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Identifying governing equations from observational data is crucial for understanding nonlinear physical systems but remains challenging due to the risk of overfitting. Here we introduce the Bi-Level Identification of Equations (BILLIE) framework, which simultaneously discovers and validates equations using a hierarchical optimization strategy. The policy gradient algorithm of reinforcement learning is leveraged to achieve the bi-level optimization. We demonstrate BILLIE's superior performance through comparisons with baseline methods in canonical nonlinear systems such as turbulent flows and three-body systems. Furthermore, we apply the BILLIE framework to discover RNA and protein velocity equations directly from single-cell sequencing data. The equations identified by BILLIE outperform empirical models in predicting cellular differentiation states, underscoring BILLIE's potential to reveal fundamental physical laws across a wide range of scientific fields.

The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD). However, the extent of rostrocaudal degeneration across clinicopathologic heterogeneity remains underexplored in AD. Using digital pathology, we quantified LC neuronal density and area at three neuroanatomic levels in a large AD series. Analysis of neuropathologic AD subtypes revealed greater middle LC vulnerability in hippocampal sparing AD compared to typical and limbic predominant AD. Regression analyses identified distinct predictor variables associated with the degeneration of rostral and middle LC. Age at onset predicted 24% of the variability in rostral LC neuronal density, whereas Braak stage, brain weight, Lewy body disease, and age at onset accounted for 15% of the variability in middle LC. Analyses of clinical presentations revealed lower rostral LC neuronal density in non-amnestic compared to amnestic AD cases. These insights demonstrate greater LC degeneration in atypical clinicopathologic forms of AD, including hippocampal sparing, young-onset, and non-amnestic presentations.

Autosomal dominant polycystic kidney disease has some effects on cholesterol metabolism and cardiovascular disease that are shared with other chronic kidney diseases and others that are distinctive and directly caused by disruption of polycystins. The pravastatin clinical trial by Gitomer et al. does not support treatment with statins for the only purpose of delaying disease progression. Emergence of novel lipid-lowering therapies presents new therapeutic opportunities but also risks. Recent studies suggest that cholesterol is important for traffic to and function of polycystins in primary cilia.

Surgery is often the only therapeutic option for the management of fibrotic Crohn's disease (FCD). Exclusive Enteral Nutrition (EEN), a nutritionally complete liquid formula, is an effective, safe, short-term treatment for Crohn's Disease. No cases were found internationally of adults with FCD on long-term EEN. We report on clinical outcomes and self-reported quality of life (QoL) after longer-term EEN provision in a patient with complex FCD. "Billie", a 54-year-old female, was admitted with ileal FCD diagnosed in 1985. Previous treatments were unsuccessful, including multiple bowel resections. Billie was chronically bedbound with pain and depression. CDAI (Crohn's disease activity index) score was 640 (<150) with &#x223c;3-20 liquid stools/day, and recurrent partial bowel obstructions. Radiological findings were so severe surgeons reluctantly considered surgery but "one more resection will result in short bowel syndrome". Billie trialled EEN given her QoL was "non-existent". Unable to tolerate the taste, EEN was administered via nasogastric tube. After two months, EEN was administered ongoing via percutaneous endoscopic gastrostomy given patient preference and dietetic advocacy. After eight weeks on EEN, Billie's pain predominantly resolved, with bowel motions of &#x223c;1-2/day, and nil bowel obstructions. Twelve months after EEN commencement, Billie's CDAI was 52, with 'no indication for surgical intervention' and was self-reporting that "life is good". After 18 months, Billie remains asymptomatic, and in clinical remission. This unique case is a wonderful example of dietetic advocacy and showcases the positive impact long-term EEN may have on surgical avoidance, clinical outcomes and self-reported QoL.

