains an underestimated complication. We aimed to discover the risk factors for this complication and the influence of these risk factors on patients and to suggest preventive surgical techniques., Methods: We retrospectively reviewed the records of 150 patients with acute distal clavicle fractures or acute AC joint dislocations treated by internal fixation with a clavicle hook plate. The patient demographics, the occurrence of midshaft clavicle fracture at the medial end of the hook plate, and functional outcomes were analyzed. The functional outcomes were evaluated with the American Shoulder and Elbow Surgeons (ASES) Shoulder Score and grading of the Constant shoulder score after the hook plate was removed., Results: In total, 17 patients had complicating midshaft clavicle fractures at the medial end of the hook plate. Elderly patients had a higher risk of developing this complication than young patients. The odds ratio was 4.4 (p < 0.05). The average ASES score and grading of Constant score of these patients were 74.1 and 16.3 points, respectively, which were significantly inferior to those of patients without complications (p < 0.001)., Conclusion: The incidence of midshaft clavicle fractures following osteosynthesis with a clavicle hook plate was not negligible, especially in elderly patients. This complication may impair shoulder function and quality of life. Awareness of this complication and the risk factors for this complication reminds us to perform such operations with caution.

Importance: The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing controversy; meta-analysis of studies across 3 decades shows an association between rs1800497 and AUD, but genome-wide analyses have detected no role for rs1800497 in any phenotype. No evidence has emerged that rs1800497, which is located in ANKK1, perturbs the expression or function of DRD2., Objective: To resolve contradictions in previous studies by identifying hidden confounders and assaying for functional effects of rs1800497 and other loci in the DRD2 region., Data Sources: PubMed (882 studies), Embase (1056 studies), and Web of Science (501 studies) databases were searched through August 2018. Three clinical populations-Finnish, Native American, and African American participants-were genotyped for 208 to 277 informative single-nucleotide polymorphisms (SNPs) across the DRD2 region to test the associations of SNPs in this region with AUD., Study Selection: Eligible studies had diagnosis of AUD made by accepted criteria, reliable genotyping methods, sufficient genotype data to calculate odds ratios and 95% CIs, and availability of control allele frequencies or genotype frequencies., Data Extraction and Synthesis: After meta-analysis of 62 studies, metaregression was performed to detect between-study heterogeneity and to explore the effects of moderators, including deviations of cases and controls from allele frequencies in large population databases (ExAC and 1000 Genomes). Linkage to AUD and the effect on gene expression of rs1800497 were evaluated in the context of other SNPs in the DRD2 region. Data analysis was performed from August 2018 to March 2019. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline., Main Outcomes and Measures: The effects of rs1800497 and other SNPs in the DRD2 region on gene expression were measured in human postmortem brain samples via differential allelic expression and evaluated in other tissues via publicly available expression quantitative locus data., Results: A total of 62 studies of DRD2 and AUD with 16 294 participants were meta-analyzed. The rs1800497 SNP was associated with AUD (odds ratio, 1.23; 95% CI, 1.14-1.31; P < .001). However, the association was attributable to spuriously low allele frequencies in controls in positive studies, which also accounted for some between-study heterogeneity (I2 = 43%; 95% CI, 23%-58%; Q61 = 107.20). Differential allelic expression of human postmortem brain and analysis of expression quantitative loci in public data revealed that a cis-acting locus or loci perturb the DRD2 transcript level; however, rs1800497 does not and is not in strong disequilibrium with such a locus. Across the DRD2 region, other SNPs are more strongly associated with AUD than rs1800497, although no DRD2 SNP was significantly associated in these 3 clinical samples., Conclusions and Relevance: In this meta-analysis, the significant association of DRD2 with AUD was reassessed. The DRD2 association was attributable to anomalously low control allele frequencies, not function, in positive studies. For genetic studies, statistical replication is not verification.

