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From the Forward: \"Contemporary groundwater management has moved well beyond a concern with how much water is stored underground or can be extracted from aquifers. Today we recognise that integrated, effective and efficient groundwater management relies on pulling together work in a variety of disciplines such as climate science, ecology, socioeconomics, public policy and law, as well as hydrogeology. However, whilst we realise the importance of multiple perspectives and a diversity of contexts and data, the challenge of integrating and organising all of this information into a decision making framework remains. It is also abundantly clear that sharing and access to water is a fundamentally political issue and that solutions depend on full engagement of stakeholders as well as mobilisation of knowledge and technologies.\"

Internists frequently care for patients who suffer from breathlessness in both the inpatient and the outpatient settings. Patients may experience chronic refractory breathlessness despite thorough evaluation and management of their underlying medical illnesses. Left unmanaged, chronic breathlessness is associated with worsened quality of life, more frequent visits to the emergency room, and decreased activity levels, as well as increased levels of depression and anxiety. This narrative review summarizes recent research on interventions for the relief of breathlessness, including both non-pharmacologic and pharmacologic options.

Diets with high proportions of foods high in fat, sugar, and/or salt (HFSS) contribute to malnutrition and rising rates of childhood obesity, with effects throughout the life course. Given compelling evidence on the detrimental impact HFSS advertising has on children's diets, the World Health Organization unequivocally supports the adoption of restrictions on HFSS marketing and advertising. In February 2019, the Greater London Authority introduced novel restrictions on HFSS advertising across Transport for London (TfL), one of the most valuable out-of-home advertising estates. In this study, we examined whether and how commercial actors attempted to influence the development of these advertising restrictions. Using requests under the Freedom of Information Act, we obtained industry responses to the London Food Strategy consultation, correspondence between officials and key industry actors, and information on meetings. We used an existing model of corporate political activity, the Policy Dystopia Model, to systematically analyse arguments and activities used to counter the policy. The majority of food and advertising industry consultation respondents opposed the proposed advertising restrictions, many promoting voluntary approaches instead. Industry actors who supported the policy were predominantly smaller businesses. To oppose the policy, industry respondents deployed a range of strategies. They exaggerated potential costs and underplayed potential benefits of the policy, for instance, warning of negative economic consequences and questioning the evidence underlying the proposal. Despite challenging the evidence for the policy, they offered little evidence in support of their own claims. Commercial actors had significant access to the policy process and officials through the consultation and numerous meetings, yet attempted to increase access, for example, in applying to join the London Child Obesity Taskforce and inviting its members to events. They also employed coalition management, engaging directly and through business associations to amplify their arguments. Some advertising industry actors also raised the potential of legal challenges. The key limitation of this study is that our data focused on industry-policymaker interactions; thus, our findings are unable to present a comprehensive picture of political activity. In this study, we identified substantial opposition from food and advertising industry actors to the TfL advertising restrictions. We mapped arguments and activities used to oppose the policy, which might help other public authorities anticipate industry efforts to prevent similar restrictions in HFSS advertising. Given the potential consequences of commercial influence in these kinds of policy spaces, public bodies should consider how they engage with industry actors.

To understand if, and how, Australian ultra-processed food industry actors use Twitter to influence food and health policy debates and produce a conceptual framework to describe such influence. Twitter data of prominent industry actors were defined through purposive sampling and inductively coded to investigate possible influence on food and health policy debates. These are described using descriptive statistics and coded extracts. Australia. Twitter accounts of nine prominent ultra-processed food industry actors, including major trade associations. Ultra-processed food industry actors actively used Twitter to influence food and health policy debates. Seven overarching strategies were identified: co-opting public health narratives; opposing regulation; supporting voluntary, co- or self-regulation; engaging policy processes and decision-makers; linking regulatory environments to the need for ongoing profitability; affecting public perceptions and value judgements; and using ignorance claims to distort policy narratives. Each lobbying strategy is underpinned with tactics described throughout and captured in a framework. The current study creates a framework to monitor how food industry actors can use social media to influence food and health policy debates. As such, social media appears to be not only an important commercial determinant of health for brand marketing, but also an extension of lobbying practices to reshape public perceptions of corporate conduct and policy-making.

A course of androgen-deprivation therapy before and during radiotherapy prolonged 10-year survival by about 7% among men with intermediate-risk prostate cancer. The risk of erectile dysfunction from the addition of hormone therapy was also about 7% higher. In the 1980s, advances in both surgery and radiotherapy for clinically localized prostate cancer led to their acceptance as successful treatments, with considerable reductions in harmful side effects as compared with earlier treatments. 1 In the 1990s, reversible androgen suppression with the use of luteinizing hormone–releasing hormone analogues and oral antiandrogen agents was shown to induce apoptotic regression in androgen-responsive cancers, 2 potentially improving the prospects of local control and the duration of survival free of metastatic disease. Among patients with locally advanced disease, phase 3 clinical trials 3 , 4 showed that when added to radiotherapy, long-term treatment with these agents (≥2 years) . . .

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti–CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed (“ inside-out ” (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.

