In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

[Resveratrol protects dopaminergic neurons in a mouse model of Parkinson's disease by regulating the gut-brain axis via inhibiting the TLR4 signaling pathway].

OBJECTIVE: To investigate the protective effect of resveratrol on intestinal barrier in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse models and its mechanism for regulating TLR4/MyD88/NF-κB signaling to protect dopaminergic neurons. METHODS: Fifty-two C57BL/6J mice were randomized into control group (n= 12), MPTP group (n=14), MPTP + resveratrol (30 mg/kg) group (n=13), and MPTP + resveratrol (90 mg/kg) group (n=13), and mouse models were established by intraperitoneal MPTP (30 mg/kg) injection for 7 days in the latter 3 groups. Behavioral tests were conducted to evaluate the effect of resveratrol on motor symptoms of the mice. Western blotting was used to detect the expression of TH, α-syn, ZO-1, Claudin-1, TLR4, MyD88, and NF-κB in the brain tissues of the mice. Immunohistochemistry, immunofluorescence, ELISA and transmission electron microscopy were used to verify the effect of resveratrol for suppressing inflammation and protecting the intestinal barrier. RESULTS: Compared with those in the normal control group, the mice in MPTP group showed significant changes in motor function, number of dopaminergic neurons, neuroinflammation, levels of LPS and LBP, and expressions of tight junction proteins in the intestinal barrier. Resveratrol treatment significantly improved motor function of the PD mice (P < 0.01), increased the number of neurons and TH protein expression (P < 0.05), down-regulated the expressions of GFAP, Iba-1, and TLR4, lowered fecal and plasma levels of LPS and LBP (P < 0.05), restored the expression levels of ZO-1 and Claudin-1 (P < 0.01), and down-regulated the expressions of TLR4, MyD88, and NF-κB in the colon tissue (P < 0.05). The mice with resveratrol treatment at 30 mg/kg showed normal morphology of the tight junction complex with neatly and tightly arranged intestinal villi. CONCLUSION: Resveratrol repairs the intestinal barrier by inhibiting TLR4/MyD88/NF-κB signaling pathway-mediated inflammatory response, thereby improving motor function and neuropathy in mouse models of MPTP-induced PD.

Gut microbiome in association with chemotherapy-induced toxicities among patients with breast cancer.

BACKGROUND: Little research has focused on the relationship between gut microbiome and chemotherapy-induced toxicity. METHODS: This prospective study involves 301 patients with breast cancer who had prechemotherapy stool samples collected. Gut microbiome was sequenced by shotgun metagenomics; associations with chemotherapy-induced toxicities during first-line treatment by gut microbial diversity, composition, and metabolic pathways with severe (i.e., grade ≥3) hematological and gastrointestinal toxicities were evaluated via multivariable logistic regression. RESULTS: High prechemotherapy α-diversity was associated with a significantly reduced risk of both severe hematological toxicity (odds ratio [OR] = 0.94; 95% CI, 0.89-0.99; p = .048) and neutropenia (OR = 0.94; 95% CI, 0.89-0.99; p = .016). A high abundance of phylum Synergistota, class Synergistia, and order Synergistales were significantly associated with a reduced risk of severe neutropenia; conversely, enrichment of phylum Firmicutes C, class Negativicutes, phylum Firmicutes I, and class Bacilli A, order Paenibacillales were significantly associated with an increased risk of severe neutropenia (p range: 0.012-2.32 × 10-3; false discovery rate <0.1). Significant positive associations were also observed between severe nausea/vomiting and high Chao1 indexes, ß-diversity (p < .05), 20 species belonging to the family Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae (p value range: 6.14 × 10-3 to 1.33 × 10-5; false discovery rate <0.1), and three metabolic pathways involved in reductive tricarboxylic acid cycle I and cycle II, and an incomplete reductive tricarboxylic acid cycle (p < .01). Conversely, a high abundance of species Odoribacter laneus and the pathway related to the L-proline biosynthesis II were inversely associated with severe nausea/vomiting. CONCLUSIONS: Our study suggests that gut microbiota may be a potential preventive target to reduce chemotherapy-induced toxicity.

