Clinical implementation of artificial-intelligence-assisted detection of breast cancer metastases in sentinel lymph nodes: the CONFIDENT-B single-center, non-randomized clinical trial.

Pathologists' assessment of sentinel lymph nodes (SNs) for breast cancer (BC) metastases is a treatment-guiding yet labor-intensive and costly task because of the performance of immunohistochemistry (IHC) in morphologically negative cases. This non-randomized, single-center clinical trial (International Standard Randomized Controlled Trial Number:14323711) assessed the efficacy of an artificial intelligence (AI)-assisted workflow for detecting BC metastases in SNs while maintaining diagnostic safety standards. From September 2022 to May 2023, 190 SN specimens were consecutively enrolled and allocated biweekly to the intervention arm (n = 100) or control arm (n = 90). In both arms, digital whole-slide images of hematoxylin-eosin sections of SN specimens were assessed by an expert pathologist, who was assisted by the 'Metastasis Detection' app (Visiopharm) in the intervention arm. Our primary endpoint showed a significantly reduced adjusted relative risk of IHC use (0.680, 95% confidence interval: 0.347-0.878) for AI-assisted pathologists, with subsequent cost savings of ~3,000 €. Secondary endpoints showed significant time reductions and up to 30% improved sensitivity for AI-assisted pathologists. This trial demonstrates the safety and potential for cost and time savings of AI assistance.

Binding of Per- and Polyfluoroalkyl Substances to ß-Lactoglobulin from Bovine Milk.

Per- and polyfluoroalkyl substances (PFAS) are known for their high environmental persistence and potential toxicity. The presence of PFAS has been reported in many dairy products. However, the mechanisms underlying the accumulation of PFAS in these products remain unclear. Here, we used native mass spectrometry and molecular dynamics simulations to probe the interactions between 19 PFAS of environmental concern and two isoforms of the major bovine whey protein ß-lactoglobulin (ß-LG). We observed that six of these PFAS bound to both protein isoforms with low- to mid-micromolar dissociation constants. Based on quantitative, competitive binding experiments with endogenous ligands, PFAS can bind orthosterically and preferentially to ß-LG's hydrophobic ligand-binding calyx. ß-Cyclodextrin can also suppress binding of PFAS to ß-LG owing to the ability of ß-cyclodextrin to directly sequester PFAS from solution. This research sheds light on PFAS-ß-LG binding, suggesting that such interactions could impact lipid-fatty acid transport in bovine mammary glands at high PFAS concentrations. Furthermore, our results highlight the potential use of ß-cyclodextrin in mitigating PFAS binding, providing insights toward the development of strategies to reduce PFAS accumulation in dairy products and other biological systems.

Clinical and Histological Response to Talimogene Laherparepvec Therapy in Advanced Melanoma: Impact on Overall Survival.

BACKGROUND: Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic herpesvirus therapy used for unresectable stage IIIB through IV metastatic melanoma. However, the correlation between clinical complete response (cCR) and pathologic complete response (pCR) in patients treated with T-VEC is understudied. STUDY DESIGN: We conducted a retrospective study from a prospectively maintained IRB-approved melanoma single-center database in patients treated with T-VEC from October 2015 to April 2022. Patients were categorized into 3 groups: cCR with pCR, cCR without pCR, and less than cCR. The primary endpoint was overall survival. We used descriptive statistics, chi-square tests, and Wilcoxon rank-sum tests to compare key covariates among exposure groups. We used survival analysis to compare survival curves and reported hazard ratio of death (95% CI) across exposure groups. RESULTS: We included 116 patients with a median overall survival (interquartile range) of 22.7 (14.8-39.3) months. The majority were men (69%) and White (97.4%), with a median age of 74.5 years. More than half of patients (n = 60, 51.6%) achieved cCR. Distribution among the groups was as follows: cCR with pCR (35.3%), cCR without pCR (16.3%), and less than cCR (48.4%). Median overall survival time (interquartile range) was 26.5 (18.6-36.0) months for cCR with pCR, 22.7 (14.4-35.5) months for cCR without pCR, and 17.8 (9.2-47.0) months for less than cCR (log-rank p value = 0.0033). CONCLUSIONS: Patients achieving cCR with pCR after T-VEC therapy have the most favorable overall survival outcomes, whereas those achieving cCR without pCR have inferior survival and those achieving less than cCR have the poorest overall survival outcomes. These findings emphasize the importance of histological confirmation and provide insights for optimizing T-VEC therapy in patients with advanced melanoma.

