Geriatric Services Hub - A Collaborative Frailty Management Model between The Hospital and Community Providers.

BACKGROUND: Frailty is an important geriatric syndrome especially with ageing populations. Frailty can be managed or even reversed with community-based interventions delivered by a multi-disciplinary team. Innovation is required to find community frailty models that can deliver cost-effective and feasible care to each local context. OBJECTIVES: We share pilot data from our Geriatric Service Hub (GSH) which is a novel frailty care model in Singapore that identifies and manages frailty in the community, supported by a hospital-based multi-disciplinary team. METHODS: We describe in detail our GSH model and its implementation. We performed a retrospective data analysis on patient characteristics, uptake, prevalence of frailty and sarcopenia and referral rates for multi-component interventions. RESULTS: A total of 152 persons attended between January 2020 to May 2021. Majority (59.9%) were female and mean age was 81.0 ± 7.1 years old. One-fifth (21.1%) of persons live alone. Mean Charlson Co-morbidity Index was 5.2 ± 1.8. Based on the clinical frailty risk scale (CFS), 31.6% were vulnerable, 51.3% were mildly frail and 12.5% were moderately frail. Based on SARC-F screening, 45.3% were identified to be sarcopenic whilst 56.9% had a high concern about falling using the Falls-Efficacy Scale-International. BMD scans were done for 41.4% of participants, of which 58.7% were started on osteoporosis treatment. In terms of referrals to allied health professionals, 87.5% were referred for physiotherapy, 71.1% for occupational therapy and 50.7% to dieticians. CONCLUSION: The GSH programme demonstrates a new local model of partnering with community service providers to bring comprehensive population level frailty screening and interventions to pre-frail and frail older adults. Our study found high rates of frailty, sarcopenia and fear of falling in community-dwelling older adults who were not presently known to geriatric care services.

Accelerating TB diagnosis during the COVID-19 pandemic.

SETTING: The COVID-19 pandemic has caused significant disruption worldwide to economies and healthcare systems, even those with well-developed infrastructure.OBJECTIVE: To examine the effects of COVID-19 on TB diagnosis in Singapore, and to identify any factors that could facilitate early detection of TB among persons screened.DESIGN: To assess the impact of testing and diagnosis of the pandemic on TB, the number of TB-related tests from January 2018 to December 2020 were collected. We also conducted a retrospective case-control study of all adult patients admitted for COVID-19, TB or coinfection from 23 January to 31 May 2020.RESULTS: Nationwide testing for TB from 2018 to 2020 increased by 24.2%. We analysed 253 adult inpatients, of whom 107 (42.3%) were diagnosed with COVID-19, 134 (53.0%) had TB, while 12 (4.7%) had co-infection. Patients with TB were more likely to have chest X-ray abnormalities than those with COVID-19 (89.9% vs. 76.0%; P < 0.01). Patients with TB were more likely to have prolonged cough vs. those with COVID-19 infection (28 vs. 5 days; P < 0.01).CONCLUSION: Early screening for TB, even among patients with COVID-19, could lead to earlier diagnosis and treatment, thereby breaking the chain of transmission.

Impact of pharmacist-involved collaborative care on the clinical, humanistic and cost outcomes of high-risk patients with type 2 diabetes (IMPACT): a randomized controlled trial.

WHAT IS KNOWN AND OBJECTIVE: With the increasing prevalence of diabetes, the physician-centred model is challenged to deliver holistic care in Asia. Diabetes may be managed effectively within a multidisciplinary collaborative care model; however, evidence on its effectiveness in Asian patients is lacking. Therefore, the primary objective was to evaluate the clinical outcomes of multidisciplinary collaborative care vs physician-centred care in diabetes. The secondary objectives were to evaluate humanistic and economic outcomes among the two types of care. METHODS: This 6-month prospective, open-label, parallel-arm, randomized, controlled study was conducted at four outpatient healthcare institutions. High-risk patients aged ≥21 years with uncontrolled type 2 diabetes, polypharmacy and comorbidities were included. Patients with type 1 diabetes or those who were unable to communicate independently were excluded. The control arm received usual care with referrals to nurses and dietitians as needed. The intervention arm (multidisciplinary collaborative care) was followed up with pharmacists regularly, in addition to receiving the usual care. The primary outcomes included HbA1c, systolic blood pressure, low-density lipoprotein and triglycerides. The secondary outcomes included scores from the Problem Areas in Diabetes (PAID) and the Diabetes Treatment Satisfaction Questionnaires (DTSQ), and diabetes-related health service utilization rates and costs. RESULTS AND DISCUSSION: Of 411 eligible patients, 214 and 197 patients were randomized into the intervention and control arms, respectively. At 6 months, 141 patients in the intervention arm (65.9%) and 189 patients in the control arm (95.9%) completed the study. Mean HbA1c reduced from 8.6%±1.5% at baseline to 8.1%±1.3% at 6 months in the intervention arm (P=.04), with up to mean HbA1c improvement of 0.8% in patients with greater levels of uncontrolled glycemia. Whereas the mean HbA1c in the control arm remained unchanged (8.5%±1.4%) throughout the 6-month period. Improvements in PAID and DTSQ scores, reduction in physician workload and an average cost savings of US$91.01 per patient were observed in the intervention arm over 6 months. WHAT IS NEW AND CONCLUSIONS: The positive clinical, humanistic and economic outcomes highlighted the value of multidisciplinary collaborative care for Asian diabetic patients, thereby supporting the effectiveness of this approach in managing chronic diseases.

