The Making Care Primary (MCP) model represents a sharp shift in Medicare’s approach to primary care, yet its current design risks duplicating failures from prior alternative payment models. Our editorial suggests refinements to address these gaps. To prevent early provider dropout from MCP’s rigid track-based system, we propose a sliding-scale infrastructure payment model that adjusts based on practice needs rather than abrupt phase-outs. Given MCP’s reliance on community-based organisations (CBOs) for social determinants of health interventions, we also advocate for direct, outcomes-based contracts between providers and CBOs, ensuring accountability for patient outcomes rather than passive referrals. We recommend that MCP enforce data-sharing mandates for commercial insurers and Medicaid agencies, drawing from Washington State’s successful Multi-Payer Collaborative, to avoid payer disengagement that plagued previous multi-payer models. To expand beyond conventional quality measures, we propose integrating patient-centred outcomes from the International Consortium for Health Outcomes Measurement, making sure MCP captures meaningful clinical impact. Finally, we propose programme adjustments frequently at two- to three-year intervals to refine risk adjustment methodologies. These approaches could enhance MCP’s sustainability, preventing the financial instability and misaligned incentives that undermined past value-based care initiatives.

Background: Late-onset Pompe disease (LOPD) is caused by a deficiency of acid α-glucosidase (GAA), leading to progressive muscle and respiratory decline. Cipaglucosidase alfa (cipa), a recombinant human GAA naturally enriched with bis-mannose-6-phosphate, exhibits improved muscle uptake but is limited by inactivation at near-neutral blood pH. Miglustat (mig), an enzyme stabiliser, binds competitively and reversibly to cipa, enhancing its stability and activity. Methods: In dose-finding studies, Gaa-/- mice were treated with cipa (20 mg/kg) +/- mig (10 mg/kg; equivalent human dose ~260 mg). Clinical study methodologies have been published (Schoser et al. Lancet Neurol 2021:20;1027–37; Schoser et al. J Neurol 2024:271;2810–23). Results: In Gaa-/- mice, cipa+mig improved muscle glycogen reduction more than cipa alone and grip strength to levels approaching wild-type mice. LOPD patients (n=11) treated with cipa alone showed dose-dependent decreases in hexose tetrasaccharide (Hex4) levels by ~15% from baseline, decreasing another ~10% with added mig (260 mg). In a head-to-head study, cipa+mig had a similar safety profile to alglucosidase alfa. Among 151 patients (three trials), mig-related adverse events occurred in 21 (13.9%), none serious. Conclusions: Mig stabilised cipa in circulation, improving cipa exposure, further reducing Hex4 levels and was well tolerated in clinical studies in patients with LOPD. Sponsored by Amicus Therapeutics, Inc.

With great fanfare, India officially launched its new criminal laws – the Bharatiya Nyaya Sanhita, the Bharatiya Nagarik Suraksha Sanhita and the Bharatiya Sakshya Adhiniyam – on 1 July 2024. These laws were heralded as a significant reform aimed at modernizing the country’s justice system and enhancing protections for victims of violence. The legislation sparked considerable optimism among various stakeholders by promising swift justice and fostering a more responsive police force. However, at six months after their implementation, a critical assessment was warranted. How effective have these laws proven to be in practice? Are the judiciary and police adapting to these changes, or are we merely witnessing another instance of legislative overreach that fails to translate into real-world improvements? This analysis urges us to examine the real impact of these statutes to assess whether they offer a genuine solution to the longstanding challenges within the Indian criminal justice system or if they are simply another bureaucratic illusion. As we examine the initial outcomes and responses from law enforcement and the judiciary, it is essential to evaluate the efficacy of the new provisions in the context of ongoing systemic challenges and societal attitudes toward justice. This evaluation will determine whether these legislative measures have genuinely ushered in a new era of accountability and victim support, or if they have fallen victim to the inertia of existing institutional practices. In this paper we examine the changes and effectiveness brought by these laws as we unchain ourselves from colonial laws.