A novel quitline intervention (counseling plus provision of alternative forms of nicotine) was developed for people using a smoke-free, alcohol and other drug (AOD) withdrawal service. The objectives were: to code the intervention manual for behavior change techniques (BCTs) and to evaluate bespoke training, delivery of counseling provided (quality, number of BCTs) and acceptability. The manual was coded for 29 BCTs. Training outcomes were measured by counselor self-reported confidence. Delivery of counseling was analyzed by independent rating of the quality (maximum 100, all components delivered) and number of BCTs used in all recorded calls (n&#xa0;=&#xa0;71) for randomly selected clients (n&#xa0;=&#xa0;30). Acceptability was measured by uptake, clients' acceptability item ratings (n&#xa0;=&#xa0;37) and recall of counseling content (n&#xa0;=&#xa0;38) at six weeks post-baseline. Coding of the manual identified 25/29 BCTs. Counselor (n&#xa0;=&#xa0;10) self-reported confidence increased post-training (p&#xa0;=&#xa0;0.03). High quality calls were delivered with a mean rating of 82.0 (SD13.16) and a mean of 8.50 (SD3.10) BCTs delivered per call. The BCTs assessment, pharmacological support and advising distraction were used frequently. Acceptability of counseling was good, with high uptake (77%; 68/88 clients contacted), counselors were rated as supportive (92%; 34/37), the majority of clients felt encouraged (87%; 32/37) and recalled counseling content for pharmacotherapy (79%; 30/38) and how to manage cravings (76%, 29/38). A novel quitline intervention for residents of smoke-free, AOD withdrawal unit was delivered with high quality, had high acceptability, offered continuity of care pre- to post-discharge and facilitated tobacco cessation. Content of skills training to manage cravings, commenced in residence, was recalled by recipients post-discharge to sustain tobacco abstinence.

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Although whale-watching tourism makes it easier for humans to learn about these animals in the wild, interactions with boats can trigger temporary or even permanent behavioural changes in their populations. In this work we studied the potential effect of boats on the welfare of common dolphins, Delphinus delphis, a protected species in the Mediterranean, as well as a female bottlenose dolphin (Billie-Tursiops truncatus) that coexists with them in the bay of Algeciras-Gibraltar (BA-G), Southern Spain and that gave birth to the first known hybrid between both species in the wild. First, the reaction of the animals (Approach, Elusive and Indifference) to the presence of boats was observed. Subsequently, we have classified the sightings into four situations: Control (C) and Impact (I) with Regulated (RS) and Unregulated (US) sightings. In each situation, six behavioural states were distinguished: Feeding (F), Resting (R), Milling (M), Socialising (S), Travelling (T) and Diving (D). It was concluded that the presence of boats and non-compliance with the protocol for approaching cetaceans were the main causes of the behavioural transitions and that they led to an absorbing D state in the Markov chains. The results showed that the feeding and resting behaviours of the dolphins were significantly altered. Possible alteration of these behaviours may have negative effects on the animals. Our results are further evidence of the need to regulate and monitor vessel activities to protect common dolphins in BA-G, a critical area for this species, which still lacks specific conservation plans.

ADPKD-IFT140 is the third most common disease-causing variant in autosomal dominant polycystic kidney disease (ADPKD) after ADPKD-PKD1 and ADPKD-PKD2. This study aimed to characterize the clinical presentation, progression, and distinctive imaging phenotype of ADPKD-IFT140. This retrospective cohort study included patients with disease-causing variants in IFT140, nontruncating PKD1 (PKD1NT), or PKD2. Patients were matched by sex (48.1% male), age (mean [SD]: 57.7 &#xb1; 13.3 years), and height-adjusted total kidney volume (TKV; htTKV) (median [Q1-Q3]: 572.9 [314.1-1137.9] ml/m). Two predictive models were developed in the development cohort (n = 81): a deep-learning model incorporating cyst-parenchymal surface area (CPSA) and cystic index, and a practical model using percentage of TKVellipsoid occupied by the 2 largest cysts, with cyst volumes estimated from cyst diameters using the formula V = &#x3c0; 6 ( d 1 3 + d 2 3 ) . Models were validated in an internal specificity cohort (n = 569) and an external sensitivity cohort (n = 36). Patients with ADPKD-IFT140 exhibited fewer (median cyst number: 42) but larger cysts (average cyst volume: 12.1 ml), with 88.9% having no liver cysts, compared with ADPKD-PKD1NT and ADPKD-PKD2. The estimated glomerular filtration rate (eGFR) of decline was slower in ADPKD-IFT140 (-0.69 ml/min per 1.73 m2/yr) than in ADPKD-PKD1NT (-1.62, P = 0.006) and in ADPKD-PKD2 (-0.90, P = 0.737). The deep-learning model demonstrated an area-under-the-curve (AUC) of 0.949 for distinguishing ADPKD-IFT140 patients in the development cohort, and 88.9% specificity in the internal cohort. A volume-to-TKV ratio &#x2265; 18.6% identified ADPKD-IFT140 with an AUC of 0.814 and demonstrated 72.2% sensitivity in the external cohort. We provide a detailed characterization of the ADPKD-IFT140 phenotype that can be distinguished using a practical or deep-learning segmentation model applicable in diverse clinical settings.

