Copper-Catalyzed Synthesis of Masked (Hetero)Aryl Sulfinates.

Catalysis using substoichiometric copper facilitates the synthesis of masked (hetero)aryl sulfinates under mild, base-free conditions from aryl iodides and the commercial sulfonylation reagent sodium 1-methyl 3-sulfinopropanoate (SMOPS). The development of a tert-butyl ester variant of the SMOPS reagent allowed the use of aryl bromide substrates. The sulfones thus generated can be unmasked and functionalized in situ to form a variety of sulfonyl-containing functional groups.

Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides.

sulfinamides, sulfonamides, and sulfonimidamides are in-demand motifs in medicinal chemistry, yet methods for the synthesis of alkyl variants that start from simple, readily available feedstocks are scarce. In addition, bespoke syntheses of each class of molecules are usually needed. In this report, we detail the synthesis of these three distinct sulfur functional groups, using readily available and structurally diverse alkyl carboxylic acids as the starting materials. The method harnesses alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products. Using the N-alkoxy sulfinylamine reagent t-BuO-NSO as the radical trap provides common N-alkoxy sulfinamide intermediates, which can be converted in a divergent manner to either sulfonamides or sulfonimidamides, by treatment with sodium hydroxide, or an amine, respectively. The reactions are scalable, tolerate a broad range of functional groups, and can be used for the diversification of complex biologically active compounds.

Relationships Between Burnout and Resilience: Experiences of Physical Therapists and Occupational Therapists During the COVID-19 Pandemic.

OBJECTIVE: Research on burnout among physical therapists and occupational therapists in the context of the coronavirus disease 2019 (COVID-19) pandemic is limited. Resilience may be important for reducing burnout and promoting well-being among rehabilitation specialists, especially during periods of elevated occupational demand and stress. The purpose of this study was to investigate experiences of burnout, COVID-19 pandemic-related distress, and resilience among physical therapists and occupational therapists during the first year of the COVID-19 pandemic. METHODS: Physical therapists and occupational therapists working in a university-affiliated health system were invited to complete an online survey assessing burnout, COVID-19 pandemic-related distress, state- and trait-like resilience, physical activity, sleep disturbance, and financial concerns. Multiple linear regressions were used to examine variables associated with burnout as well as the contribution of specific aspects of resilience to burnout. RESULTS: Greater COVID-19 pandemic-related distress was associated with greater emotional exhaustion and depersonalization, whereas state-like resilience at work was associated with lower emotional exhaustion, greater personal accomplishment, and lower depersonalization. Analyses examining the impact of specific components of resilience at work suggested that several components are associated with less burnout, with finding one's calling being particularly relevant for all 3 domains of burnout. CONCLUSION: Symptoms of burnout were reported by many physical therapists and occupational therapists. COVID-19-related distress and state-like resilience at work, particularly the perception of finding one's calling, emerged as consistently being associated with burnout in the context of the COVID-19 pandemic. IMPACT: These findings can inform the development of interventions to reduce burnout among physical therapists and occupational therapists amid the continuing COVID-19 pandemic.

The EU-funded I3LUNG Project: Integrative Science, Intelligent Data Platform for Individualized LUNG Cancer Care With Immunotherapy.

Although immunotherapy (IO) has changed the paradigm for the treatment of patients with advanced non-small cell lung cancers (aNSCLC), only around 30% to 50% of treated patients experience a long-term benefit from IO. Furthermore, the identification of the 30 to 50% of patients who respond remains a major challenge, as programmed Death-Ligand 1 (PD-L1) is currently the only biomarker used to predict the outcome of IO in NSCLC patients despite its limited efficacy. Considering the dynamic complexity of the immune system-tumor microenvironment (TME) and its interaction with the host's and patient's behavior, it is unlikely that a single biomarker will accurately predict a patient's outcomes. In this scenario, Artificial Intelligence (AI) and Machine Learning (ML) are becoming essential to the development of powerful decision-making tools that are able to deal with this high-complexity and provide individualized predictions to better match treatments to individual patients and thus improve patient outcomes and reduce the economic burden of aNSCLC on healthcare systems. I3LUNG is an international, multicenter, retrospective and prospective, observational study of patients with aNSCLC treated with IO, entirely funded by European Union (EU) under the Horizon 2020 (H2020) program. Using AI-based tools, the aim of this study is to promote individualized treatment in aNSCLC, with the goals of improving survival and quality of life, minimizing or preventing undue toxicity and promoting efficient resource allocation. The final objective of the project is the construction of a novel, integrated, AI-assisted data storage and elaboration platform to guide IO administration in aNSCLC, ensuring easy access and cost-effective use by healthcare providers and patients.