Very long baseline interferometry (VLBI) astrometry is used to determine the three-dimensional position and proper motion of astronomical objects. A typical VLBI astrometric campaign generally includes around ten observations, making it challenging to characterise systematic uncertainties. Our study on two bright pulsars, B0329+54 and B1133+16, involves analysis of broadband Very Long Baseline Array (VLBA) data over $\sim30$ epochs (spanning approximately 3.5 yr). This extended dataset has significantly improved the precision of the astrometric estimates of these pulsars. Our broadband study suggests that, as expected, the primary contribution to systematic uncertainties in L-band VLBI astrometry originates from the ionosphere. We have also assessed the effectiveness of the modified total electron content (TEC) mapping function, which converts vertical TEC to slant TEC, in correcting ionospheric dispersive delays using global TEC maps. The astrometric parameters (parallax and proper motion) obtained from the multiple datasets, calibrated using the traditional and the modified TEC mapping functions, are consistent. However, the reduced chi-square values from least-squares fitting and precision of the fitted astrometric parameters show no significant improvement, and hence, the effectiveness of the new TEC mapping function on astrometry is unclear. For B0329+54, the refined parallax estimate is $0.611^{+0.013}_{-0.013}$ mas, with best-fit proper motion of $\mu_{\alpha} = 16.960^{+0.011}_{-0.010}\, \textrm{mas}\,{\rm yr}^{-1}$ in R.A. and and $\mu_{\delta} = -10.382^{+0.022}_{-0.022}\,\textrm{mas}\,{\rm yr}^{-1}$ in Dec. These correspond to a distance of $1.64^{+0.03}_{-0.03}$ kpc and a transverse velocity of $\sim 154\, \textrm{km}\,{\rm s}^{-1}$. For B1133+16, the new estimated parallax is $2.705^{+0.009}_{-0.009}$ mas, with proper motions of $\mu_{\alpha} = -73.777^{+0.008}_{-0.008}\, \textrm{mas}\,{\rm yr}^{-1}$ and $\mu_{\delta} = 366.573^{+0.019}_{-0.019}\, \textrm{mas}\,{\rm yr}^{-1}$, implying a distance of $370^{+1}_{-1}$ pc and a transverse velocity of $\sim 656\, \textrm{km}\,{\rm s}^{-1}$. The proper motions of B0329+54 and B1133+16 are consistent within $1\sigma$ of the most precise values reported in the literature to date while achieving more than a twofold improvement in precision. Similarly, the parallax measurements for both pulsars show a $\sim 73\%$ enhancement in precision, with differences of approximately $\lt 1\sigma$ compared to the most precise published values to date.

Ventilated cavities in the wake of a two-dimensional bluff body are studied experimentally via time-resolved X-ray densitometry. With a systematic variation of flow velocity and gas injection rate, expressed as Froude number ($\textit{Fr}$) and ventilation coefficient ($C_{qs}$), four cavities with different closure types are identified. A regime map governed by $\textit{Fr}$ and $C_{qs}$ is constructed to estimate flow conditions associated with each cavity closure type. Each closure exhibits a different gas ejection mechanism, which in turn dictates the cavity geometry and the pressure in the cavity. Three-dimensional cavity closure is seen to exist for the supercavities at low $\textit{Fr}$. However, closure is nominally two-dimensional for supercavities at higher $\textit{Fr}$. At low $C_{qs}$, cavity closure is seen to be wake-dominated, while supercavities are seen to have interfacial perturbation near the closure at higher $C_{qs}$, irrespective of $\textit{Fr}$. With the measured gas fraction, a gas balance analysis is performed to quantify the gas ejection rate at the transitional cavity closure during its formation. For a range of $\textit{Fr}$, the transitional cavity closure is seen to be characterised by re-entrant flow, whose intensity depends on the flow inertia, dictating the gas ejection rates. Two different ventilation strategies were employed to systematically investigate the formation and maintenance gas fluxes. The interaction of wake and gas injection is suspected to dominate the cavity formation process and not the maintenance, resulting in ventilation hysteresis. Consequently, the ventilation gas flux required to maintain the supercavity is significantly less than the gas flux required to form the supercavity.

Japan today is showing extraordinary interest in India and nothing reflects this more strongly than Prime Minister Shinzo Abe's visit to New Delhi in August. Moreover, Abe is the third successive Japanese prime minister to make such a visit and, starting this year, India is the only country with which Japan will conduct annual talks at the prime ministerial level.