Motor-vehicle crash (MVC) deaths increased by a record 10% from 2020 to 2021 in the United States and disproportionately impacted persons of certain racial/ethnic groups. Mortality data from the National Vital Statistics System was used to describe MVC death rate trends during 2019-2022 by six racial/ethnic groups: non-Hispanic (NH) American Indian or Alaska Native (AIAN), NH Asian, NH Black, NH Native Hawaiian or Other Pacific Islander (NHOPI), NH White, and Hispanic. Age-adjusted death rates per 100,000 population, 95% confidence intervals (CIs), and annual percent change in rates were calculated. Overall MVC death rates increased during 2019-2022, and rates were highest among NH AIAN and NH Black persons across all years. During 2019-2020, death rates increased the most among NH Black persons (+26.0%). During 2020-2021, rates increased among all racial/ethnic groups, with the greatest increase among NH NHOPI persons (+66.7%) and NH AIAN persons (+27.8%). These findings highlight stark differences by racial/ethnic group in MVC death rates and changes in these rates. Between 2019 and 2022, NH AIAN, NH Black, and NH NHOPI populations experienced the largest increases in MVC death rates, although there was large variation in rates and trends. Widespread adoption of a comprehensive suite of prevention strategies, such as the Safe System approach, while targeting subpopulations with the greatest burden of MVC deaths could reduce these differences and the overall burden of MVCs. These findings show which subpopulations could experience the greatest impacts from transportation safety investments in reducing overall MVC death rates in the United States.

Vasopressin plays a major role in the pathogenesis of autosomal dominant polycystic kidney disease (PKD), the fourth leading cause of end-stage kidney disease. The vasopressin V2 receptor (V2R) antagonist tolvaptan is the only approved treatment. The role of vasopressin V1a and V1b receptors (V1aR and V1bR) has not been studied. Pkd1RC/RC mice were allocated to control and 5 experimental groups treated with tolvaptan, OPC21268 (V1aR antagonist), SSR149415 (V1bR antagonist), tolvaptan plus OPC21268, or tolvaptan plus SSR149415, from 4 to 16 wk of age, to compare their separate effects on PKD and to determine whether addition of OPC21268 or SSR149415 potentiates or hinders the therapeutic effect of tolvaptan. Tolvaptan significantly reduced total kidney volume (TKV) measured by MRI and rate of TKV growth. OPC21268 had no effect on PKD when administered alone. SSR149415 reduced TKV and TKV growth in female mice only. The sex-dependent effect may be due to the increased expression of the V2 and V1b receptors in the kidneys of female compared with male Pkd1RC/RC mice. When OPC21268 or SSR149415 was administered in combination with tolvaptan, TKV, TKV growth, kidney weights, kidney weights adjusted by body weight, cyst indices and volumes, and plasma urea concentrations were not different from those observed with administration of tolvaptan alone. These results indicate that the beneficial effects of tolvaptan in PKD are mainly mediated by the inhibition of V2 receptors and provide no support for clinical trials of V2R antagonists combined with either V1a or V1b receptor antagonists.NEW & NOTEWORTHY Currently, the vasopressin V2 receptor antagonist tolvaptan is the only approved treatment for autosomal dominant polycystic kidney disease (ADPKD). It has been suggested that vasopressin acting on V1a or V1b receptors may also affect its development. We show that a V1aR antagonist has no effect in an ADPKD mouse model (Pkd1RC/RC), whereas a V2R antagonist has a modest attenuating effect in female mice only. Neither potentiates or hinders the beneficial effect of tolvaptan when administered in combination with this drug.