Gut Microbiome of Patients With Breast Cancer in Vietnam.

PURPOSE: Gut microbiota play an important role in human health, including cancer. Cancer and its treatment, in turn, may alter the gut microbiome. To understand this complex relationship, we profiled the gut microbiome of 356 Vietnamese patients with breast cancer. MATERIALS AND METHODS: Stool samples were collected before chemotherapy, with 162 pre- and 194 postsurgery. The gut microbiome was measured by shotgun metagenomic sequencing. Associations of gut microbial diversity, taxa abundance, and gut microbiome health index (GMHI) with sociodemographic, clinical factors, and tumor characteristics were evaluated. RESULTS: Postsurgery samples were associated with significantly lower α- and ß-diversities (P < .001) and showed significant differences in the abundance of 15% of 2,864 investigated taxa (false discovery rate [FDR] <0.1) compared with presurgery samples. An unhealthy gut microbiome was prevalent among patients with breast cancer, with a mean GMHI of -0.79 and -2.81 in pre- and postsurgery stool samples, respectively. In an analysis of 162 presurgery stool samples, diagnosis delay was significantly associated with lower α-diversity, variation in ß-diversity, an increased abundance of species Enorma massiliensis, and a decreased abundance of Faecalicoccus pleomorphus. High intake of fiber was significantly associated with lower α-diversity and a higher abundance of species belonging to Bifidobacterium, Prevotella, and Bacteroides gena (FDR < 0.1). We did not find that cancer stage and subtype, menopausal status, comorbidity, antibiotic use during 3 months before stool collection, or physical activity was significantly associated with α- and ß-diversities or GMHI although a few significant differences were observed in taxa abundance. CONCLUSION: Our study revealed that diagnosis delay, high fiber intake, and breast cancer surgery, which is always followed by antibiotic prophylaxis in Vietnam, led to a less diverse and unhealthy gut microbiome among patients with breast cancer.

Clinical and radiological outcomes with an augmented baseplate for superior glenoid wear in reverse shoulder arthroplasty.

Aims: This study aimed to assess the impact of using the metal-augmented glenoid baseplate (AGB) on improving clinical and radiological outcomes, as well as reducing complications, in patients with superior glenoid wear undergoing reverse shoulder arthroplasty (RSA). Methods: From January 2016 to June 2021, out of 235 patients who underwent primary RSA, 24 received a superior-AGB after off-axis reaming (Group A). Subsequently, we conducted propensity score matching in a 1:3 ratio, considering sex, age, follow-up duration, and glenoid wear (superior-inclination and retroversion), and selected 72 well-balanced matched patients who received a standard glenoid baseplate (STB) after eccentric reaming (Group B). Superior-inclination, retroversion, and lateral humeral offset (LHO) were measured to assess preoperative glenoid wear and postoperative correction, as well as to identify any complications. Clinical outcomes were measured at each outpatient visit before and after surgery. Results: There were no significant differences in demographic data and preoperative characteristics between the two groups. Both groups showed significant improvements in patient-reported outcome measures (visual analogue scale for pain, visual analogue scale for function, American Shoulder and Elbow Surgeons, Constant, and Simple Shoulder Test scores) from preoperative to final assessment (p < 0.001). However, AGB showed no additional benefit. Notably, within range of motion, Group B showed significant postoperative decrease in both external rotation and internal rotation, unlike Group A (p = 0.028 and 0.003, respectively). Both groups demonstrated a significant correction of superior-inclination after surgery, while patients in Group B exhibited a significant decrease in LHO postoperatively (p = 0.001). Regarding complications, Group A experienced more acromial stress fractures (3 cases; 12.5%), whereas Group B had a higher occurrence of scapular notching (24 cases; 33.3%) (p = 0.008). Conclusion: Both eccentric reaming with STB and off-axis reaming with AGB are effective methods for addressing superior glenoid wear in RSA, leading to improved clinical outcomes. However, it is important to be aware of the potential risks associated with eccentric reaming, which include excessive bone loss leading to reduced rotation and scapular notching.

