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Immunotherapy and associated immune-related adverse events at a large UK centre: a mixed methods study
Liz Jamieson1,
Martin D. Forster2,3,4,
Kam Zaki3,
Sanjena Mithra3,
Heena Alli4,
Anne O'Connor4,
Apini Patel4,
Ian C. K. Wong1,5 &
Pinkie Chambers ORCID: orcid.org/0000-0002-6669-94111,4
The development and rapid uptake of immune checkpoint inhibitors (CPI) has changed the outlook for patients with cancer. However, CPIs have different adverse event (AE) profiles to other systemic therapies, and prompt AE management is essential to assure optimal outcomes. In order to understand what and when adverse events are experienced, reported and managed during CPI treatment, a mixed methods study was conducted, including a case note review of patients who were receiving immunotherapy and semi-structured interviews with patients to understand their experience, management and reporting of AEs after receiving immune CPI treatment.
This mixed methods study was conducted at a large cancer hospital in the United Kingdom. A case note review identified how and where patients reported AEs. Data relating to patients with lung, bladder, prostate and head & neck cancers who received CPI treatment between 01/04/2015 and 31/07/2018 were extracted from e-prescribing databases and clinical data were included for analysis at a single time point (31 July 2018). Semi-structured interviews were conducted with patients receiving CPI treatment, exploring experience of AEs and reasons for delays in AE reporting and management.
Sixty-two patients were included in the case note review, with 78 AEs being experienced by 36 patients (58%), including one patient experiencing 10 AEs. Serious AEs were experienced by 12 patients (19%) and ten AEs (17%) required oral steroids as treatment. The majority of AEs were reported to clinicians prior to further dosing, although milder AEs were often not addressed until subsequent clinic appointments. Interviews with 13 patients yielded major themes: variability, causality, decision making and impact.
Most CPI-associated AEs are manageable if reported and treated promptly. Both the case note review and interviews found that reporting of non-serious AEs is often left until routine clinic visits, despite impacting patient experience, leaving the opportunity for AEs to be left unreported and implying a potential benefit for real time monitoring. Our study highlights a need to provide patients with reminders around AEs and their timely reporting even when apparently innocuous; patients must understand that AEs can occur at any cycle and even following treatment completion.
The development and rapid uptake of immunotherapy agents, namely immune checkpoint inhibitors (CPI), is changing the outlook for the treatment of many solid cancers. Long-lasting responses observed in some patients has supported the expansion of their use for a number of malignancies. Additionally, use of combination approaches is growing, with chemotherapy, targeted therapies (such as axitinib for advanced kidney cancer [1], radiotherapy or other novel immune modulating agents. However, caution must temper the excitement of treatment with these agents. Although largely well tolerated, CPIs can generate toxicities including immune-related adverse events (irAEs) [2]. The release of the immune system to activate and expand to fight the cancer may cause inflammation, tissue damage, and even misdirected immune activation against the patient's own body [3, 4]. Immune checkpoints importantly contribute to the regulation of peripheral tolerance of tissue-specific self-antigens. Therapeutic blockade of these checkpoints may result in a disruption of the balance between tolerance and immunity. This may lead to the development of irAEs although immune regulation is complex and other mechanisms such as epitope spreading may also contribute.
IrAEs mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue [3]. Meta-analyses of clinical trials have shown that 27% of patients treated with CPI inhibitors develop irAEs of some degree, with 6% being severe; a minority experience rare but important side effects that may result in treatment discontinuation [5]; however, the quality of irAE reporting in clinical trials has been shown to be suboptimal [6] and it is likely to be less consistent outside of a clinical trial setting. A more recent systematic review and meta-analysis of 125 studies by Wang et al. (2019) in relation to Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials found that there was an incidence of at least 66% of patients having 1 irAE or more, with 14% having grade 3 irAEs [7].
The reporting of irAEs is dependent on successful education of patients and carers. Most irAEs experienced due to CPI treatment are mild or moderate and management can be simple if they are recognised early and appropriately treated; with prompt treatment enabling patients to receive the best possible outcomes. However, if not managed quickly and effectively, irAEs can cause long-term harm to patients and are more likely to deem them ineligible for further treatment [8]. It is therefore essential to have effective irAE management pathways in place, to ensure safe delivery and maximise the potential of the agents.