Nicotine-containing electronic cigarettes (e-cigarettes) have been shown to be effective for smoking cessation among general populations, but there is little evidence in people with substance use disorders (SUDs). We aimed to assess the effectiveness of e-cigarettes for smoking abstinence in people with SUD following discharge from smoke-free inpatient withdrawal services. We conducted a pragmatic, two-arm, single-blinded, parallel-group randomised controlled trial. The majority of this study took place in the community after the participants were discharged from inpatient stay. Adults who were tobacco smokers (motivated to quit; not using e-cigarettes) from five smoke-free inpatient withdrawal services in Australia were recruited and randomly assigned by computer using stratified block (1:1) to receive a 12-week supply of either e-cigarettes or combination nicotine replacement therapy (cNRT) with Quitline behavioural counselling on discharge. Participants were advised to use e-cigarettes as much or as often as necessary or desired and cNRT according to instructions. Researchers collecting outcome data were masked to treatment group. The primary outcome was 7 months continuous tobacco smoking abstinence as measured at 9 months after randomisation. The primary analysis was performed using an intention-to-treat approach, with sensitivity analyses following per-protocol, treatment adherence, and complete case analysis approaches. Serious adverse events were classified by a physician as non-serious or serious and causality assessed. We analysed serious adverse events by treatment group and calculated an incident rate ratio for each comparison. This trial is completed and is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619001787178). Between Sept 29, 2020, and June 3, 2022, 363 participants were enrolled. Of 363 participants, 207 (57%) were men and 151 (42%) were women; 179 (49%) were randomly assigned to e-cigarettes and 184 (51%) to cNRT. At follow-up, 19 (11%) of 179 participants in the e-cigarette group reported 7 months' continuous abstinence, compared with 18 (10%) of 184 participants in the cNRT group, with no significant differences between groups (risk ratio 1&#xb7;09; 95% credible interval [CrI] 0&#xb7;52-1&#xb7;89). The probability of a positive risk difference was 60% and Bayes factor was 0&#xb7;04, indicating little evidence of a treatment effect. 15 serious adverse events occurred in the e-cigarette group and 13 occurred in the cNRT group (incident rate ratio 1&#xb7;18; 95% CrI 0&#xb7;56-2&#xb7;54, p=0&#xb7;65). None were treatment-related. There was no evidence of a difference in cessation rates or adverse effects after 9 months of follow-up between participants given e-cigarettes or cNRT following discharge from inpatient SUD withdrawal services. Both treatments had approximately 10% smoking continuous abstinence rates among a population that is hard to treat and who have disproportionate tobacco-related morbidity and mortality. National Health and Medical Research Council of Australia.

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To evaluate the association between body mass index (BMI) and age at initiation of renal replacement therapy (RRT) of patients with autosomal dominant polycystic kidney disease (ADPKD) in the United States and Japan, 2 populations with different dietary habits and BMIs. We performed a cross-sectional analysis using data from the United States Renal Data System (USRDS) and the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR) to compare age, BMI, and other clinical characteristics of the patients who initiated RRT in the 2 countries between January 1, 2006, and December 31, 2007. This study included 3556 patients (1877 men and 1679 women) with RRT from the USRDS (n=2491) and JRDR (n=1065). Mean ages at RRT were 56.6&#xb1;13.1 years in the United States and 61.6&#xb1;12.5 years in Japan (P<.001). The BMI was 28.2&#xb1;7.1 kg/m2 in the USRDS and 22.0&#xb1;3.3 kg/m2 in the JRDR (P<.001). Japanese participants were the oldest, followed in descending order by Asian Americans, White Americans, and African Americans. Japanese participants had the lowest BMI, followed in ascending order by Asian Americans, White Americans, and African Americans. Univariable and adjusted analyses found that BMI was significantly and inversely associated with age at RRT, both overall and separately in American and Japanese populations. Lower BMI is significantly associated with older age at RRT in patients with ADPKD in both the United States and Japan. Japanese individuals had lower BMI and were older than US people of various ethnicities. Lower BMI in Japan is likely to be associated with a slower progression of ADPKD.

