Responsive Versus Continuous Deep Brain Stimulation for Speech in Essential Tremor: A Pilot Study.

BACKGROUND: Responsive deep brain stimulation (rDBS) uses physiological signals to deliver stimulation when needed. rDBS is hypothesized to reduce stimulation-induced speech effects associated with continuous DBS (cDBS) in patients with essential tremor (ET). OBJECTIVE: To determine if rDBS reduces cDBS speech-related side effects while maintaining tremor suppression. METHODS: Eight ET participants with thalamic DBS underwent unilateral rDBS. Both speech evaluations and tremor severity were assessed across three conditions (DBS OFF, cDBS ON, and rDBS ON). Speech was analyzed using intelligibility ratings. Tremor severity was scored using the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: During unilateral cDBS, participants experienced reduced speech intelligibility (P = 0.025) compared to DBS OFF. rDBS was not associated with a deterioration of intelligibility. Both rDBS (P = 0.026) and cDBS (P = 0.038) improved the contralateral TRS score compared to DBS OFF. CONCLUSIONS: rDBS maintained speech intelligibility without loss of tremor suppression. A larger prospective chronic study of rDBS in ET is justified. © 2024 International Parkinson and Movement Disorder Society.

Abatacept increases T cell exhaustion in early RA individuals who carry HLA risk alleles.

Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGIT+KLRG1+ TEX with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGIT+KLRG1+ TEX is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGIT+KLRG1+ CD8 TEX population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive in vitro, together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells. In HC and RA subjects, lower levels of EOMES transcriptional modules and frequency of TIGIT+KLRG1+ TEX were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and cytomegalovirus (CMV) seropositivity. Moreover, the frequency of TIGIT+KLRG1+ TEX was significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig). The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of TEX may be more effective in DR4 subjects and TEX may be indirectly influenced by cellular interactions that are blocked by abatacept.

A morphological review of medial malleolar fractures - A large single centre series.

BACKGROUND: Many approaches to management of medial malleolar fractures are described in the literature however, their morphology is under investigated. The aim of this study was to analyse the morphology of medial malleolar fractures to identify any association with medial malleolar fracture non-union or malunion. METHODS: Patients who had undergone surgical fixation of their MMF were identified from 2012 to 2022, using electronic patient records. Retrospective analysis of their preoperative, intraoperative, and postoperative radiographs was performed to determine their morphology and prevalence of non-union and malunion. Lauge-Hansen classification was used to characterise ankle fracture morphology and Herscovici classification to characterise MMF morphology. RESULTS: A total of 650 patients were identified across a 10-year period which could be included in the study. The overall non-union rate for our cohort was 18.77% (122/650). The overall malunion rate was 6.92% (45/650). Herscovici type A fractures were significantly more frequently mal-reduced at time of surgery as compared to other fracture types (p = .003). Medial wall blowout combined with Hercovici type B fractures showed a significant increase in malunion rate. There is a higher rate of bone union in patients who had been anatomically reduced. CONCLUSION: The morphology of medial malleolar fractures does have an impact of the radiological outcome following surgical management. Medial wall blowout fractures were most prevalent in adduction-type injuries; however, it should not be ruled out in rotational injuries with medial wall blowouts combined with and Herscovici type B fractures showing a significant increase in malunions. Herscovici type A fractures had significantly higher malreductions. LEVEL OF EVIDENCE: Level 3 - Retrospective Cohort Study.

Use of the Pfizer Respiratory Syncytial Virus Vaccine During Pregnancy for the Prevention of Respiratory Syncytial Virus-Associated Lower Respiratory Tract Disease in Infants: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among U.S. infants. Nirsevimab (Bevfortus, Sanofi and AstraZeneca) is recommended to prevent RSV-associated lower respiratory tract infection (LRTI) in infants. In August 2023, the Food and Drug Administration (FDA) approved RSVpreF vaccine (Abrysvo, Pfizer Inc.) for pregnant persons as a single dose during 32-36 completed gestational weeks (i.e., 32 weeks and zero days' through 36 weeks and 6 days' gestation) to prevent RSV-associated lower respiratory tract disease in infants aged <6 months. Since October 2021, CDC's Advisory Committee on Immunization Practices (ACIP) RSV Vaccines Pediatric/Maternal Work Group has reviewed RSV epidemiology and evidence regarding safety, efficacy, and potential economic impact of pediatric and maternal RSV prevention products, including RSVpreF vaccine. On September 22, 2023, ACIP and CDC recommended RSVpreF vaccine using seasonal administration (i.e., during September through end of January in most of the continental United States) for pregnant persons as a one-time dose at 32-36 weeks' gestation for prevention of RSV-associated LRTI in infants aged <6 months. Either maternal RSVpreF vaccination during pregnancy or nirsevimab administration to the infant is recommended to prevent RSV-associated LRTI among infants, but both are not needed for most infants. All infants should be protected against RSV-associated LRTI through use of one of these products.