Understanding the reasons for patients' delay in reporting AEs and subsequent management is fundamental to improving management pathways. Studies in the chemotherapy setting have shown improved outcomes for those reporting chemotherapy toxicity promptly [5]. However, due to the limited experience of wider health professionals around CPI treatment, it is not currently clear why delays in management may be occurring. The use of CPI both in studies and within licensed use has exploded over recent years; much of the available data around irAEs stems from clinical trials, and research is ongoing in the real-world patient populations [9].
The aim of our study was to evaluate all AE reporting and subsequent management in patients receiving CPI treatment. AEs included any AEs that were believed to be treatment-related and this would include irAEs.
We conducted a mixed methods study to fully understand the reporting management pathway for all AEs experienced during CPI treatment, consisting of a retrospective case note review and semi-structured interviews with a subset of these patients. The case note review study was designed to evaluate the types and numbers of AEs experienced and to ascertain where reporting took place and where and how management was initiated. The interviews enabled a more detailed understanding of the patient experience in order to understand any reasons for delays in reporting and management.
Patients were included if aged 18 or above and had received CPI (+/− chemotherapy) at UCLH since treatment was available for Lung, Head and Neck, Prostate, and Bladder cancer within late phase studies, early access schemes (EAS) or as standard of care. Patients were excluded if they were receiving treatment within an early phase trial or a placebo-controlled trial in order to ensure that all patients were on a standard CPI. Patients were only included in the interview study if they had received at least 1 cycle of treatment and were receiving or had received CPI treatment within a 6-week window. Further exclusions for the interview element were if patients were unable to make an informed decision to take part or if they did not speak English and a suitable translator was not found.
Case note review data collection and analysis
Patients were identified through electronic prescribing (EP) systems at UCLH. The following patient details were extracted: age, details of co-morbidities, previous and subsequent treatments, date of first CPI dose, date of death (or the last follow up), number of treatment cycles and deferrals. Two members of the clinical care team (SM and PC) conducted a case note review using electronic hospital records to extract the data, using a structured data extraction form (see supplementary Table 1). This documented the regimen received and the healthcare management of AEs experienced and reported by the patients, along with timing and grade of AEs. Data were recorded electronically and analysed using SPSS version 24 for analysis (SPSS Inc., Chicago, IL, USA). Descriptive statistics were used to summarise the findings.
AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [10]. Grade 1 was defined as a mild AE, grade 2 as moderate and grades 3/4 classed as severe. Some patients were taking part in a clinical trial and in these cases trial criteria were used to grade the irAE.
AEs were categorised into organ-specific groups for analysis. We used the coding system of Mekki et al. (2018) to help classify the adverse events [11]. General AEs encompassed non-specific symptoms including fatigue/lethargy, asthenia, pyrexia, and decreased appetite.
Semi structured interview data collection and analysis
Eligible patients were identified sequentially by clinical pharmacists working in clinical care teams (AP, HA or AOC) through the chemotherapy electronic prescribing records and recruited in the clinic setting.
Information sheets were then given to eligible patients and informed written consent was taken prior to taking part in an interview. Screening logs documented reasons for ineligibility and/ or non-participation of eligible candidates.
Semi-structured interviews were conducted by LJ either on the telephone or face-to-face according to patient preference using an interview guide that was developed specifically for this study by LJ, PC and MDF and has not been published elsewhere (see supplementary file 2). The interview guide included questions relating to patient experience of CPI treatment, irAE reporting, management and impact. With patient permission, interviews were audio-recorded. Due to the nature of the topics discussed in the interview, a safety review was conducted with an independent clinician (KZ) to ensure that all irAEs had been appropriately reported to responsible clinicians. Patients were informed at the start of the interview that this check was necessary for their safety, as the interviewer was non-clinical.
Interview data were transcribed verbatim and identifying data removed. Transcripts were read and coded independently by author LJ and a sample coded by author PC using a general thematic coding methodology. LJ selected all citations that were relevant to the semi-structured questions and coded these into themes using descriptive content analysis. Citations within each theme were further analysed and arranged into subcategories using an inductive process. The team discussed any discrepancies until consensus was reached. The initial coding framework was used to code the subsequent transcripts, and new codes were added as they emerged using a constant comparative technique to compare new and previously collected data to understand emerging themes. Finally, LJ examined the raw data again to ensure that all data were reflected in the coding. The qualitative analysis was facilitated by the use of NVivo software (QSR International [UK] Limited, Southport, UK).