This proof-of-concept study aimed to assess whether digital PCR (dPCR) technology could improve the detection of M. tuberculosis complex (MTB) from formalin-fixed paraffin-embedded (FFPE) tissue when compared to real-time PCR. A laboratory developed test using real-time PCR assay targeting the MTB-IS6110 was transitioned to dPCR technology. The analytical sensitivity of dPCR using strain H37Rv genomic DNA was 2.5 fg/reaction, which was lower than the 5 fg/reaction detected by real-time PCR. Archived DNA from 72 samples were evaluated retrospectively and compared to real-time PCR. The dPCR demonstrated 100 % (33/33) PPA and 94.7 % (38/39) NPA with real-time PCR. Thirteen samples with results near the limit of detection by real-time PCR were also at the limit of detection by dPCR. This study demonstrated that, while dPCR provided high analytical sensitivity, its performance for the MTB detection in FFPE tissues was comparable to that of real-time PCR. Both dPCR and real-time PCR are valuable tools for MTB detection especially in the absence of mycobacterial culture.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and is the most common inherited kidney disorder worldwide. ADPKD accounts for 5% to 10% of kidney failure in the US and Europe, and its prevalence in the US is 9.3 per 10&#x202f;000 individuals. ADPKD is typically diagnosed in individuals aged 27 to 42 years and is primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes. Most persons with ADPKD have an affected parent, but de novo disease is suggested in 10% to 25% of families. More than 90% of patients older than 35 years have hepatic cysts, which may cause abdominal discomfort and occasionally require medical or surgical intervention. Hypertension affects 70% to 80% of patients with ADPKD, and approximately 9% to 14% develop intracranial aneurysms, which have a rupture rate of 0.57 per 1000 patient-years. Approximately 50% of individuals with ADPKD require kidney replacement therapy by 62 years of age. The severity of kidney disease can be quantified using the Mayo Imaging Classification (MIC), which stratifies patients based on total kidney volume adjusted for height and age and ranges from 1A to 1E. Patients with MIC 1C to MIC 1E have larger kidneys because of more rapid growth (6%-10% per year) compared with those with MIC 1A and 1B (1%-5% per year) and have earlier progression to kidney replacement therapy, which occurs at a mean age of 58.4 years for MIC 1C, 52.5 years for MIC 1D, and 43.4 years for MIC 1E. Optimal management of ADPKD includes systolic blood pressure lower than 120 mm Hg for most patients, but lower than 110/75 mm Hg for patients with MIC 1C to 1E who have an estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m2 and are younger than 50 years, dietary sodium restriction (<2000 mg/d), weight management, and adequate hydration (>2.5 L daily). The vasopressin type 2 receptor antagonist tolvaptan reduces the annual rate of eGFR decline by 0.98 to 1.27 mL/min/1.73 m2 and is indicated for patients with MIC 1C to 1E or an eGFR decline greater than 3 mL/min/1.73 m2 per year to slow disease progression and delay the onset of kidney failure. ADPKD is the most common genetic kidney disease worldwide and is characterized by progressive development of kidney cysts. Patients typically have hypertension and liver cysts, and 9% to 14% develop intracranial aneurysms. First-line treatment includes blood pressure control, dietary and weight management, and adequate hydration. Tolvaptan reduces the rate of eGFR decline for those at high risk of rapid progression to kidney failure.