Real-world long-term effects on blood pressure and other cardiovascular risk factors for patients in digital therapeutics.

PURPOSE: Hypertension is a leading causeof premature death worldwide and a major public health problem. This study investigated the long-term effects (>1 year) of digital hypertension monitoring by home blood pressure (HBP) measurements in combination with individualized remote treatment via a Swedish Digital Therapeutics platform in a large patient population. METHODS: The primary endpoint, HBP, and exploratory endpoints, BMI, alcohol consumption, stress level, physical activity, and smoking, were assessed every 3 months for 540 and 360 days, respectively, in 7752 Swedish primary hypertension patients. Patients received individualized medical treatments and lifestyle advice via asynchronous text-based communication in an app. Changes from baseline in endpoints were calculated for the whole population and for subgroups defined by baseline SBP ≥135 (high SBP), 125-135 (suboptimal SBP), 115-125 (optimal SBP), and <115 mmHg (low SBP). RESULTS: After 360 days of treatment, the whole population showed a significant increase of 57% (from 37 to 58%) in the proportion of patients with controlled SBP (i.e. SBP of 115-135 mmHg). The largest reduction in SBP of 13.8 mmHg was observed for the high SBP subgroup, whereas for the low SBP subgroup, SBP increased by 13.4 mmHg. BP improved most in the first three months, and for both the high and low BP subgroups, the improvement continued during the 540-day study period. Significant beneficial changes were also observed for some exploratory endpoints including BMI and smoking. CONCLUSIONS: In conclusion, the digital therapeutics platform was associated with significant improvement in BP control and associated risk factors, which were maintained over a longer period.

Severe Fatigue and Persistent Symptoms at 3 Months Following Severe Acute Respiratory Syndrome Coronavirus 2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study.

BACKGROUND: Most research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants focuses on initial symptomatology with limited longer-term data. We characterized prevalences of prolonged symptoms 3 months post-SARS-CoV-2 infection across 3 variant time-periods (pre-Delta, Delta, and Omicron). METHODS: This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, organ system-based symptoms, and ≥3 symptoms across variants among participants with a positive ("COVID-positive") or negative SARS-CoV-2 test ("COVID-negative") at 3 months after SARS-CoV-2 testing. Variant periods were defined by dates with ≥50% dominant strain. We performed multivariable logistic regression modeling to estimate independent effects of variants adjusting for sociodemographics, baseline health, and vaccine status. RESULTS: The study included 2402 COVID-positive and 821 COVID-negative participants. Among COVID-positives, 463 (19.3%) were pre-Delta, 1198 (49.9%) Delta, and 741 (30.8%) Omicron. The pre-Delta COVID-positive cohort exhibited more prolonged severe fatigue (16.7% vs 11.5% vs 12.3%; P = .017) and presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; P < .001) compared with the Delta and Omicron cohorts. No differences were seen in the COVID-negatives across time-periods. In multivariable models adjusted for vaccination, severe fatigue and odds of having ≥3 symptoms were no longer significant across variants. CONCLUSIONS: Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during pre-Delta than with Delta and Omicron; however, these differences were no longer significant after adjusting for vaccination status, suggesting a beneficial effect of vaccination on risk of long-term symptoms. Clinical Trials Registration. NCT04610515.

Modular Two-Step Route to Sulfondiimidamides.

Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by imidic nitrogens, such as sulfoximines and sulfonimidamides, are gaining attraction. Despite this activity, the double aza-variants of sulfonamides, termed sulfondiimidamides, are almost completely absent from the literature. The reason for this is poor synthetic accessibility. Although a recent synthesis has established sulfondiimidamides as viable motifs, the length of the route and the capricious nature of the key sulfondiimidoyl fluoride intermediates mean that direct application to discovery chemistry is challenging. Herein, we describe a two-step synthesis of sulfondiimidamides, exploiting a hypervalent iodine-mediated amination as the key step. The starting materials are organometallic reagents, an unsymmetrical sulfurdiimide, and amines. The method allowed >40 examples to be prepared, including derivatives of three sulfonamide-based drugs. The operational simplicity, broad scope, and concise nature make this route attractive for discovery chemistry applications.

Transient ice loss in the Patagonia Icefields during the 2015-2016 El Niño event.