In situ production and secretion of proteins endow therapeutic benefit against psoriasiform dermatitis and melanoma.

Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over extracellular localization of therapeutic proteins. A critical gap therefore remains the need to develop and incorporate methodologies that allow for posttranslational control over expression dynamics, localization, and stability of nucleic acid-generated protein therapeutics. To address this, we explored how the body's endogenous machinery controls protein localization through signal peptides (SPs), including how these motifs could be incorporated modularly into therapeutics. SPs serve as a virtual zip code for mRNA transcripts that direct the cell where to send completed proteins within the cell and the body. Utilizing this signaling biology, we incorporated secretory SP sequences upstream of mRNA transcripts coding for reporter, natural, and therapeutic proteins to induce secretion of the proteins into systemic circulation. SP sequences generated secretion of various engineered proteins into the bloodstream following intravenous, intramuscular, and subcutaneous SP mRNA delivery by lipid, polymer, and ionizable phospholipid delivery carriers. SP-engineered etanercept/TNF-α inhibitor proteins demonstrated therapeutic efficacy in an imiquimod-induced psoriasis model by reducing hyperkeratosis and inflammation. An SP-engineered anti-PD-L1 construct mediated mRNA encoded proteins with longer serum half-lives that reduced tumor burden and extended survival in MC38 and B16F10 cancer models. The modular nature of SP platform should enable intracellular and extracellular localization control of various functional proteins for diverse therapeutic applications.

Effect of using a small baseplate on the radiological and clinical outcomes of reverse total shoulder arthroplasty in Asian patients.

Aims: The aim of this study was to compare the clinical and radiological outcomes of reverse shoulder arthroplasty (RSA) using small and standard baseplates in Asian patients, and to investigate the impact of a mismatch in the sizes of the glenoid and the baseplate on the outcomes. Methods: This was retrospective analysis of 50 and 33 RSAs using a standard (33.8 mm, ST group) and a small (29.5 mm, SM group) baseplate of the Equinoxe reverse shoulder system, which were undertaken between January 2017 and March 2021. Radiological evaluations included the size of the glenoid, the ß-angle, the inclination of the glenoid component, inferior overhang, scapular notching, the location of the central cage in the baseplate within the vault and the mismatch in size between the glenoid and baseplate. Clinical evaluations included the range of motion (ROM) and functional scores. In subgroup analysis, comparisons were performed between those in whom the vault of the glenoid was perforated (VP group) and those in whom it was not perforated (VNP group). Results: Perforation of the vault of the glenoid (p = 0.018) and size mismatch in height (p < 0.001) and width (p = 0.013) were significantly more frequent in the ST group than in the SM group. There was no significant difference in the clinical scores and ROM in the two groups, two years postoperatively (all p > 0.05). In subgroup analysis, the VP group had significantly less inferior overhang (p = 0.009), more scapular notching (p = 0.018), and more size mismatch in height (p < 0.001) and width (p = 0.025) than the VNP group. Conclusion: In Asian patients with a small glenoid, using a 29.5 mm small baseplate at the time of RSA was more effective in reducing size mismatch between the glenoid and the baseplate, decreasing the incidence of perforation of the glenoid vault, and achieving optimal positioning of the baseplate compared with the use of a 33.8 mm standard baseplate. However, longer follow-up is required to assess the impact of these findings on the clinical outcomes.

Clinical observation of posterior decompression, fusion and fixation in the treatment of spinal gout: a case series.