Table 1 provides an overview of the demographics of patients included in the two elements of the study. The majority of patients in the study were receiving treatment for non-small cell lung cancer (NSCLC), were male, with a median age of 66.
Table 1 Overview of Patients included in the study
Table 2 shows an overview of AEs from the case note review. The total number of any grade AEs in our case note review was 78, experienced by 36 patients (58%) in 65 episodes, with one patient experiencing 10 AEs. Twenty-six patients (42%) did not experience any documented AEs, 22 of these patients having received fewer than 3 cycles and therefore presumably having little time to experience an AE. Twelve people (19%) experienced at least one serious adverse event. Nine patients had multiple synchronous AEs, where two or three AEs were reported at the same time. The most common any-grade AEs were gastrointestinal (mainly diarrhoea), general (fatigue, fever etc.), respiratory (breathlessness, wheezing) and skin problems (itching, rash). Serious AEs accounted for 21% of the total AEs and included gastrointestinal (multiple GI symptoms), respiratory (acute breathlessness) and rheumatological issues (joint problems).
Table 2 Sites of AEs by Grade Following Cycle of Treatment
Management of AEs
From the case note review, the majority of mild or moderate AEs were reported to a doctor (oncologist) at a scheduled pre-treatment clinic visit as shown in Table 3. Ten AEs (experienced by 10 patients) required oral steroids as treatment. Steroids were prescribed in accordance with the European Society of Medical Oncology guidelines [12]. Specifically, the AEs that led to steroid initiation were diarrhoea (n = 6), derangement in liver function (n = 1), pain (n = 2), and shortness of breath (n = 1). Although systemic steroids are primarily used in the management of moderate-severe grade AEs, one patient with a mild but persistent AE also required systemic steroids. The time to initiate steroid was dependent both on the time of AE reporting and severity of the AE. Seven of the ten patients given steroids had either presented via the Emergency Department (ED) or required a hospital admission. Overall, eight AEs resulted in a hospital admission and 8 in attendance at the ED, the patient either going straight there or advised to attend ED by helpline staff and one patient was admitted to hospital when AEs were reported in clinic.
Table 3 Method of reporting immune related adverse events by patients
Figure 1 depicts the recruitment of patients for interviews. In total 13 patients participated in the interview study and Fig. 2 shows the initial model that was developed through thematic analysis of the interview data (Supplementary file 2 (tables 2–5) contain supporting quotes for the development of themes from the interview data).
Flow diagram of Patients Recruited to the Interview Study
Thematic model of Patient Experiences with irAEs
Some of these initial themes were subsumed under overarching themes: in relation to diagnosis, reporting and management of irAEs, variability, causality, decision-making and impact.
Variability was found across the following
Patient histories (prior treatments, co-existing conditions and other medications)
Knowledge and understanding of immunotherapy and what constitutes an adverse event (how CPI work, realisation and knowledge that CPIs are a new, expensive treatment, understanding of the information seeking
Type and number of irAEs experienced
Time to irAE
Patients receiving CPI treatment varied significantly in their medical histories, personal experiences and other co-morbidities (e.g. diabetes, stroke, COPD, arthritis), all of which contributed to their experience and management of AEs. This variability was also seen in their knowledge and understanding of AEs, despite all receiving treatment at the same hospital. Most patients knew the name of their treatment, even if they were unable to pronounce it. Some referred to it by the trade name, e.g. Tecentriq. Patients had mixed understanding of how CPI works. However, all understood that immunotherapy is a new treatment and there is a need for further research as to its effectiveness. Most people had some recollection of types of AEs to look out for, but several people had sought out further information, either from friends or family or from the internet. One man had obtained additional leaflets from the MacMillan Cancer Centre Information point.
The number of cycles of immunotherapy treatment that the participants had received ranged from 2 to 30 with a median of 9.
There was some confusion about what constituted an AE. The impact or potential impact of treatment was a factor that influenced reporting. All patients who had experienced prior chemotherapy or radiotherapy described feeling physically much better very soon after commencing the CPI treatment. There was a wide range of AEs discussed by participants that varied in presentation and onset. Six patients had not experienced any AEs at all, whereas others had quite severe symptoms such as breathlessness, skin problems, and diarrhoea.