Human intestinal organoids from primary human tissues have the potential to revolutionize personalized medicine and preclinical gastrointestinal disease models. A tunable, fully defined, designer matrix, termed hyaluronan elastin‐like protein (HELP) is reported, which enables the formation, differentiation, and passaging of adult primary tissue‐derived, epithelial‐only intestinal organoids. HELP enables the encapsulation of dissociated patient‐derived cells, which then undergo proliferation and formation of enteroids, spherical structures with polarized internal lumens. After 12 rounds of passaging, enteroid growth in HELP materials is found to be statistically similar to that in animal‐derived matrices. HELP materials also support the differentiation of human enteroids into mature intestinal cell subtypes. HELP matrices allow stiffness, stress relaxation rate, and integrin‐ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid–matrix interactions and potential patient‐specific optimization. Organoid formation in HELP materials is most robust in gels with stiffer moduli (G’ ≈ 1 kPa), slower stress relaxation rate (t1/2 ≈ 18 h), and higher integrin ligand concentration (0.5 × 10−3–1 × 10−3 m RGD peptide). This material provides a promising in vitro model for further understanding intestinal development and disease in humans and a reproducible, biodegradable, minimal matrix with no animal‐derived products or synthetic polyethylene glycol for potential clinical translation. A tunable, designer matrix, termed hyaluronan elastin‐like protein (HELP) that enables the formation, differentiation, and passaging of adult primary tissue‐derived organoids is reported. HELP matrices allow stiffness, stress relaxation rate, and integrin‐ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid–matrix interactions and potential patient‐specific optimization.

Controlling graft-versus-host disease (GVHD) remains a major unmet need in stem cell transplantation, and new, targeted therapies are being actively developed. CD28-CD80/86 costimulation blockade represents a promising strategy, but targeting CD80/CD86 with CTLA4-Ig may be associated with undesired blockade of coinhibitory pathways. In contrast, targeted blockade of CD28 exclusively inhibits T cell costimulation and may more potently prevent GVHD. Here, we investigated FR104, an antagonistic CD28-specific pegylated-Fab', in the nonhuman primate (NHP) GVHD model and completed a multiparameter interrogation comparing it with CTLA4-Ig, with and without sirolimus, including clinical, histopathologic, flow cytometric, and transcriptomic analyses. We document that FR104 monoprophylaxis and combined prophylaxis with FR104/sirolimus led to enhanced control of effector T cell proliferation and activation compared with the use of CTLA4-Ig or CTLA4-Ig/sirolimus. Importantly, FR104/sirolimus did not lead to a beneficial impact on Treg reconstitution or homeostasis, consistent with control of conventional T cell activation and IL-2 production needed to support Tregs. While FR104/sirolimus had a salutary effect on GVHD-free survival, overall survival was not improved, due to death in the absence of GVHD in several FR104/sirolimus recipients in the setting of sepsis and a paralyzed INF-γ response. These results therefore suggest that effectively deploying CD28 in the clinic will require close scrutiny of both the benefits and risks of extensively abrogating conventional T cell activation after transplant.

We assessed effectiveness, safety, and tolerability of paclitaxel or fluorouracil when added to radiation plus cisplatin followed by adjuvant chemotherapy in a programme of selected bladder preservation for patients with muscle invasive bladder cancer. In our randomised phase 2 trial, we enrolled patients with T2–4a transitional cell carcinoma of the bladder at 24 medical centres in the USA. We randomly allocated patients to receive paclitaxel plus cisplatin (paclitaxel group) or fluorouracil plus cisplatin (fluorouracil group) with twice-daily radiation in random block sizes per site on the basis of clinical T-stage (T2 vs T3–4). Patients and physicians were aware of treatment assignment. All patients had transurethral resection of bladder tumour and twice-daily radiotherapy to 40·3 Gy, along with allocated chemotherapy, followed by cystoscopic and biopsy assessment of response. Patients who had a tumour response with downstaging to T0, Tcis, or Ta received consolidation chemoradiotherapy to 64·3 Gy, with the same chemotherapy regimen as in the induction phase. Patients received adjuvant cisplatin-gemcitabine-paclitaxel after the end of chemoradiotherapy. If, after induction, persistent disease was graded as T1 or worse, we recommended patients undergo cystectomy and adjuvant chemotherapy. We assessed the primary endpoints of rates of treatment completion and toxic effects in all randomly allocated patients. This study is registered with ClinicalTrials.gov, number NCT00055601. Between Dec 13, 2002, and Jan 11, 2008, we enrolled 97 patients, of whom 93 were eligible for analysis. Median follow-up was 5·0 years (IQR 5·0–6·2). Of 46 patients in the paclitaxel group, 45 (98%) completed induction (16 [35%] with grade 3–4 toxicity), 39 (85%) completed induction and consolidation (11 [24%] with grade 3–4 toxicity due to consolidation), and 31 (67%) completed the entire protocol with adjuvant chemotherapy. 34 (85%) of 40 assessable patients in the paclitaxel group had grade 3–4 toxicity during adjuvant chemotherapy. Of 47 patients in the fluorouracil group, 45 (96%) completed induction (nine [19%] with grade 3–4 toxicity), 39 (83%) completed induction and consolidation (12 [26%] had grade 3–4 toxicity due to consolidation), and 25 (53%) completed the entire protocol with adjuvant chemotherapy. 31 (76%) of 41 assessable patients in the fluorouracil group had grade 3–4 toxicity during adjuvant chemotherapy. Five (11%) patients treated with the paclitaxel regimen and three (6%) patients treated with the fluorouracil regimen developed late grade 3–4 radiotherapy toxicities. 11 (24%) patients treated with the paclitaxel regimen and 16 (34%) patients treated with the fluorouracil regimen developed late grade 3–4 toxicities unrelated to radiotherapy. One patient (in the fluorouracil group) died during follow-up. Six (13%) patients in the paclitaxel group and in three (6%) patients in the fluorouracil group discontinued due to treatment-related toxicity. In the absence of phase 3 data, our findings could inform selection of a bladder-sparing trimodality chemotherapy regimen for patients with muscle invasive bladder cancer. US National Cancer Institute.