De Novo Design, Synthesis, and Mechanistic Evaluation of Short Peptides That Mimic Heat Shock Protein 27 Activity.

We report the first small molecule peptides based on the N-terminal sequence of heat shock protein 27 (Hsp27, gene HSPB1) that demonstrates chaperone-like activity. The peptide, comprising the SWDPF sequence located at Hsp27's amino (N)-terminal domain, directly regulates protein aggregation events, maintaining the disaggregated state of the model protein, citrate synthase. While traditional inhibitors of protein aggregation act via regulation of a protein that facilitates aggregation or disaggregation, our molecules are the first small peptides between 5 and 8 amino acids in length that are based on the N-terminus of Hsp27 and directly control protein aggregation. The presented strategy showcases a new approach for developing small peptides that control protein aggregation in proteins with high aggregate levels, making them a useful approach in developing new drugs.

Novel Recombinant Foot-and-Mouth Disease Virus Circulating in Vietnam.

We report the genome sequences of 12 recombinant foot-and-mouth disease virus isolates from Vietnam. The recombinant strain has a capsid region from an A/Sea-97 strain and a nonstructural segment from an O/ME-SA/PanAsia strain. The isolates were obtained from two outbreak samples collected in June 2017 and 10 subclinical samples collected between 2017 and 2019.

Foot-and-Mouth Disease Virus Serotype O/CATHAY Genome Sequences from Five Outbreaks in Vietnam, 2017 to 2019.

We report the genomes of five foot-and-mouth disease viruses (FMDVs) from distinct provinces in Vietnam. All five viruses were grouped within the O/CATHAY topotype. Sequences contain the full polyprotein coding sequence and partial untranslated regions. These genomes provide critical data on the spread and evolution of FMDVs in the region.

First Genome Sequence of Foot-and-Mouth Disease Virus Serotype O Sublineage Ind2001e from Southern Vietnam.

We report the polyprotein coding sequence of the newly defined Ind2001e sublineage of foot-and-mouth disease virus (FMDV) serotype O, isolated from a bovine epithelial tissue sample collected in 2017 in Kon Tum Province, Vietnam. This discovery updates FMDV diversity in Vietnam, has implications for FMDV epidemiology, and influences future vaccine selections.

Efficacy and safety of systemic treatments in psoriatic arthritis: a systematic review, meta-analysis and GRADE evaluation.

Twenty per cent of patients with plaque psoriasis also have psoriatic arthritis - a disease affecting joints and entheses. Different treatment options exist but currently no succinct systematic overview exists. A systematic review of approved systemic treatments for psoriatic arthritis was conducted. We systematically searched in three databases (last update September 2017). Data were extracted for ACR20/50, HAQ-DI, SF-36 and adverse/serious adverse events after 16-24 weeks. We assessed the quality of evidence using GRADE. Twenty trials were included. Three trials compared two active substances. Results for ACR20 were infliximab + methotrexate vs. methotrexate: RR 1.40 (95% CI 1.07-1.84) very low quality evidence; ixekizumab Q2W vs. adalimumab Q2W: RR 1.08 (95% CI 0.86-1.36) very low quality, leflunomide vs. methotrexate: RR 1.01, (95% CI 0.84-1.21) low quality. Eighteen drug vs. placebo comparisons were included. For ACR20/50, HAQ-DI and SF-36, the active treatment was efficacious and the quality of the evidence was mostly moderate to low (15 of 18 comparisons). The quality of evidence for (serious) adverse events was mostly low; differences were rare. In three placebo-controlled comparisons, leflunomide, MTX and sulfasalazine failed to show statistical superiority for ACR. Besides the established treatment of anti-TNF antibodies and ustekinumab for psoriatic arthritis, the newer treatment options of IL17 antibodies and apremilast are also effective for the treatment of psoriatic arthritis. Based on just one comparative trial and one drug each, the new class of anti-IL 17 antibodies appears to be equally effective as the group of anti-TNF antibodies; for apremilast, this is yet unclear.