Background: The endoscopic modified Lothrop procedure (EMLP) is used to manage ongoing refractory frontal sinusitis after failed previous endoscopic sinus surgery (ESS), but this approach has a significant restenosis rate. We evaluated the potential benefits of mucosal grafts and pedicled flaps on the opening of the newly formed frontal ostium., Methods: Fifty patients with refractory frontal sinusitis or mucoceles after ESS were randomized to undergo EMLP, either with (n = 27) or without (n = 23) mucosal grafts and pedicled flap reconstruction of the neo-ostium. The frontal neo-ostium was measured with Lindholm distending forceps, and anteroposterior (A-P) and lateral dimensions were measured intraoperatively, and then again at 6 weeks, 6 months, and 12 months postoperatively. Olfaction outcomes were assessed using the Taiwan Smell Identification Test (TWSIT) and a smell visual analog scale (VAS) score preoperatively and at 6 months postsurgery., Results: The initial intraoperative mean lateral and A-P dimensions were 23.2 ± 2.7 mm and 14.8 ± 2.3 mm and were significantly decreased at all time-points postoperatively. The mucosal grafts and pedicled flaps had greater lateral and A-P dimensions, and a greater percentage of intraoperative frontal neo-ostium area at all time-points postoperatively (all p < 0.05). At 6 months postoperatively, TWSIT (p = 0.027), but not the smell VAS score (p = 0.063), was significantly improved compared with baseline. TWSIT and smell VAS score changes did not differ between groups (p = 0.92 and p = 0.85, respectively)., Conclusion: The use of mucosal grafts and pedicled flaps reduces stenosis of the frontal neo-ostium postsurgery and should be considered after EMLP., (© 2019 ARS-AAOA, LLC.)

Artificially selected model organisms can reveal hidden features of the genetic architecture of the complex disorders that they model. Addictions are disease phenotypes caused by different intermediate phenotypes and pathways and thereby are potentially highly polygenic. High responder (bHR) and low responder (bLR) rat lines have been selectively bred (b) for exploratory locomotion (EL), a behavioral phenotype correlated with novelty-seeking, impulsive response to reward, and vulnerability to addiction, and is inversely correlated with spontaneous anxiety and depression-like behaviors. The rapid response to selection indicates loci of large effect for EL. Using exome sequencing of HR and LR rats, we identified alleles in gene-coding regions that segregate between the two lines. Quantitative trait locus (QTL) analysis in F2 rats derived from a bHR × bLR intercross confirmed that these regions harbored genes affecting EL. The combined effects of the seven genome-wide significant QTLs accounted for approximately one-third of the total variance in EL, and two-thirds of the variance attributable to genetic factors, consistent with an oligogenic architecture of EL estimated both from the phenotypic distribution of F2 animals and rapid response to selection. Genetic association in humans linked APBA2 , the ortholog of the gene at the center of the strongest QTL, with substance use disorders and related behavioral phenotypes. Our finding is also convergent with molecular and animal behavioral studies implicating Apba2 in locomotion. These results provide multilevel evidence for genes/loci influencing EL. They shed light on the genetic architecture of oligogenicity in animals artificially selected for a phenotype modeling a more complex disorder in humans., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10 -13 ) and African ancestries (rs2066702; P = 2.2 × 10 -9 ). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Background: The intranasal endoscopic prelacrimal recess approach (PLRA) access to all aspects of the maxillary sinus while preserving the inferior turbinate and nasolacrimal duct and its use have been reported in the treatment of many maxillary sinus and lateral skull base diseases., Objective: To retrospectively assess the effectiveness of a 10-year multicenter follow-up for the resection of inverted papilloma of the maxillary sinus (IPMS) via a PLRA., Methods: A total of 71 patients were admitted and underwent IPMS excision via an intranasal endoscopic PLRA from 2003 to 2013. All patients underwent high-resolution computed tomography scanning of the nasal sinus, and some also underwent magnetic resonance imaging examination., Results: Based on the Krouse staging system, all 71 patients belong to T3 staging. The PLRA was employed to remove IPMS in 71 patients. The postoperative pathological examination of the excised tissue revealed inverted papilloma, and cancerization was identified in 3 patients. The median follow-up time was 37.3 months (range: 13-134 months). Of the 71 patients, reoccurrence was seen in 5 patients (7.04%); 5 patients (7.04%) experienced numbness of the upper lid and the ala of the nose and 4 (5.63%) experienced mild collapse of the ala of the nose., Conclusions: These multicenter follow-up results demonstrated that the PLRA is a safe and effective method for the excision of primary or recurrent IPMS with lower postoperative complications and recurrent rate.