Abe hewed to his foreign visits schedule and made a week-long trip to Indonesia, India and Malaysia – beginning 19 August despite political uncertainties in Japan and his weakened position as prime minister following the Liberal Democratic Party's dismal performance at the July House of Councillors elections. Recognising strategic competition for energy security, Abe signed a bilateral free trade agreement with Indonesia, the largest supplier of liquefied natural gas to Japan. In return Japan guaranteed Indonesia liberal access to its markets for a range of Indonesian products including farm produce – rice exempted.

The on-body flow and near-to-intermediate wake of a 6:1 prolate spheroid at a pitch angle of $\alpha = 10^{\circ }$ and a length-based Reynolds number, ${Re}_L = U_\infty L / \nu = 3 \times 10^4$, are investigated using large eddy simulation (LES) across four stratification levels: ${\textit {Fr}} = U_{\infty }/ND = \infty , 6, 1.9$ and $1$. A streamwise vortex pair, characteristic of non-zero $\alpha$ in unstratified flow over both slender and blunt bodies, is observed. At ${\textit {Fr}} = \infty$ (unstratified) and $6$, the vortex pair has a lateral left–right asymmetry as has been reported in several previous studies of unstratified flow. However, at higher stratification levels of ${\textit {Fr}} = 1.9$ and $1$, this asymmetry disappears and there is a complex combination of body-shed vorticity that is affected by baroclinicity and vorticity associated with internal gravity waves. Even at the relatively weak stratification of ${\textit {Fr}} = 6$, the wake is strongly influenced by buoyancy from the outset: (a) the vertical drift of the wake is more constrained at ${\textit {Fr}} = 6$ than at ${\textit {Fr}} = \infty$ throughout the domain; and (b) the streamwise vortex pair loses coherence by $x/D = 10$ in the ${\textit {Fr}} = 6$ wake, unlike the ${\textit {Fr}} = \infty$ case. For the ${\textit {Fr}} = 1$ wake, flow separation characteristics differ significantly from those at ${\textit {Fr}} = \infty$ and $6$, resulting in a double-lobed wake topology that persists throughout the domain.

Despite the increased awareness and action towards Equality, Diversity and Inclusion (EDI), the glaciological community still experiences and perpetuates examples of exclusionary and discriminatory behavior. We here discuss the challenges and visions from a group predominantly composed of early-career researchers from the 2023 edition of the Karthaus Summer School on Ice Sheets and Glaciers in the Climate System. This paper presents the results of an EDI-focused workshop that the 36 students and 12 lecturers who attended the summer school actively participated in. We identify common threads from participant responses and distill them into collective visions for the future of the glaciological research community, built on actionable steps toward change. In this paper, we address the following questions that guided the workshop: What do we see as current EDI challenges in the glaciology research community and which improvements would we like to see in the next fifty years? Contributions have been sorted into three main challenges we want and need to face: making glaciology (1) more accessible, (2) more equitable and (3) more responsible.

Thyroid disorders are increasingly prevalent globally and are considered metabolic-lifestyle diseases. While medications can manage thyroid dysfunction, they are usually lifelong, costly and not always practical. Intermittent fasting (IF), a highly adaptable dietary regimen, has been shown to influence lifestyle, gut microbiome and circadian rhythms. Our study hypothesised that IF, combined with vitamin supplementation, could reduce the risk of thyroid disorders due to their antioxidant effects. In this study, experimental animals were divided into five groups: euthyroid, hypothyroidism control, IF + vitamin E (Vit. E), Vit. E and IF. Hypothyroidism was induced using propylthiouracil over 24 days, and IF and Vit. E (66 mg/ml) were administered based on the experimental group. The hypothyroid animals exhibited increased anxiety, weight gain, lipid peroxidation and a significant reduction in thyroid hormone levels, locomotor activity and antioxidant levels—clear signs of thyroid dysfunction’s impact on metabolism and overall health. Our proposed therapies IF and Vit. E effectively mitigated thyroid damage. Drawing inspiration from ancient ayurveda and modern healthcare strategies, these cost-effective and practical regimens offer a promising solution to managing thyroid disorders globally.