Use of Respiratory Syncytial Virus Vaccines in Older Adults: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.

Respiratory syncytial virus (RSV) is a cause of severe respiratory illness in older adults. In May 2023, the Food and Drug Administration approved the first vaccines for prevention of RSV-associated lower respiratory tract disease in adults aged ≥60 years. Since May 2022, the Advisory Committee on Immunization Practices (ACIP) Respiratory Syncytial Virus Vaccines Adult Work Group met at least monthly to review available evidence regarding the safety, immunogenicity, and efficacy of these vaccines among adults aged ≥60 years. On June 21, 2023, ACIP voted to recommend that adults aged ≥60 years may receive a single dose of an RSV vaccine, using shared clinical decision-making. This report summarizes the body of evidence considered for this recommendation and provides clinical guidance for the use of RSV vaccines in adults aged ≥60 years. RSV vaccines have demonstrated moderate to high efficacy in preventing RSV-associated lower respiratory tract disease and have the potential to prevent substantial morbidity and mortality among older adults; postmarketing surveillance will direct future guidance.

Pneumococcal Vaccine for Adults Aged ≥19 Years: Recommendations of the Advisory Committee on Immunization Practices, United States, 2023

his report compiles and summarizes all published recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) for use of pneumococcal vaccines in adults aged ≥19 years in the United States. This report also includes updated and new clinical guidance for implementation from CDC. Before 2021, ACIP recommended 23-valent pneumococcal polysaccharide vaccine (PPSV23) alone (up to 2 doses), or both a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) in combination with 1­3 doses of PPSV23 in series (PCV13 followed by PPSV23), for use in U.S. adults depending on age and underlying risk for pneumococcal disease. In 2021, two new pneumococcal conjugate vaccines (PCVs), a 15-valent and a 20-valent PCV (PCV15 and PCV20), were licensed for use in U.S. adults aged ≥18 years by the Food and Drug Administration. ACIP recommendations specify the use of either PCV20 alone or PCV15 in series with PPSV23 for all adults aged ≥65 years and for adults aged 19­64 years with certain underlying medical conditions or other risk factors who have not received a PCV or whose vaccination history is unknown. In addition, ACIP recommends use of either a single dose of PCV20 or ≥1 dose of PPSV23 for adults who have started their pneumococcal vaccine series with PCV13 but have not received all recommended PPSV23 doses. Shared clinical decision-making is recommended regarding use of a supplemental PCV20 dose for adults aged ≥65 years who have completed their recommended vaccine series with both PCV13 and PPSV23. Updated and new clinical guidance for implementation from CDC includes the recommendation for use of PCV15 or PCV20 for adults who have received PPSV23 but have not received any PCV dose. The report also includes clinical guidance for adults who have received 7-valent PCV (PCV7) only and adults who are hematopoietic stem cell transplant recipients.

Use of Nirsevimab for the Prevention of Respiratory Syncytial Virus Disease Among Infants and Young Children: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among U.S. infants. In July 2023, the Food and Drug Administration approved nirsevimab, a long-acting monoclonal antibody, for passive immunization to prevent RSV-associated lower respiratory tract infection among infants and young children. Since October 2021, the Advisory Committee on Immunization Practices (ACIP) Maternal and Pediatric RSV Work Group has reviewed evidence on the safety and efficacy of nirsevimab among infants and young children. On August 3, 2023, ACIP recommended nirsevimab for all infants aged <8 months who are born during or entering their first RSV season and for infants and children aged 8-19 months who are at increased risk for severe RSV disease and are entering their second RSV season. On the basis of pre-COVID-19 pandemic patterns, nirsevimab could be administered in most of the continental United States from October through the end of March. Nirsevimab can prevent severe RSV disease among infants and young children at increased risk for severe RSV disease.