OBJECTIVE: The aim of the present study was to assess the effect of posterior decompression, fusion and fixation in the treatment of spinal gout. Spinal gout is a disease of gouty arthritis involving the spine, which can affect all segments of the spine. At present, the etiology and pathogenesis of spinal gout are not clear, and there are no definite methods for the treatment of spinal gout. METHODS: This was a case series of seven patients (seven men) who underwent posterior decompression, fusion and fixation in the treatment of spinal gout between January 2016 and January 2020. Physical examination, radiography, CT, MRI, Japanese Orthopaedic Association (JOA) score and visual analog scale (VAS) score were used to evaluate the effect of this procedure. All patients were followed up every 3 months. The evaluation time point was 12 months after the operation. Comparisons of the functional indexes of the patients before and after the operation were performed using SPSS 22.0 (IBM, Armonk, NY, USA). RESULTS: The JOA score was 13.43 ± 6.55 and the VAS score was 7.43 ± 1.51 preoperatively. The JOA score was 24.43 ± 3.74 and the VAS score was 0.86 ± 0.90 postoperatively at 12 months after surgery. At 12 months after surgery, the JOA and VAS score showed significant improvements when compared with those before surgery (P = 0.004 and P = 0.002, respectively). None of the patients had re-surgery of the gout due to actively and reasonably controlling uric acid. No loosening or displacement of screws was reported. There was only one screw tail cap loosening. Radiographic examination revealed that there was no obvious accumulation of gout or surrounding bone destruction, and the segmental instability was significantly improved. There was no progressive aggravation of neurological symptoms of the seven patients. CONCLUSIONS: Posterior approach decompression, fusion and fixation can stabilize the vertebral body, remove gout and directly relieve local spinal cord compression. The method is a reliable surgical choice for the treatment of spinal gout.

Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-specific mRNA delivery.

A new methodology termed selective organ targeting (SORT) was recently developed that enables controllable delivery of nucleic acids to target tissues. SORT lipid nanoparticles (LNPs) involve the inclusion of SORT molecules that accurately tune delivery to the liver, lungs and spleen of mice after intravenous administration. Nanoparticles can be engineered to target specific cells and organs in the body by passive, active and endogenous targeting mechanisms that require distinct design criteria. SORT LNPs are modular and can be prepared using scalable, synthetic chemistry and established engineering formulation methods. This protocol provides detailed procedures, including the synthesis of a representative ionizable cationic lipid, preparation of multiple classes of SORT LNPs by pipette, vortex and microfluidic mixing methods, physical characterization, and in vitro/in vivo mRNA delivery evaluation. Depending on the scale of the experiments, the synthesis of the ionizable lipid requires 4-6 d; LNPs can be formulated within several hours; LNP characterization can be completed in 2-4 h; and in vitro/in vivo evaluation studies require 1-14 d, depending on the design and application. Our strategy offers a versatile and practical method for rationally designing nanoparticles that accurately target specific organs. The SORT LNPs generated as described in this protocol can therefore be applied to multiple classes of LNP systems for therapeutic nucleic acid delivery and facilitate the development of protein replacement and genetic medicines in target tissues. This protocol does not require specific expertise, is modular to various lipids within defined physicochemical classes, and should be accomplishable by researchers from various backgrounds.

Effective Medical Waste Management for Sustainable Green Healthcare.

This study examines the importance of medical waste management activities for developing a sustainable green healthcare environment. This study applied a multiple methodological approach as follows. A thorough review of the literature was performed to delineate the factors that have been explored for reducing medical waste; hospital staff who handle medical waste were surveyed to obtain their opinions on these factors; the analytic hierarchy process (AHP) was applied to determine the priorities among the identified key factors; and experts' opinions were consulted to assess the actual applicability of the results derived by the AHP. The study identified the following factors as the most important: medical waste management (26.6%), operational management issues (21.7%), training for medical waste management procedures (17.8%), raising awareness (17.5%), and environmental assessment (16.4%). This study analyzed the contributing factors to the generation of medical waste based on the data collected from medical staff and the AHP for developing a sustainable green healthcare environment. The study results provide theoretical and practical implications for implementing effective medical waste management toward a sustainable green healthcare environment.

Arthroscopic biceps augmentation does not improve clinical outcomes during incomplete repair of large to massive rotator cuff tears.