First Detection and Genome Sequence of Senecavirus A in Vietnam.

In 2018, senecavirus A was detected for the first time in Vietnam. This report contains the first complete genome of a senecavirus A isolate collected from pigs in Kon Tum Province, Vietnam. This novel incursion has substantial implications for regional control of vesicular transboundary diseases.

Mid-term outcomes of routine proximal row carpectomy compared with proximal row carpectomy with dorsal capsular interposition arthroplasty for the treatment of late-stage arthropathy of the wrist.

AIMS: The aims of this study were to compare the mid-term outcomes of patients with late-stage arthritis of the wrist treated with proximal row carpectomy (PRC) and dorsal capsular interposition (DCI) arthroplasty with a matched cohort treated with routine PRC alone. PATIENTS AND METHODS: A total of 25 arthritic wrists (24 patients) with pre-existing degenerative changes of the proximal capitate and/or the lunate fossa of the radius were treated with PRC + DCI over a ten-year period. This group of patients were matched 1:2 with a group of 50 wrists (48 patients) without degenerative changes in the capitate or lunate fossa that were treated with a routine PRC alone during the same period. The mean age of the patients at the time of surgery was 56.8 years (25 to 81), and the demographics and baseline range of movement of the wrist, grip strength, Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, and Patient-Rated Wrist Evaluation (PRWE) score were similar in both groups. RESULTS: At a mean follow-up of 5.9 years (1.8 to 11.8), significant improvements in mean grip strength, the flexion-extension arc of movement of the wrist, QuickDASH, and PRWE scores were seen in both groups. There was no diifference between the groups for any of the outcomes. One patient in the PRC + DCI group required additional surgery for a deep infection, while two in the PRC group had complications (one wound dehiscence requiring revision closure, one transient radial sensory neuritis). One patient in each group required total arthrodesis of the wrist for progressive degenerative radiocarpal changes. A total of 70 patients (93%) were satisfied with the outcomes. CONCLUSION: PRC with DCI is an effective form of treatment for late-stage arthritis of the wrist involving the capitolunate joint, with mid-term outcomes that are similar to those in patients without degenerative changes affecting the capitate or lunate fossa who are treated with a routine PRC alone. Cite this article: Bone Joint J 2018;100-B:197-204.

Birefringence of flow-assembled chitosan membranes in microfluidics.

Biopolymer membrane assembly in microfluidics offers precise spatial and temporal resolution for biomolecular and cellular interactions during and after assembly. Control over molecular transport across the biofabricated membranes requires microstructural characterization. This study investigates, for the first time, the birefringence of chitosan membranes assembled with flow in a microfluidic environment, and the effects of pH and flow rate on the membrane's micro-alignment. The optical anisotropy of the formed membranes was quantified using a de Sénarmont compensator for transmitted quantitative polarized light microscopy. The chitosan membranes were biofabricated within a small aperture in a microfluidic network with various flow and pH conditions of chitosan and alginate solutions. The measured optical retardance and parallelism index clearly indicate that the microstructure of the flow-assembled membrane was well organized and aligned along the direction of chitosan flow. Optical retardance increased significantly with the pH of the alginate solution, but was less sensitive to the variation of the flow rates of the polymer solutions during the biofabrication process. It was also determined that the birefringence signal dropped significantly across the membrane growth direction regardless of the molecular density in the membrane. The mechanism of the micro-alignment was discussed, which was presumably due to the molecular un-wrapping by shear flow. We envision that the current study paves a path to further understand and actively manipulate the microstructure of flow-assembled membranes for broad lab-on-a-chip applications.