The Patagonia Icefields (PIF) are the largest non-polar ice mass in the southern hemisphere. The icefields cover an area of approximately 16,500 km2 and are divided into the northern and southern icefields, which are ~ 4000 km2 and ~ 12,500 km2, respectively. While both icefields have been losing mass rapidly, their responsiveness to various climate drivers, such as the El Niño-Southern Oscillation, is not well understood. Using the elastic response of the earth to loading changes and continuous GPS data we separated and estimated ice mass changes observed during the strong El Niño that started in 2015 from the complex hydrological interactions occurring around the PIF. During this single event, our mass balance estimates show that the northern icefield lost ~ 28 Gt of mass while the southern icefield lost ~ 12 Gt. This is the largest ice loss event in the PIF observed to date using geodetic data.

Photocatalytic Late-Stage Functionalization of Sulfonamides via Sulfonyl Radical Intermediates.

A plethora of drug molecules and agrochemicals contain the sulfonamide functional group. However, sulfonamides are seldom viewed as synthetically useful functional groups. To confront this limitation, a late-stage functionalization strategy is described, which allows sulfonamides to be converted to pivotal sulfonyl radical intermediates. This methodology exploits a metal-free photocatalytic approach to access radical chemistry, which is harnessed by combining pharmaceutically relevant sulfonamides with an assortment of alkene fragments. Additionally, the sulfinate anion can be readily obtained, further broadening the options for sulfonamide functionalization. Mechanistic studies suggest that energy-transfer catalysis (EnT) is in operation.

Cost-Effectiveness of Once-Weekly Semaglutide 1 mg versus Canagliflozin 300 mg in Patients with Type 2 Diabetes Mellitus in a Canadian Setting.

OBJECTIVE: Our objective was to evaluate the long-term cost-effectiveness of once-weekly semaglutide 1 mg versus once-daily canagliflozin 300 mg in patients with type 2 diabetes mellitus (T2DM) uncontrolled with metformin from the healthcare payer and societal perspectives in Canada. METHODS: Head-to-head data from the SUSTAIN 8 randomised trial (NCT03136484) were extrapolated over 40 years using economic simulation modelling. The cost-effectiveness of once-weekly semaglutide 1 mg versus canagliflozin 300 mg for treating T2DM was estimated using the Swedish Institute for Health Economics-Diabetes Cohort Model (IHE-DCM) and the Economic and Health Outcomes Model of T2DM (ECHO-T2DM). Unit costs and disutility weights capturing treatments and key macro- and microvascular complications were sourced from the literature to best match the Canadian setting. A probabilistic base-case simulation and sensitivity analyses were conducted. RESULTS: Once-weekly semaglutide 1 mg was associated with reductions in macro- and microvascular complications, yielding incremental cost-effectiveness ratios (ICERs) of (Canadian dollars [CAD]) CAD16,392 and 18,098 per incremental quality-adjusted life-year (QALY) gained versus canagliflozin 300 mg for IHE-DCM and ECHO-T2DM, respectively, from a healthcare payer perspective. Accounting for productivity loss as well, ICERs were CAD14,127 and 13,188 per QALY gained for IHE-DCM and ECHO-T2DM, respectively, from a societal perspective. Sensitivity analyses confirmed that the base-case results were robust to changes in input parameters and assumptions used. CONCLUSIONS: At a willingness-to-pay threshold of CAD50,000 per QALY gained, once-weekly semaglutide 1 mg was cost-effective over 40 years versus once-daily canagliflozin 300 mg for the treatment of T2DM in patients failing to maintain glycemic control with metformin alone.

Reductant-Free Cross-Electrophile Synthesis of Di(hetero)arylmethanes by Palladium-Catalyzed Desulfinative C-C Coupling.

An efficient Pd-catalyzed one-pot desulfinative cross-coupling to access medicinally relevant di(hetero)arylmethanes is reported. The method is reductant-free, and involves a sulfinate transfer reagent and a Pd-catalyst mediating the union of two electrophilic coupling partners; a (hetero)aryl halide and a benzyl halide. We establish for the first time that benzyl sulfinates, generated in situ, undergo efficient Pd-catalyzed desulfinative cross-coupling with (hetero)aryl halides to generate di(hetero)arylmethanes. The reaction can be extended to benzylic pseudohalides derived from benzyl alcohols. The reactions are straightforward to perform and scalable, and all reaction components are commercially available.

A Silyl Sulfinylamine Reagent Enables the Modular Synthesis of Sulfonimidamides via Primary Sulfinamides.