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML.

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations.

TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties.

TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis. Primary cultures of progenitor cells derived from acute myeloid leukemia (AML) and polycythemia vera patients are very sensitive to TG02. Comparison with reference inhibitors that block only one of the main targets of TG02 demonstrate the benefit of combined CDK and JAK2/FLT3 inhibition in cell lines as well as primary cells. In vivo, TG02 exhibits favorable pharmacokinetics after oral dosing in xenograft models and accumulates in tumor tissues, inducing an effective blockade of both CDK and STAT signaling. TG02 induces tumor regression after oral dosing on both daily and intermittent schedules in a murine model of mutant-FLT3 leukemia (MV4-11) and prolongs survival in a disseminated AML model with wild-type FLT3 and JAK2 (HL-60). These data demonstrate that TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias.

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies.

SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.

Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia.

FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC(50)=22 n) and Janus kinase 2 (JAK2, IC(50)=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy.

The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin.

Protein kinase RNA-regulated (PKR) is an established component of innate antiviral immunity. Recently, PKR has been shown to be essential for signal transduction in other situations of cellular stress. The relationship between PKR and the stress-activated protein kinases (SAPKs), such as p38 mitogen-activated protein kinase (MAPK), is not clear. Using embryonic fibroblasts from PKR wild-type and null mice, we established a requirement for PKR in the activation of SAPKs by double-stranded RNA, lipopolysaccharide (LPS) and proinflammatory cytokines. This does not reflect a global failure to activate SAPKs in the PKR-null background as these kinases are activated normally by anisomycin and other physicochemical stress. Activation of p38 MAPK was restored in immortalized PKR-null cells by reconstitution with human PKR. We also show that LPS induction of interleukin-6 and interleukin-12 mRNA is defective in PKR-null cells, and that production of these cytokines is impaired in PKR-null mice challenged with LPS. Our findings indicate, for the first time, that PKR is required for p38 MAPK signaling and plays a potentially important role in the innate response against bacterial endotoxin.

Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways.

Interferons (IFNs) inhibit cell growth in a Stat1-dependent fashion that involves regulation of c-myc expression. IFN-gamma suppresses c-myc in wild-type mouse embryo fibroblasts, but not in Stat1-null cells, where IFNs induce c-myc mRNA rapidly and transiently, thus revealing a novel signaling pathway. Both tyrosine and serine phosphorylation of Stat1 are required for suppression. Induced expression of c-myc is likely to contribute to the proliferation of Stat1-null cells in response to IFNs. IFNs also suppress platelet-derived growth factor (PDGF)-induced c-myc expression in wild-type but not in Stat1-null cells. A gamma-activated sequence element in the promoter is necessary but not sufficient to suppress c-myc expression in wild-type cells. In PKR-null cells, the phosphorylation of Stat1 on Ser727 and transactivation are both defective, and c-myc mRNA is induced, not suppressed, in response to IFN-gamma. A role for Raf-1 in the Stat1-independent pathway is revealed by studies with geldanamycin, an HSP90-specific inhibitor, and by expression of a mutant of p50(cdc37) that is unable to recruit HSP90 to the Raf-1 complex. Both agents abrogated the IFN-gamma-dependent induction of c-myc expression in Stat1-null cells.

p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons.

Activation of cytosolic phospholipase A(2 )(cPLA(2)) is a prerequisite for the formation of the transcription factor complex interferon-stimulated gene factor 3 (ISGF3) in response to interferon-alpha (IFN-alpha). Here we show that p38 mitogen-activated protein kinase (MAPK), an activator of cPLA(2), is essential for both IFN-alpha and IFN-gamma signalling. SB203580, a specific inhibitor of p38, was found to inhibit ISGF3 formation but had no apparent effects on signal transducer and activator of transcription (STAT)1 homodimer formation. Regardless of this, the antiviral activities of both IFN-alpha and IFN-gamma were attenuated by SB203580. Treatment with either IFN led to rapid and transient activation of p38. Both IFNs induced STAT1 Ser727 phosphorylation, which was inhibited by SB203580 but not by an extracellular signal related kinase (ERK)1/2 inhibitor (PD98059). In an inducible 3T3-L1 clone, expression of dominant-negative p38 led to defective STAT1 serine phosphorylation and diminished IFN-gamma-mediated protection against viral killing. Reporter activity mediated by ISGF3 or STAT1 homodimer was diminished by SB203580 and enhanced by a constitutively active mutant of MKK6, the upstream activator of p38. Therefore, p38 plays a key role in the serine phosphorylation of STAT1 and transcriptional changes induced by both IFNs.