Despite ethnic differences in allele frequencies of variants in dopaminergic genes associated with dopamine D2/D3 receptor availability (D2R), no study to date has investigated the relationship between genetic ancestry and striatal D2R. Here, we show that ancestry-informative markers significantly predict dorsal striatal D2R in 117 healthy ethnically diverse residents of the New York metropolitan area using Positron Emission Tomography (PET) with [ 11 C]raclopride (P<0.0001), while correcting for age, sex, BMI, education, smoking status, and estimated socioeconomic status (ZIP codes). Effects of ethnicity on D2R were not driven by variation in dopaminergic candidate genes. Instead, candidate gene associations with striatal D2R were diminished when correcting for ancestry. These findings imply that future studies investigating D2 receptor genes should covary for genetic ancestry or study homogeneous populations. Moreover, ancestry studies on human neurobiology should control for socioeconomic differences between ethnic groups.

Genome-wide association studies (GWAS) of complex, heritable, behavioral phenotypes have yielded an incomplete accounting of the genetic influences. The identified loci explain only a portion of the observed heritability, and few of the loci have been shown to be functional. It is clear that current GWAS techniques overlook key components of phenotypically relevant genetic variation, either because of sample size, as is frequently asserted, or because of methodology. Here we use arginine vasopressin receptor 1a (AVPR1a) as an in-depth model of a methodologic limitation of GWAS: the functional genetic variation (in the form of short tandem repeats) of this key gene involved in affiliative behavior cannot be captured by current GWAS methodologies. Importantly, we find evidence of differential allele expression, twofold or more, in at least a third of human brain samples heterozygous for a reporter SNP in the AVPR1a transcript. We also show that this functional effect and a downstream phenotype, externalizing behavior, are predicted by AVPR1a STRs but not SNPs.

Aim: This study assesses whether genetic variants in stress-related genes are associated with prolonged abstinence from heroin in subjects that are not in long-term methadone treatment., Methods: Frequencies of 117 polymorphisms in 30 genes were compared between subjects with history of heroin addiction, either without agonist treatment (n = 129) or in methadone maintenance treatment (n = 923)., Results: SNP rs1500 downstream of CRHBP and an interaction of SNPs rs10482672 (NR3C1) and rs4234955 (NPY1R/NPY5R) were significantly associated with prolonged abstinence without agonist treatment., Conclusion: This study suggests that variability in stress-related genes may contribute to the ability of certain subjects to remain in prolonged abstinence from heroin, possibly due to higher resilience to stress.

Background: Endoscopic endonasal nasopharyngectomy(EEN) can be a promising option for select patients with recurrent nasopharyngeal carcinoma, but serious complications can occur in terms of parapharyngeal internal carotid artery (PPICA) injury. Several landmarks have been proposed for locating the PPICA. In this study, we investigated the spatial relationship between the tensor veli palatini (TVP) muscle and the PPICA in a cadaveric model., Methods: Seven fresh cadaver heads were available for anatomic study. Eustachian tube and the levator veli palatine (LVP) muscle were partially sacrificed or truncated to maximize the surgical field, and the TVP muscle was carefully preserved. Complete dissection was defined as when the PPICA could be visualized. We then measured the distance between the posterior margin of the TVP muscle and PPICA (z-axis), and the distance from the midline of the nasopharynx to the PPICA (x-axis)., Results: Thirteen sides of the PPICA were successfully identified. The mean distance between the posterior margin of the TVP to the PPICA (z) was 20.3 mm (range, 12 to 28 mm), and the mean distance between the midline of the nasopharynx to the PPICA (x) was 19.6 mm (range, 15 to 24 mm)., Conclusion: The PPICA was located in the same sagittal plane as the TVP muscle during dissection posteriorly. The PPICA appeared to lie around 2 cm laterally from the midline at around 2 cm in depth from the posterior margin of the TVP muscle. However, the exact position of the PPICA should be assessed using preoperative magnetic resonance imaging and intraoperative image-guided systems., (© 2017 ARS-AAOA, LLC.)