Use of Respiratory Syncytial Virus Vaccines in Older Adults: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.

Respiratory syncytial virus (RSV) is a cause of severe respiratory illness in older adults. In May 2023, the Food and Drug Administration approved the first vaccines for prevention of RSV-associated lower respiratory tract disease in adults aged ≥60 years. Since May 2022, the Advisory Committee on Immunization Practices (ACIP) Respiratory Syncytial Virus Vaccines Adult Work Group met at least monthly to review available evidence regarding the safety, immunogenicity, and efficacy of these vaccines among adults aged ≥60 years. On June 21, 2023, ACIP voted to recommend that adults aged ≥60 years may receive a single dose of an RSV vaccine, using shared clinical decision-making. This report summarizes the body of evidence considered for this recommendation and provides clinical guidance for the use of RSV vaccines in adults aged ≥60 years. RSV vaccines have demonstrated moderate to high efficacy in preventing RSV-associated lower respiratory tract disease and have the potential to prevent substantial morbidity and mortality among older adults; postmarketing surveillance will direct future guidance.

Pan-cancer evaluation of clinical value of mitotic network activity index (MNAI) and its predictive value for immunotherapy.

Increased mitotic activity is associated with the genesis and aggressiveness of many cancers. To assess the clinical value of mitotic activity as prognostic biomarker, we performed a pan-cancer study on the mitotic network activity index (MNAI) constructed based on 54-gene mitotic apparatus network. Our pan-cancer assessment on TCGA (33 tumor types, 10,061 patients) and validation on other publicly available cohorts (23 tumor types, 9,209 patients) confirmed the significant association of MNAI with overall survival, progression-free survival, and other prognostic endpoints in multiple cancer types, including lower-grade gliomas (LGG), breast invasive carcinoma (BRCA), as well as many others. We also showed significant association between MNAI and genetic instability, which provides a biological explanation of its prognostic impact at pan-cancer landscape. Our association analysis revealed that patients with high MNAI benefitted more from anti-PD-1 and Anti-CTLA-4 treatment. In addition, we demonstrated that multimodal integration of MNAI and the AI-empowered Cellular Morphometric Subtypes (CMS) significantly improved the predictive power of prognosis compared to using MNAI and CMS alone. Our results suggest that MNAI can be used as a potential prognostic biomarker for different tumor types toward different clinical endpoints, and multimodal integration of MNAI and CMS exceeds individual biomarker for precision prognosis.

Facilitators and Barriers of Human Milk Donation.

PURPOSE: The purpose of this study is to examine perceptions and experiences of women who donate human milk and highlight various aspects of the breast milk donation process. STUDY DESIGN: A cross-sectional descriptive study. METHODS: An online survey was conducted with a convenience sample of women who donated milk at several milk banks in the United States. A questionnaire of 36 closed and open-ended items were developed and validated by the research team. Descriptive statistics and content analysis were used. Semantic content analysis involved three procedures: coding, categorizing text units, and refining the identified themes. RESULTS: A total of 236 women who donated breast milk completed the questionnaire. Mean age of participants was 32.7±4.27 and 89.40% were non-Hispanic White women with a bachelor's degree (32.20%) or graduate degree (54.70%). Most participants were women who actively donated breast milk, ranging from one to four times. Two themes, facilitators and barriers of milk donation, were identified. Facilitators to milk donation included attitudes toward milk donation, commitment for donating, motivation in donating, and support. Barriers included personal factors, environment, milk donor process, and psychosocial factors. CLINICAL IMPLICATIONS: Nurses, health care providers, and lactation professionals should educate women about milk donation resources and opportunities. Strategies to increase awareness about milk donation among underrepresented groups such as women of color are highly recommended. Future research is needed to further explore specific factors that increase milk donation awareness and minimize barriers to potential donors.

Western Australian women's expectations for expanded NIPT-An online survey regarding NIPT for single gene, recessive and chromosomal conditions.