First detection of foot-and-mouth disease virus O/Ind-2001d in Vietnam.

In recent years, foot-and-mouth disease virus (FMDV) serotype O, topotype Middle East-South Asia (ME-SA), lineage Ind-2001d has spread from the Indian subcontinent to the Middle East, North Africa, and Southeast Asia. In the current report, we describe the first detection of this lineage in Vietnam in May, 2015 in Dak Nông province. Three subsequent outbreaks caused by genetically related viruses occurred between May-October, 2015 after which the virus was not detected in clinical outbreaks for at least 15 subsequent months. The observed outbreaks affected (in chronological order): cattle in Dak Nông province, pigs in Dak Lak province and Dak Nông province, and cattle in Ninh Thuan province. The clinical syndromes associated with these outbreaks were consistent with typical FMD in the affected species. Overall attack rate on affected premises was 0.85 in pigs and 0.93 in cattle over the course of the outbreak. Amongst 378 pigs at risk on affected premises, 85 pigs died during the outbreaks; there were no deaths among cattle. The manner in which FMDV/O/ME-SA/Ind-2001d was introduced into Vietnam remains undetermined; however, movement of live cattle is the suspected route. This incursion has substantial implications for epidemiology and control of FMD in Southeast Asia.

Genome Sequence of Foot-and-Mouth Disease Virus Serotype O Lineage Ind-2001d Collected in Vietnam in 2015.

In 2015, foot-and-mouth disease (FMD) virus lineage Ind-2001 was detected for the first time in Southeast Asia. This report contains the first near-complete genome sequence of a viral isolate from this lineage collected from an outbreak in Vietnam. This novel incursion has substantial implications for regional FMD control measures.

Development and use of an Arctic charr cell line to study antiviral responses at extremely low temperatures.

Arctic charr (Salvelinus alpinus) are the northernmost distributed freshwater fish and can grow at water temperatures as low as 0.2 °C. Other teleost species have impaired immune function at temperatures that Arctic charr thrive in, and thus, charr may maintain immune function at these temperatures. In this study, a fibroblastic cell line, named ACBA, derived from the bulbus arteriosus (BA) of Arctic charr was developed for use in immune studies at various temperatures. ACBA has undergone more than forty passages at 18 °C over 3 years, while showing no signs of senescence-associated ß-galactosidase activity and producing nitric oxide. Remarkably, ACBA cells survived and maintained some mitotic activity even at 1 °C for over 3 months. At these low temperatures, ACBA also continued to produce MH class I proteins. After challenge with poly I:C, only antiviral Mx proteins were induced while MH proteins remained constant. When exposed to live viruses, ACBA was shown to permit viral infection and replication of IPNV, VHSV IVa and CSV at 14 °C. Yet at the preferred temperature of 4 °C, only VHSV IVa was shown to replicate within ACBA. This study provides evidence that Arctic charr cells can maintain immune function while also resisting infection with intracellular pathogens at low temperatures.

Early introduction of palliative care and advanced care planning for children with complex chronic medical conditions: a pilot study.

BACKGROUND: Children with complex chronic medical conditions benefit from early introduction of palliative care services and advanced care planning for symptom management and to support quality of life and medical decision-making. This study evaluated whether introducing palliative care during primary care appointments (1) was feasible; (2) increased access and improved knowledge of palliative care; and (3) facilitated advanced care planning. METHODS: Pilot study of a multi-modal intervention including targeted education for primary care providers (PCPs), an informational packet for families and presence of a palliative care team member in the outpatient clinic. PCPs completed pre- and post-surveys assessing experience, knowledge and comfort with palliative care. Enrolled families received an information packet; a subset also met a palliative care team member. All families were encouraged to make an appointment with the palliative care team, during which the team assessed palliative care needs and goals of care. Upon study completion, the investigators assessed family and PCP satisfaction and collected feedback on project feasibility. RESULTS: Twenty families were enrolled and received the information packet; 15 met a palliative care team member. Of the 17 participating families who were reached and completed a post-study survey, 11 families had never heard of palliative care and 13 were unaware that the palliative care team existed. Most families perceived palliative care information as 'very helpful' and 'very important'. All would recommend palliative care team services to others. Nine families followed up with the palliative care team, but none was prepared to complete an advanced care plan. PCPs reported lack of training in communicating bad news and conducting goals of care discussions. However, they felt increasingly comfortable introducing palliative care to families and supported program continuation. CONCLUSIONS: Initiating palliative care services in the outpatient primary care setting is logistically challenging but increases access to palliative care for children with complex chronic medical conditions and improves palliative care knowledge and comfort for PCPs.