AIMS: This study compared patients who underwent arthroscopic repair of large to massive rotator cuff tears (LMRCTs) with isolated incomplete repair of the tear and patients with incomplete repair with biceps tendon augmentation. We aimed to evaluate the additional benefit on clinical outcomes and the capacity to lower the re-tear rate. METHODS: We retrospectively reviewed 1,115 patients who underwent arthroscopic rotator cuff repair for full-thickness tears between October 2011 and May 2019. From this series, we identified 77 patients (28 male, 49 female) with a mean age of 64.1 years (50 to 80). Patients were classified into groups A (n = 47 incomplete) and B (n = 30 with biceps augmentation) according to the nature of their reconstruction. Clinical scores were checked preoperatively and at six months, one year, and two years postoperatively. In preoperative MRI, we measured the tear size, the degree of fatty infiltration, and muscle volume ratio of the supraspinatus. In postoperative MRI, the integrity of the repaired rotator cuff tendon was assessed using the Sugaya classification. Tendon thickness at the footprint was evaluated on T2-weighted oblique coronal view. RESULTS: There were no significant differences in the initial preoperative demographic characteristics. In both groups, there were significant improvements in postoperative clinical scores (p < 0.001). However, most clinical outcomes, including range of motion measurements (forward elevation, external rotation, internal rotation, and abduction), showed no differences between the pre- and postoperative values. Comparing the postoperative outcomes of both groups, no further improvement from biceps augmentation was found. Group B, although not reaching statistical significance, had more re-tears than group A (30% vs 15%; p = 0.117). CONCLUSION: In LMRCTs, biceps augmentation provided no significant improvement of an incomplete repair. Therefore, biceps augmentation is not recommended in the treatment of LMRCTs.Cite this article: Bone Joint J 2022;104-B(11):1234-1241.

Chemotherapy-Induced Toxicities and Their Associations with Clinical and Non-Clinical Factors among Breast Cancer Patients in Vietnam.

Understanding the burden and factors related to chemotherapy-induced toxicity is important in treatment planning for breast cancer patients. We conducted a prospective study among 396 newly diagnosed and chemotherapy-treated breast cancer patients recruited in two major cancer hospitals in northern Vietnam. Toxicities were captured through medical chart reviews and patient self-reports and graded using NCI CTCAE classification. Associations for sociodemographic and clinical factors with chemotherapy-induced toxicities during first-line chemotherapy were evaluated via multivariable logistic regression. Severe (i.e., grade ≥ 3) hematological (38.6%), and gastrointestinal (12.9%) toxicities were common. A pre-existing nephrological condition was significantly associated with the risk of severe hematological toxicity with adjusted odds ratios (OR) and 95% confidence intervals (CIs) of 2.30 (1.32-4.01). Patients living in rural areas had a lower risk of severe hematological toxicity (OR = 0.48; 95% CI, 0.30-0.77). Patients diagnosed with stage II and stage III-IV had a lower risk of severe gastrointestinal toxicity with ORs and 95% CIs of 0.26 (0.12-0.59) and 0.47 (0.20-1.10), respectively. Triple-negative/basal-like subtype was associated with a higher risk of severe hematological (OR = 3.15; 95% CI, 1.56-6.34) and gastrointestinal toxicities (OR = 3.60; 95% CI, 1.45-8.95) comparing to hormone receptor (HR)-positive HER2-negative subtype. Further research investigating underlying mechanisms would facilitate the development and delivery of personalized treatment and care plans.

Lipid Nanoparticle (LNP) Chemistry Can Endow Unique In Vivo RNA Delivery Fates within the Liver That Alter Therapeutic Outcomes in a Cancer Model.