Prenatal screening has evolved rapidly following the introduction of non-invasive prenatal testing (NIPT), with screening now available for an increasing number of conditions. We explored the attitudes and expectations of women within the context of using NIPT to detect multiple different single gene and chromosome conditions during pregnancy. An online survey was used to assess these issues with a sample of 219 women from Western Australia. In our study, the majority of women (96%) support of the concept of expanded NIPT for single gene and chromosome conditions provided the test involves no risk to the pregnancy and can provide the parents with relevant medical information about the fetus at any stage of pregnancy. 80% believed that expanded NIPT for single gene and chromosome conditions should be available at any stage during pregnancy and 68% of women indicated that test cost would be a factor in determining their participation in testing. Under half (43%) of the women favored an option to terminate a pregnancy at any stage if the fetus had a medical condition that would interfere with day to day functioning. The majority (78%) of women believed that testing for multiple genetic conditions would provide reassurance and lead to the delivery of a healthy child.

Guide to diagnosing and managing skin diseases in horses.

Reviewed by Sarah Long, lecturer in veterinary dermatology at Bristol vet school.

Characterization of the mechanism of bile salt hydrolase substrate specificity by experimental and computational analyses.

Bile salt hydrolases (BSHs) are currently being investigated as target enzymes for metabolic regulators in humans and as growth promoters in farm animals. Understanding structural features underlying substrate specificity is necessary for inhibitor design. Here, we used a multidisciplinary workflow including mass spectrometry, mutagenesis, molecular dynamic simulations, machine learning, and crystallography to demonstrate substrate specificity in Lactobacillus salivarius BSH, the most abundant enzyme in human and farm animal intestines. We show the preference of substrates with a taurine head and a dehydroxylated sterol ring for hydrolysis. A regression model that correlates the relative rates of hydrolysis of various substrates in various enzyme mutants with the residue-substrate interaction energies guided the identification of structural determinants of substrate binding and specificity. In addition, we found T208 from another BSH protomer regulating the hydrolysis. The designed workflow can be used for fast and comprehensive characterization of enzymes with a broad range of substrates.

Identification and classification of pathology and artifacts for human intracranial cognitive research.

Intracranial electroencephalography (iEEG) presents a unique opportunity to extend human neuroscientific understanding. However, typically iEEG is collected from patients diagnosed with focal drug-resistant epilepsy (DRE) and contains transient bursts of pathological activity. This activity disrupts performances on cognitive tasks and can distort findings from human neurophysiology studies. In addition to manual marking by a trained expert, numerous IED detectors have been developed to identify these pathological events. Even so, the versatility and usefulness of these detectors is limited by training on small datasets, incomplete performance metrics, and lack of generalizability to iEEG. Here, we employed a large annotated public iEEG dataset from two institutions to train a random forest classifier (RFC) to distinguish data segments as either 'non-cerebral artifact' (n = 73,902), 'pathological activity' (n = 67,797), or 'physiological activity' (n = 151,290). We found our model performed with an accuracy of 0.941, specificity of 0.950, sensitivity of 0.908, precision of 0.911, and F1 score of 0.910, averaged across all three event types. We extended the generalizability of our model to continuous bipolar data collected in a task-state at a different institution with a lower sampling rate and found our model performed with an accuracy of 0.789, specificity of 0.806, and sensitivity of 0.742, averaged across all three event types. Additionally, we created a custom graphical user interface to implement our classifier and enhance usability.

WAGR, Sex Reversal, Bilateral Gonadoblastomas, and Intralobar Nephrogenic Rests: Uncertainties of Pre-Biopsy Chemotherapy in a High Risk Syndrome for Nephroblastoma.

Background: WT1 deletions are associated with nephroblastomas, WT mutations are associated with 46, XY sex reversal. It is unclear why only a few WT1 deletions are associated with sex reversal. Case report. This 46, XY female had a 15.2 MB interstitial deletion of 11p14.1p11.2, which included WT1 and FSHB. No pathogenic abnormalities were identified in 156 other genes associated with disorders of sexual development. Bilateral gonadoblastomas were incidentally diagnosed at 17 months of age at the time of prophylactic gonadectomies. She was treated without biopsy for bilateral nephroblastomas radiologically identified at 18 months of age. Bilateral partial nephrectomies contained treated intralobular nephrogenic rests. Conclusion: It is unclear why WT1 deletions are less associated with 46, XY sex reversal than WT1 mutations. Treating suspected nephroblastomas without biopsy, even in patients with syndromes associated with bilateral nephroblastomas, may still lead to diagnostic and therapeutic uncertainties.