Temporary protection of rainbow trout gill epithelial cells from infection with viral haemorrhagic septicaemia virus IVb.

The branchial epithelium is not only a primary route of entry for viral pathogens, but is also a site of viral replication and subsequent shedding may also occur from the gill epithelium. This study investigated the potential of agents known to stimulate innate immunity to protect rainbow trout epithelial cells (RTgill-W1) from infection with VHSV IVb. RTgill-W1 cells were pretreated with poly I:C, FuGENE(®) HD + poly I:C, lipopolysaccharide (LPS), LPS + poly I:C or heat-killed VHSV IVb and then infected with VHSV IVb 4 days later. Cytopathic effect (CPE) was determined at 2, 3, 4, 7 and 11 days post-infection. Virus in cells and supernatant was detected using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All of the treatments delayed the onset of CPE (per cent of monolayer destruction), compared with untreated controls; however, killed VHSV or poly I:C combined with LPS was the most effective. Similarly, the detection of viral RNA in the supernatant was delayed, and the quantity was significantly (P < 0.05) reduced by all treatments with the exception of LPS alone (4 days). Unlike many of the other treatments, pretreatment of RTgill-W1 with heat-killed VHSV did not upregulate interferon 1, 2 or MX 1 gene expression.

Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis.

BACKGROUND: Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization. RESULTS: A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08). CONCLUSIONS: Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.).

Localised impedance monitoring device for the remote clinical assessment of home-based dialysis patients.

BioImpedance Spectroscopy (BIS) has been clinically used to determine the hydrational status of patients undergoing haemodialysis (HD). In the present project we are developing a calf-localised, integrated impedimetric device to periodically and conveniently measure and transmit information on the hydrational status of home-based patients to a remote clinic. Surprisingly, we have found that simple postural changes before or during measurement lead to significant fluid shifts in the lower leg that are as important and as long lasting as the effects of haemodialysis. These must be taken into account if potentially hazardous errors are not to be made in assessing a patient's hydrational status.

Use of cell lines and primary cultures to explore the capacity of rainbow trout to be a host for frog virus 3 (FV3).

The capacity of rainbow trout, Oncorhynchus mykiss, to be a host for frog virus 3 (FV3) was evaluated at the cellular level. Cell cultures from this species were tested for their ability to express FV3 major capsid protein (MCP) gene, to develop cytopathic effect (CPE), and to produce FV3. After FV3 addition, MCP transcripts were detected in six of six cell lines and in primary macrophage cultures. CPE developed in all cell culture systems, except primary lymphocytes. For the macrophage cell line, RTS11, and primary macrophages, cell death was by apoptosis because DNA laddering and Annexin staining were detected. By contrast, markers of apoptosis did not accompany CPE in three epithelial cell lines from the gill (RTgill-W1), intestine (RTgut-GC), and liver (RTL-W1) and in two fibroblast cell lines from gonads (RTG-2) and skin (RTHDF). Therefore, FV3 was able to enter and begin replicating in several cell types. Yet, FV3 was produced in only two cell lines, RTG-2 and RTL-W1, and only modestly. Overall, these results suggest that if tissue accessibility were possible, FV3 would have the capacity to induce injury, but the ability to replicate would be limited, likely making rainbow trout a poor host for FV3.