Objectives/Goals: Colorectal cancer (CRC) is classified into right-sided, left-sided, and rectal cancer. Clinicopathological and molecular features vary along the colorectum, even within subsites, leading to inconsistencies in identifying relevant biomarkers. We created a CRC metabolome map to explore diagnostic and survival heterogeneity across subsites. Methods/Study Population: A total of 372 patient-matched tumor and normal tissue samples were collected from seven colorectal subsites: cecum (n = 63), ascending colon (n = 44), transverse colon (n = 32), descending colon (n = 28), sigmoid colon (n = 75), rectosigmoid colon (n = 38), and rectum (n = 92). Liquid chromatography–mass spectrometry was used to compare metabolite abundances. Cox proportional hazards regression assessed metabolite impact on survival, adjusted for clinical covariates. Parametric and nonparametric tests were applied to compare the metabolite abundances. An interactive, publicly accessible online platform was developed to allow researchers to explore and generate hypotheses from this data. Results/Anticipated Results: Our study identified 39 and 70 significantly altered metabolites, including bile acids and lysophosphatidylcholines, across tumors and normal mucosa, showing metabolic heterogeneity between CRC subsites. We observed significant linear trends in metabolite gradients from the cecum to the rectum, and it was depended on the disease status. Comparison of tumors to patient-matched normal mucosa revealed metabolite changes exclusive to each subsite. Metabolite differences correlated with survival were unique to each subsite. Additionally, we developed an interactive, publicly accessible CRC metabolome database to share this valuable resource: https://colorectal-cancer-metabolome.com/yale-university. Discussion/Significance of Impact: This study provides the first CRC metabolome map, revealing metabolic differences across colorectal subsites. It challenges the right vs. left CRC classification, highlighting subsite-specific biomarker identification. Findings offer insights for personalized treatments tailored to the tumor type to improve patient outcomes.

Objectives/Goals: Immune checkpoint inhibitors (IO) have dramatically improved survival outcomes in patients with metastatic melanoma. Still, many patients do not respond these treatments, and others may experience harmful adverse events (irAEs). Thus, there an unmet need for biomarkers for real-time monitoring and management of patients exposed to IO therapies. Methods/Study Population: Serial serum samples were collected from patients with BRAFV600-mutant metastatic melanoma treated with ipilimumab/nivolumab (IO, n = 14) or dabrafenib/trametinib (TT, n = 10). Methylated cell-free DNA (cfDNA) was isolated and sequenced using enzymatic methyl-seq. We develop a robust computational pipeline to identify the top 250 cell-type specific regions of differential methylation (DMRs) across 24 cell-types. Using these differentially methylated regions, a deconvolution tool was developed to determine the abundance of cell type-specific cfDNA in patient serum, and changes in abundance were tracked over treatment time-course to assess response treatment and identify signals of adverse events. Results/Anticipated Results: We demonstrated improved precision in DMR detection evidenced by a higher area under the receiver operator characteristic curve (AUROC) of 0.85 on average. Pathway and functional annotation analysis revealed melanocyte-specific methylation marker regions regulated genes related to melanocyte development and differentiation, including MITF, SOX9/10, and FOXD3. We show these regions are conserved through the transformation to malignant melanoma, indicating melanocyte cfDNA abundance can be used as a marker for tumor burden. We characterize the dynamics of melanocyte-derived cfDNA over the course of treatment in responders and nonresponders to both IO and TT. We observe that changes in concentrations of cfDNA from other cell types correlate with clinically observed irAE-mediated damage to normal tissue. Discussion/Significance of Impact: We demonstrated the utility of decoding the origins of cfDNA fragments obtained from serial liquid biopsy samples. Using cell-specific methylation marks, we identified a signature from the primary melanoma to assess response to treatment, while also obtaining a signal from other tissues throughout the body to monitor immune related adverse events.

This paper contributes to an underdeveloped yet critical feature of international criminal law – victim assistance. With the creation of the ICC and the Trust Fund for Victims, the idea of victim assistance in situations of mass criminalities was provided an institutional backbone. However, much of its operational principles remain theoretically ill-defined. Through a methodological study of over a decade of assistance programmes administered by the Fund, this paper sheds light on some of the critical operational principles which have emerged in practice. Additionally, in light of these principles, this paper argues that there exist two major causes of ineffectiveness which hamper the Fund’s assistance work – first, the problem of defining its goals in definite, strategic terms, and second, the overlap between assistance mandate of the Fund and reparations regime of the ICC. It concludes by making course-correction suggestions for the Fund to chart a future towards an effective organization building.