Within the field of lipid nanoparticles (LNPs) for RNA delivery, the focus has been mainly placed on organ level delivery, which can mask cellular level effects consequential to therapeutic applications. Here, we studied a pair of LNPs with similar physical properties and discovered how the chemistry of the ionizable amino lipid can control the endogenous LNP identity, affecting cellular uptake in the liver and altering therapeutic outcomes in a model of liver cancer. Although most LNPs accumulate in the liver after intravenous administration (suggesting that liver delivery is straightforward), we observed an unexpected behavior when comparing two similar LNP formulations (5A2-SC8 and 3A5-SC14 LNPs) that resulted in distinct RNA delivery within the organ. Despite both LNPs possessing similar physical properties, ability to silence gene expression in vitro, strong accumulation within the liver, and a shared pKa of 6.5, only 5A2-SC8 LNPs were able to functionally deliver RNA to hepatocytes. Factor VII (FVII) activity was reduced by 87%, with 5A2-SC8 LNPs carrying FVII siRNA (siFVII), while 3A5-SC14 LNPs carrying siFVII produced baseline FVII activity levels comparable to the nontreatment control at a dosage of 0.5 mg/kg. Protein corona analysis indicated that 5A2-SC8 LNPs bind apolipoprotein E (ApoE), which can drive LDL-R receptor-mediated endocytosis in hepatocytes. In contrast, the surface of 3A5-SC14 LNPs was enriched in albumin but depleted in ApoE, which likely led to Kupffer cell delivery and detargeting of hepatocytes. In an aggressive MYC-driven liver cancer model relevant to hepatocytes, 5A2-SC8 LNPs carrying let-7g miRNA were able to significantly extend survival up to 121 days. Since disease targets exist in an organ- and cell-specific manner, the clinical development of RNA LNP therapeutics will require an improved understanding of LNP cellular tropism within organs. The results from our work illustrate the importance of understanding the cellular localization of RNA delivery and incorporating further checkpoints when choosing nanoparticles beyond biochemical and physical characterization, as small changes in the chemical composition of LNPs can have an impact on both the biofate of LNPs and therapeutic outcomes.

Racial/Ethnic Disparities in Mortality Related to Access to Care for Major Cancers in the United States.

Importance: The reasons underlying racial/ethnic mortality disparities for cancer patients remain poorly understood, especially regarding the role of access to care. Participants: Over five million patients with a primary diagnosis of lung, breast, prostate, colon/rectum, pancreas, ovary, or liver cancer during 2004-2014, were identified from the National Cancer Database. Cox proportional hazards models were applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for total mortality associated with race/ethnicity, and access to care related factors (i.e., socioeconomic status [SES], insurance, treating facility, and residential type) for each cancer. Results: Racial/ethnic disparities in total mortality were observed across seven cancers. Compared with non-Hispanic (NH)-white patients, NH-black patients with breast (HR = 1.27, 95% CI: 1.26 to 1.29), ovarian (HR = 1.20, 95% CI: 1.17 to 1.23), prostate (HR = 1.31, 95% CI: 1.30 to 1.33), colorectal (HR = 1.11, 95% CI: 1.10 to 1.12) or pancreatic (HR = 1.03, 95% CI: 1.02 to 1.05) cancers had significantly elevated mortality, while Asians (13-31%) and Hispanics (13-19%) had lower mortality for all cancers. Racial/ethnic disparities were observed across all strata of access to care related factors and modified by those factors. NH-black and NH-white disparities were most evident among patients with high SES or those with private insurance, while Hispanic/Asian versus NH-white disparities were more evident among patients with low SES or those with no/poor insurance. Conclusions and Relevance: Racial/ethnic mortality disparities for major cancers exist across all patient groups with different access to care levels. The influence of SES or insurance on mortality disparity follows different patterns for racial/ethnic minorities versus NH-whites. Impact: Our study highlights the need for racial/ethnic-specific strategies to reduce the mortality disparities for major cancers.

Developing Green Healthcare Activities in the Total Quality Management Framework.

This study examines the effectiveness of green healthcare activities in hospitals based on the total quality management (TQM) framework. The proposed research model and associated hypotheses were tested using structural equations modeling based on the data collected from 261 employees at general hospitals in South Korea. The results of the study revealed that the role of top management is essential for the successful implementation of green healthcare activities through motivating employees for their active participation in the program, providing continuous education and training on the importance of environmental sustainability, and diligent monitoring of the progress at the organization level. The study findings provide theoretical and practical implications on strategic approaches to planning and implementing green healthcare activities in hospitals for the greater good.

A unified theory of free energy functionals and applications to diffusion.

SignificanceThe free energy functional is a central component of continuum dynamical models used to describe phase transitions, microstructural evolution, and pattern formation. However, despite the success of these models in many areas of physics, chemistry, and biology, the standard free energy frameworks are frequently characterized by physically opaque parameters and incorporate assumptions that are difficult to assess. Here, we introduce a mathematical formalism that provides a unifying umbrella for constructing free energy functionals. We show that Ginzburg-Landau framework is a special case of this umbrella and derive a generalization of the widely employed Cahn-Hilliard equation. More broadly, we expect the framework will also be useful for generalizing higher-order theories, establishing formal connections to microscopic physics, and coarse graining.