Tubulin polyglutamylation is a posttranslational modification that occurs primarily along the axoneme of cilia. Defective axoneme polyglutamylation impairs cilia function and has been correlated with ciliopathies, including Joubert Syndrome (JBTS). However, the precise mechanisms regulating proper axoneme polyglutamylation remain vague. Here, we show that cyclin-dependent kinase 6 (CDK6), but not its paralog CDK4, localizes to the cilia base and suppresses axoneme polyglutamylation by phosphorylating RAB11 family interacting protein 5 (FIP5) at site S641, a critical regulator of cilia import of glutamylases. S641 phosphorylation disrupts the ciliary recruitment of FIP5 and its association with RAB11, thereby reducing the ciliary import of glutamylases. Encouragingly, the FDA-approved CDK4/6 inhibitor Abemaciclib can effectively restore cilia function in JBTS cells with defective glutamylation. In summary, our study elucidates the regulatory mechanisms governing axoneme polyglutamylation and suggests that developing CDK6-specific inhibitors could be a promising therapeutic strategy to enhance cilia function in ciliopathy patients.

Pteridophytes-vascular land plants that disperse by spores-are a powerful system for studying plant evolution, particularly with respect to the impact of abiotic factors on evolutionary trajectories through deep time. However, our ability to use pteridophytes to investigate such questions-or to capitalize on the ecological and conservation-related applications of the group-has been impaired by the relative isolation of the neo- and paleobotanical research communities and by the absence of large-scale biodiversity data sources. Here we present the Pteridophyte Collections Consortium (PCC), an interdisciplinary community uniting neo- and paleobotanists, and the associated PteridoPortal, a publicly accessible online portal that serves over three million pteridophyte records, including herbarium specimens, paleontological museum specimens, and iNaturalist observations. We demonstrate the utility of the PteridoPortal through discussion of three example PteridoPortal-enabled research projects. The data within the PteridoPortal are global in scope and are queryable in a flexible manner. The PteridoPortal contains a taxonomic thesaurus (a digital version of a Linnaean classification) that includes both extant and extinct pteridophytes in a common phylogenetic framework. The PteridoPortal allows applications such as greatly accelerated classic floristics, entirely new "next-generation" floristic approaches, and the study of environmentally mediated evolution of functional morphology across deep time. The PCC and PteridoPortal provide a comprehensive resource enabling novel research into plant evolution, ecology, and conservation across deep time, facilitating rapid floristic analyses and other biodiversity-related investigations, and providing new opportunities for education and community engagement.

In congenital scoliosis, the surgical strategy approach of hemivertebra excision, with or without instrumentation and fusion, is a common approach to correction of scoliosis. However, hemivertebra excisions are technically challenging, with potential complications including spinal cord injury, nerve root injury and cerebrospinal fluid leak. The purpose of this study was to determine whether correction of congenital scoliosis can be achieved using a posterior instrumentation/fusion-only approach without the need for hemivertebra excision. &#xa0;35 patients with congenital scoliosis and hemivertebra operated between 2007 and 2024 were matched to 35 AIS patients by BMI, levels fused, and preoperative Cobb. Wilcoxon&#xa0;rank-sum tests, chi-square tests, and Fisher's Exact tests were utilized. Age (p&#x2009;=&#x2009;0.22), BMI (p&#x2009;=&#x2009;0.25) and preoperative Cobb (p&#x2009;=&#x2009;0.79) were similar between hemivertebra and AIS patients. Cobb correction (HV: 71.8% vs. AIS: 70.4%; p&#x2009;=&#x2009;0.92) and EBL (500&#xa0;cc vs. 400&#xa0;cc; p&#x2009;=&#x2009;1.0) were similar. Operative time (310.0&#xa0;min vs. 242.0&#xa0;min; p&#x2009;<&#x2009;0.001) and length of stay (7.0&#xa0;days vs. 5.0&#xa0;days; p&#x2009;<&#x2009;0.001) were statistically different. Patients operated on after 2018, when the Rapid Recovery Protocol was implemented, had a similar length of stay (4.5 vs. 5.0; p&#x2009;=&#x2009;0.92). Patients in both cohorts had similar SRS-22 scores. &#xa0;Choosing fusion levels in congenital patients, on similar principles to AIS, leads to avoidance of hemivertebra excision, including lumbosacral hemivertebrae. This approach is safer than hemivertebra excision and has similar, or better, curve correction than previously reported.