A new N-silyl sulfinylamine reagent allows the rapid preparation of a broad range of (hetero)aryl, alkenyl, and alkyl primary sulfinamides, using Grignard, organolithium, or organozinc reagents to introduce the carbon fragment. Treatment of these primary sulfinamides with an amine in the presence of a hypervalent iodine reagent leads directly to NH-sulfonimidamides. This two-step sequence is straightforward to perform and provides a modular approach to sulfonimidamides, allowing ready variation of both reaction components, including primary and secondary amines.

Diverse saturated heterocycles from a hydroacylation/conjugate addition cascade.

Rhodium-catalyzed hydroacylation using alkynes substituted with pendant nucleophiles, delivers linear α,ß-unsaturated enone intermediates with excellent regioselectivity. These adducts are used to construct a broad range of diversely substituted, saturated O-, N- and S-heterocycles in a one-pot process. Judicious choice of cyclisation conditions enabled isolation of O-heterocycles with high levels of diastereoselectivity. A variety of derivatisation reactions are also performed, generating functionalised hydroacylation products. This sequence serves as a general approach for the synthesis of fully saturated heterocycles.

The public economic burden of suboptimal type 2 diabetes control upon taxpayers in Sweden: Looking beyond health costs.

AIM: To estimate the fiscal burden for taxpayers in Sweden associated with type 2 diabetes (T2D) attributed to diabetes-related complications in patients failing to meet HbA1c targets. MATERIAL AND METHODS: We developed a public economic framework to assess how changes in diabetes-related complications influenced projected tax contributions and government disability payments for people with T2D. The analysis applied accepted disease-modelling practices to estimate different rates of diabetes-related complications based on an HbA1c of 6.9% (52 mmol/mol) and of 6.0% (42 mmol/mol). We adjusted the employment activity rates for those experiencing T2D-related events, applying age-specific earnings to estimate lifetime tax losses. Furthermore, the likelihood of receiving payments for health-related employment inactivity was estimated. Direct healthcare costs are excluded from this analysis. RESULTS: The estimated per person earnings loss for immediate and delayed HbA1c control was Swedish krona (SEK) 42 299 and SEK 44 157, respectively, over 10 years. The lost employment activity of people with T2D translates to lost tax revenues of SEK 23 265 and SEK 24 287 for immediate and delayed control, respectively. The estimated difference in disability payments was SEK 538. Combining the tax revenue loss and excess disability payments defines the broader fiscal costs, where we observe combined fiscal losses that favour immediate and sustained control by SEK 1560 over 10 years. CONCLUSIONS: We show that conducting fiscal analysis of diabetes interventions offers an enriched perspective capturing a range of costs that fall on government in relation to lost tax revenue and disability payments. Tax-financed health systems may benefit from broadening the consideration of costs and benefits when evaluating new interventions and treatment practices.

Health economic modelling of diabetic kidney disease in patients with type 2 diabetes treated with Canagliflozin in Belgium.

OBJECTIVES: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed reduced renal and cardiovascular (CV) events in patients with type 2 diabetes (T2D) and diabetic kidney disease (DKD) treated with canagliflozin 100 mg added to Standard of Care (SoC) versus SoC alone. This led to an extension of the canagliflozin 100 mg European marketing authorisation, making canagliflozin the first pharmacological therapy to receive authorisation for the treatment of DKD since the RENAAL and IDNT trials more than 20 years ago. Given the importance of cost-effectiveness analyses in health care, this study aimed to leverage the CREDENCE trial outcomes to estimate the cost-effectiveness of canagliflozin 100 mg from the perspective of the Belgian healthcare system. METHODS: A microsimulation model (CREDENCE Economic Model of DKD), developed using patient-level CREDENCE trial data, was leveraged to model the progression of DKD and CV outcomes, associated costs, and life quality. Unit costs and quality-adjusted life years (QALYs) were sourced from the literature. The time horizon was 10 years and sensitivity analyses were performed. RESULTS: Canagliflozin was associated with sizable gains in life-years and QALYs over 10 years, and the incremental cost-effectiveness ratio cost offsets associated with reductions in CV and renal complications resulted in overall net cost savings from the perspective of the Belgian healthcare system. CONCLUSION: Model-based results suggest that adding canagliflozin 100 mg to SoC can improve outcomes for patients with DKD while reducing overall net costs for the Belgian healthcare system.

Exploring Structural Uncertainty and Impact of Health State Utility Values on Lifetime Outcomes in Diabetes Economic Simulation Models: Findings from the Ninth Mount Hood Diabetes Quality-of-Life Challenge.