Suc1-associated neurotrophic factor target (SNT) protein is a major FGF-stimulated tyrosine phosphorylated 90-kDa protein which binds to the SH2 domain of GRB2.

In Swiss 3T3 fibroblasts, basic fibroblast growth factor (bFGF) stimulates the unique tyrosine phosphorylation of a protein complex around 90 kDa, as ascertained by high resolution 2-D PAGE and anti-phosphotyrosine blotting. The majority of this complex consists of the protein(s) designated previously as SNT (suc1-associated neurotrophic factor target). Tyrosine phosphorylated SNT binds to both p13suc1 protein and the SH2 domain of Grb2. Binding of SNT to Grb2 is likely to be mediated through the consensus binding motif, pYXN, on SNT. The binding of SNT to p13suc1 is independent of the pYXN motif. Tyrosine phosphorylated SNT is localised in the plasma membrane where it could form a complex with Grb2 and Sos, enabling the initiation of a novel FGF-specific signalling pathway.

Identification of p90, a prominent tyrosine-phosphorylated protein in fibroblast growth factor-stimulated cells, as 80K-H.

Tyrosine phosphorylation of cellular proteins occurs rapidly upon treatment of fibroblasts with acidic or basic fibroblast growth factors (aFGF, bFGF), suggesting a role for protein phosphorylation in the FGF signaling pathway. Stimulation of Swiss 3T3 cells and MRC-5 fibroblasts with bFGF results in the tyrosine phosphorylation of several proteins, of which the most prominent has been designated as p90. The phosphorylation of p90 is observed within 30 s of treating the cells with FGF but not with other growth factors. Microsequencing of p90 resolved on two-dimensional polyacrylamide gel electrophoresis indicated an N-terminal amino acid sequence which corresponded to a protein previously named as 80K-H. Polyclonal antibodies raised against the predicted C terminus of 80K-H recognized p90 on all Western blots. p90 was found to bind specifically to GRB-2-glutathione S-transferase fusion protein and to be immunoreactive with 80K-H antibody. In addition, anti-phosphotyrosine antibodies immunoprecipitated 80K-H from cell lysates of FGF-stimulated but not from control fibroblasts. The biological function of 80K-H is yet unknown. However, from this study and a previous observation of the obligatory dependence of p90 phosphorylation on FGF receptor occupation, it appears that 80K-H is involved in FGF signaling.

Prediction of arterial blood gases by transcutaneous O2 and CO2 in critically ill hyperdynamic trauma patients.

The management of severe adult respiratory distress syndrome in critically injured patients requires the frequent measurement of arterial blood gases for adjustment of cardiovascular and ventilatory support. Since these require blood withdrawal and laboratory determinations, a noninvasive method of assessment of arterial gas tensions would permit more frequent assessment of the patient as well as permitting rapid changes in the patient's ventilatory status to be detected earlier in the clinical course. The role of transcutaneous O2 and CO2 tension in providing these measurements was evaluated in 92 studies in 38 critically ill patients with ARDS due to trauma and/or sepsis. All patients were normodynamic or hyperdynamic at the time of study (cardiac index 2.5 to 7.6 L/min/m2) and were intubated and on increased inspired oxygen fractions (FIO2 = 30 to 100%) delivered by mechanical ventilation, had a range of body temperature from 35.0 to 39.5 degrees C and pH from 7.29 to 7.57 The data from a transcutaneous O2 and CO2 sensor applied to the skin of the anterior thorax were analyzed by multiple regression analysis of variances. Prediction of the arterial oxygen tension (PaO2) from 52 to 253 torr was possible from regression-corrected measurements of the transcutaneous O2 (TcO2): [PaO2 = 1.1 (TcO2) - 0.28 (FIO2) + 45.5]. The arterial carbon dioxide tension (PaCO2) from 26 to 57 torr was predicted from the transcutaneous CO2 (TcCO2):[PaCO2 = 0.76 (TcCO2) + 0.06 (FIO2) + 0.035 (TcO2) + 4.1]. With these corrections, a noninvasive Respiratory Index was computed for assessing ARDS severity, and dynamic changes in arterial gases could be followed in response to postural changes, ventilatory alterations, or cardiovascular perturbations. These data suggest that a reasonable estimate of the arterial blood gases can be obtained from a regression-corrected measurement of the transcutaneous O2 and CO2 tensions in critically injured normodynamic or hyperdynamic ARDS patients.