Association of Fruit, Vegetable, and Animal Food Intakes with Breast Cancer Risk Overall and by Molecular Subtype among Vietnamese Women.

BACKGROUND: Evidence on associations between dietary intake and risk of breast cancer subtypes is limited and inconsistent. We evaluated associations of fruit, vegetable, meat, and fish consumption with risk of breast cancer overall and by molecular subtype in the Vietnamese Breast Cancer Study (VBCS). METHOD: VBCS includes 476 incident breast cancer cases and 454 age-matched controls. Dietary habits over the past 5 years were assessed by in-person interviews using a validated food frequency questionnaire. Associations of food groups with breast cancer were evaluated via logistic regression for overall and molecular subtype with adjustment for age, education, income, family history of cancer, menopausal status, body mass index, exercise, total energy intake, and other potential dietary confounders. Odds ratio (OR) was used to approximate relative risk. RESULTS: High fruit intake was inversely associated with breast cancer risk, with adjusted ORs [95% confidence intervals (CI)] of 0.67 (95% CI, 0.47-0.95) and 0.41 (95% CI, 0.27-0.61) for second and third tertiles versus first tertile, respectively (Ptrend < 0.001). This association was stronger for triple-negative than other subtypes (Pheterogeneity < 0.001). High intake of freshwater fish was inversely associated with overall breast cancer (ORT3vsT1 = 0.63; 95% CI, 0.42-0.95; Ptrend = 0.03). An inverse association was observed between HER2-enriched subtype and red and organ meat intake (ORT3vsT1 = 0.40; 95% CI, 0.17-0.93; Ptrend = 0.04; Pheterogeneity = 0.50). CONCLUSIONS: High intakes of fruit and freshwater fish were associated with reduced breast cancer risk; association for the former was stronger for triple-negative subtype. IMPACT: Our findings suggest high intakes of fruit and freshwater fish may reduce breast cancer risk among Vietnamese women.

HIV and STI prevalence and testing history among men who have sex with men in Hanoi, Vietnam.

BACKGROUND: HIV and other sexually transmitted infections (STIs) have disproportionately affected communities of men who have sex with men (MSM). We describe HIV and STI prevalence and testing patterns among urban Vietnamese MSM. METHODS: We conducted a cross-sectional community-based study of MSM in Hanoi, Vietnam in 2016. Participants self-reported experiences of social stigma in healthcare settings and previous HIV and STI testing. STI testing included HIV, herpes simplex virus-2 (HSV-2), syphilis, gonorrhea, and chlamydia. RESULTS: 205 MSM participated in the study. STI prevalence was HIV (10%), HSV-2 (4%), syphilis (13%), gonorrhea (34%), and chlamydia (19%). More than half (55%) of participants tested positive for at least one STI. Most participants had been previously tested for HIV or another STI (72%), with 24% previously receiving a positive result. Perceived and enacted social stigma in healthcare contexts was negatively associated with previous HIV or STI testing (adjusted prevalence odds ratio (aPOR): 0.22; 95% confidence interval (CI): 0.10-0.48). DISCUSSION: High prevalence of STIs was observed among Vietnamese MSM, and perceived and enacted stigma was related to HIV and STI testing. Our findings reaffirm the importance of regular STI screening among this population as well as additional outreach to promote safe HIV and STI healthcare engagement.

Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes.

Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low in vivo efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes in vivo. This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers. ZPPs mediated up to 39 500-fold higher protein expression than their parent cationic counterparts in vitro and enabled efficacious mRNA delivery selectively in spleen and lymph nodes following intravenous administration in vivo. This zwitterionic phospholipidation methodology provides a versatile and generalizable postmodification strategy to introduce zwitterions into the side chains of cationic polymers, extending the utility of cationic polymer families for precise mRNA delivery and demonstrating substantial potential for immunotherapeutic applications.