BACKGROUND: Structural uncertainty can affect model-based economic simulation estimates and study conclusions. Unfortunately, unlike parameter uncertainty, relatively little is known about its magnitude of impact on life-years (LYs) and quality-adjusted life-years (QALYs) in modeling of diabetes. We leveraged the Mount Hood Diabetes Challenge Network, a biennial conference attended by international diabetes modeling groups, to assess structural uncertainty in simulating QALYs in type 2 diabetes simulation models. METHODS: Eleven type 2 diabetes simulation modeling groups participated in the 9th Mount Hood Diabetes Challenge. Modeling groups simulated 5 diabetes-related intervention profiles using predefined baseline characteristics and a standard utility value set for diabetes-related complications. LYs and QALYs were reported. Simulations were repeated using lower and upper limits of the 95% confidence intervals of utility inputs. Changes in LYs and QALYs from tested interventions were compared across models. Additional analyses were conducted postchallenge to investigate drivers of cross-model differences. RESULTS: Substantial cross-model variability in incremental LYs and QALYs was observed, particularly for HbA1c and body mass index (BMI) intervention profiles. For a 0.5%-point permanent HbA1c reduction, LY gains ranged from 0.050 to 0.750. For a 1-unit permanent BMI reduction, incremental QALYs varied from a small decrease in QALYs (-0.024) to an increase of 0.203. Changes in utility values of health states had a much smaller impact (to the hundredth of a decimal place) on incremental QALYs. Microsimulation models were found to generate a mean of 3.41 more LYs than cohort simulation models (P = 0.049). CONCLUSIONS: Variations in utility values contribute to a lesser extent than uncertainty captured as structural uncertainty. These findings reinforce the importance of assessing structural uncertainty thoroughly because the choice of model (or models) can influence study results, which can serve as evidence for resource allocation decisions.HighlightsThe findings indicate substantial cross-model variability in QALY predictions for a standardized set of simulation scenarios and is considerably larger than within model variability to alternative health state utility values (e.g., lower and upper limits of the 95% confidence intervals of utility inputs).There is a need to understand and assess structural uncertainty, as the choice of model to inform resource allocation decisions can matter more than the choice of health state utility values.

Sulfonyl fluorides as targets and substrates in the development of new synthetic methods.

The advent of sulfur(VI)-fluoride exchange (SuFEx) processes as transformations with click-like reactivity has invigorated research into electrophilic species featuring a sulfur-fluorine bond. Among these, sulfonyl fluorides have emerged as the workhorse functional group, with diverse applications being reported. Sulfonyl fluorides are used as electrophilic warheads by both medicinal chemists and chemical biologists. The balance of reactivity and stability that is so attractive for these applications, particularly the resistance of sulfonyl fluorides to hydrolysis under physiological conditions, has provided opportunities for synthetic chemists. New synthetic approaches that start with sulfur-containing substrates include the activation of sulfonamides using pyrilium salts, the deoxygenation of sulfonic acids, and the electrochemical oxidation of thiols. Employing non-sulfur-containing substrates has led to the development of transition-metal-catalysed processes based on palladium, copper and nickel, as well as the use of SO2F2 gas as an electrophilic hub. Selectively manipulating molecules that already contain a sulfonyl fluoride group has also proved to be a popular tactic, with metal-catalysed processes again at the fore. Finally, coaxing sulfonyl fluorides to engage with nucleophiles, when required, and under suitable reaction conditions, has led to new activation methods. This Review provides an overview of the challenges in the efficient synthesis and manipulation of these intriguing functional groups.

Azine-N-oxides as effective controlling groups for Rh-catalysed intermolecular alkyne hydroacylation.

Heterocycle-derived aldehydes are challenging substrates in metal-catalysed hydroacylation chemistry. We show that by using azine N-oxide substituted aldehydes, good reactivity can be achieved, and that they are highly effective substrates for the intermolecular hydroacylation of alkynes. Employing a Rh(i)-catalyst, we achieve a mild and scalable aldehyde C-H activation, that permits the coupling with unactivated terminal alkynes, in good yields and with high regioselectivities (up to >20 : 1 l:b). Both substrates can tolerate a broad variety of functional groups. The reaction can also be applied to diazine aldehydes that contain a free N-lone pair. We demonstrate conversion of the hydroacylation products to the corresponding azine, through a one-pot hydroacylation/deoxygenation sequence. A one-pot hydroacylation/cyclisation, using N-Boc propargylamine, additionally leads to the synthesis of a bidentate pyrrolyl ligand.