Epicardial electrical activation analyzed via frequency-wavenumber spectrum estimation for the characterization of arrhythmiagenic states.

The application of a new signal processing methodology to the analysis of epicardial array ECG signals is presented as an alternative to isopotential or isochrones mapping by the use of a zero-delay wavenumber spectrum (ZDWS) estimation technique. The methodology "explains" the array data as the sum of modulated wideband (non-sinusoidal) propagating waves projected onto the array plane and provides an accurate estimate of their number and bearing. The slowness distribution of each of the waves is then obtained by estimating their temporal spectrum. In this experimental study the effects of localized noninfarcting reversible low flow ischemia, digoxin toxicity and verapamil reversal of digoxin toxicity are quantified via the ZDWS methodology and are compared with the information that can be extracted from isopotential mapping. It is demonstrated that the ZDWS methodology permits the epicardial electric activation to be decomposed into a number of quantification parameters which possess a hierarchical "tree" structure and therefore provide a means for an objective and robust characterization of the effects of agents which alter myocardial conduction and arrhythmia generation.

Advanced signal-processing method for the detection, localization, and quantification of acute myocardial ischemia.

In this study of a canine heart model of localized reversible ischemia, a computer-based single-processing method is developed to detect and localize the epicardial projections of ischemic myocardial electrocardiograms (ECGs) during the cardiac activation, rather than the repolarization, phase. This is done by transforming ECG signals from an epicardial sensor array into the multichannel spectral domain and identifying three decision variables: (1) the frequency in hertz of the spectral peak (f0), its frequency band width 50% below the peak value (w0), and the maximum eigenvalue difference of the ECG signal's autocorrelation matrix (e0). With use of the histograms of the f0, w0, and e0 parameters of 3256 ECGs from normal and 957 from ischemic areas of myocardium obtained from 12 dogs, it was possible to predict ischemia in a new test group of nine animals from a Neyman-Pearson (NP) test in which the threshold probabilities of detecting ischemia for each decision variable are compared with those of detecting normality. Quantification of each sensor area by the NP tests revealed that, compared with the control, ECG spectra with decreased F0 and w0 and increased e0 relative to their respective thresholds had increased myocardial lactate (p less than 0.01), decreased adenosine triphosphate (ATP) (p less than 0.05), and reduced creatine phosphate (p less than 0.01). Prediction of f0 (p less than 0.0006) as a continuous variable could be obtained from the regression of the myocardial levels of ATP plus creatine phosphate, which demonstrated that this decision variable appears to directly reflect myocardial energetics. It appears that an advanced signal-processing method for ECG array data can be used to detect, localize, and quantify reversible myocardial ischemia.

Quantification of asymmetric lung pathophysiology as a guide to the use of simultaneous independent lung ventilation in posttraumatic and septic adult respiratory distress syndrome.

The management of impaired respiratory gas exchange in patients with nonuniform posttraumatic and septic adult respiratory distress syndrome (ARDS) contains its own therapeutic paradox, since the need for volume-controlled ventilation and PEEP in the lung with the most reduced compliance increases pulmonary barotrauma to the better lung. A computer-based system has been developed by which respiratory pressure-flow-volume relations and gas exchange characteristics can be obtained and respiratory dynamic and static compliance curves computed and displayed for each lung, as a means of evaluating the effectiveness of ventilation therapy in ARDS. Using these techniques, eight patients with asymmetrical posttraumatic or septic ARDS, or both, have been managed using simultaneous independent lung ventilation (SILV). The computer assessment technique allows quantification of the nonuniform ARDS pattern between the two lungs. This enabled SILV to be utilized using two synchronized servo-ventilators at different pressure-flow-volumes, inspiratory/expiratory ratios, and PEEP settings to optimize the ventilatory volumes and gas exchange of each lung, without inducing excess barotrauma in the better lung. In the patients with nonuniform ARDS, conventional ventilation was not effective in reducing shunt (QS/QT) or in permitting a lower FIO2 to be used for maintenance of an acceptable PaO2. SILV reduced per cent v-a shunt and permitted a higher PaO2 at lower FIO2. Also, there was x-ray evidence of ARDS improvement in the poorer lung. While the ultimate outcome was largely dependent on the patient's injury and the adequacy of the septic host defense, by utilizing the SILV technique to match the quantitative aspects of respiratory dysfunction in each lung at specific times in the clinical course, it was possible to optimize gas exchange, to reduce barotrauma, and often to reverse apparently fixed ARDS changes. In some instances, this type of physiologically directed ventilatory therapy appeared to contribute to a successful recovery.