Background: Reduction in brain volume, especially gray matter volume, has been shown to be one of the many deleterious effects of prolonged alcohol consumption. High variance in the degree of gray matter tissue shrinkage among alcohol-dependent individuals and a previous neuroimaging genetics report suggest the involvement of environmental and/or genetic factors, such as superoxide dismutase 2 (SOD2). Identification of such underlying factors will help in the clinical management of alcohol dependence., Methods: We analyzed quantitative magnetic resonance imaging and genotype data from 103 alcohol users, including both light drinkers and treatment-seeking alcohol-dependent individuals. Genotyping was performed using a custom gene array that included genes selected from 8 pathways relevant to chronic alcohol-related brain volume loss., Results: We replicated a significant association of a functional SOD2 single nucleotide polymorphism with normalized gray matter volume, which had been reported previously in an independent smaller sample of alcohol-dependent individuals. The SOD2-related genetic protection was observed only at the cohort's lower drinking range. Additional associations between normalized gray matter volume and other candidate genes such as alcohol dehydrogenase gene cluster (ADH), GCLC, NOS3, and SYT1 were observed across the entire sample but did not survive corrections for multiple comparisons., Conclusion: Converging independent evidence for a SOD2 gene association with gray matter volume shrinkage in chronic alcohol users suggests that SOD2 genetic variants predict differential brain volume loss mediated by free radicals. This study also provides the first catalog of genetic variations relevant to gray matter loss in chronic alcohol users. The identified gene-brain structure relationships are functionally pertinent and merit replication., (Published by Oxford University Press on behalf of CINP 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: This study was undertaken to analyze the results of a novel surgical method-the endoscopic prelacrimal recess approach (PLRA)-in patients with tumors involving the pterygopalatine fossa (PPF) and infratemporal fossa (ITF). The surgical technique and indications for this approach are also discussed., Methods: The authors analyzed data from 7 cases involving patients who underwent resection of PPF and ITF tumors by means of the endoscopic PLRA from 2004 to 2013. Preoperative and postoperative imaging studies were available in all cases and were reviewed. The surgical specimens were all confirmed to be schwannomas., Results: All tumors were completely resected via endoscopic PLRA. There were no recurrences noted over a 28-month follow-up period. In 4 cases, the patients experienced postoperative facial numbness during the first two weeks after surgery, which gradually lessened thereafter. One patient continued to have mild facial numbness at most recent follow-up. The numbness had fully resolved in the other 3 cases., Conclusions: The intranasal endoscopic removal of schwannoma from PPF and ITF via PLRA can spare the whole lateral nasal wall, resulting in a reduction in morbidity. This is a novel minimally invasive surgical method for PPF and ITF tumors.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Background: Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal gamma-aminobutyric acid (GABA) transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore, variants in these genes might predict risk/resilience for alcoholism., Methods: This study included 3 populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid antisocial personality disorder, 181 controls; and a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1 tag single nucleotide polymorphisms were genotyped in the AA and Finnish samples; rs29220 was genotyped in the PI for replication. Also, a uniquely African, functional SLC6A1 insertion promoter polymorphism (IND) was genotyped in the AAs., Results: We found a significant and congruent association between GABBR1 rs29220 and alcoholism in all 3 populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 IND was more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR1 rs29220 and SLC6A1 IND genotypes showed that rs29220 heterozygotes, irrespective of their IND status, had an increased risk for alcoholism, whereas carriers of the IND allele and either rs29220 homozygote were more resilient., Conclusions: Our results show that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist., (Copyright © 2016 by the Research Society on Alcoholism. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)