Justification of symptoms by patients (symptom(s) related to cancer, symptom(s) legacy from prior treatment, e.g. chemotherapy or radiotherapy, symptom(s) related to other medication and psychological side effects, e.g. tiredness, anxiety, psychosomatic symptoms
Personalisation – "normalisation" of symptoms by patients
Uncertainty on the part of clinicians
Understanding the causality of symptoms by both patients and healthcare professionals came through as a theme influencing reporting and management. Patients ignored symptoms such as tiredness, flaky nails, mild aches and pains; one or two people denied experience of any AEs and then described potential AEs on further questioning. Determination of causality was often a process of elimination whereby patients tried to reason whether a symptom was likely to be caused by the cancer itself, or the treatment: examples include tiredness and breathlessness, especially in patients with NSCLC. Sometimes patients felt that the symptoms were caused by other medication, e.g. sleepiness or diarrhoea, or by other factors such as having eaten something, being abroad, or diarrhoea causing fatigue. Patients used personalisation, i.e. what is 'usual' or 'normal' for them to judge the type and severity of any AE using that as a benchmark in this appraisal process. A few patients also believed that AEs would only occur when commencing treatment (within the first few cycles) and seemed unaware that occurrence could be at any point.
"It all started after the 5th cycle. I started to get the diarrhoea and I never actually gave it a thought that it was anything to do with the treatment…The thing about the diarrhoea was it didn't wake me up so I went, I was going, say, 5 or 6 times during the day but not the night, I wasn't feeling sick, I had no stomach cramps. No nausea, my appetite was okay so I thought this is strange". [0004]
"I never actually gave it a thought that it (the diarrhoea) was anything to do with the treatment." [0003]
Clinicians and patients alike were often unsure whether an AE was related to the CPI treatment or not, mainly due to multiple possible confounding factors, and would frequently choose to monitor symptoms initially. This was seen in the case note review when patients had gaps in the treatment schedule from commencing steroid.
"… they thought it might have been a clot on the PICC line, but they did a scan and that was all fine, so they eliminated that, they eliminated any sort of blood clots around the line or anything, and came to the conclusion that it probably was the drug, that was like a reaction to it." [0007].
Reporting a potential irAE by patients (how reported, factors affecting method of reporting, length of time to report, factors affecting length of time to report)
Management of a potential irAE by patients (self-medication, forums and websites, other strategies)
Management of a potential irAE by clinicians (medication, input from other specialists/ liaising with hospitals, send patient to A&E, hospitalisation)
A theme of considered decision making by the patient and health professionals contacted was frequently found in the interviews. Some participants reported AEs quickly via the hospital helpline whereas some patients waited to discuss symptoms at the next clinic appointment.
.. "so this was a period of days before your next clinic?"[interviewer] "It was a week". [0002]
Most patients preferred to wait until their next clinic appointment to discuss any symptoms with their clinician; this was observed in both the case note review and interviews. Participants described how they viewed their oncologist as the expert but also, they often did not believe their symptom(s) to be serious. Some patients were reluctant to call hospital helplines not wanting to be a nuisance and recognising that clinic staff were very busy.
"I did that a couple of times, had to phone out-of-hours, and in general, they're going, "Oh, I don't know, can you phone back in the morning". [0002]
"I actually virtually crashed in the clinic. And they looked after me until they could get me round to A&E (Accident & Emergency/ ED), who looked after me some more while they all decided what was wrong with me, a big committee of doctors surrounding me in resus (resuscitation) in A&E, and eventually at about eleven o'clock at night they threw me in an ambulance and shot me off to hospital". [0002]
Some patients tried to manage their irAE by self-medication using their community pharmacies, e.g. E45 cream for skin problems, Imodium for diarrhoea, naproxen for arthritis, paracetamol for pain. Advice was gained from forums and websites involving others experiencing similar symptoms. Patients additionally described discussions with family members and knowledgeable friends.
Management of AEs by clinicians included giving medication for symptoms, e.g., antibiotics, steroids, or obtaining input from specialists such as rheumatology and haematology or by liaising with other hospitals. Several patients spoke of being directed to A&E by the clinic staff or, in one or two cases, hospitalised.
Of CPI treatment (Physical, Psychological)
° Of irAE (Physical, Psychological)
All patients who had experienced prior chemotherapy or radiotherapy described feeling physically better very soon after commencing the CPI treatment.
Apart from the physical impact of the disease and immunotherapy treatment, patients also described psychological side effects, some of which were related to the CPI treatment itself, for example, their own expectations and the significance of the treatment being their last chance at extending their life. The gratitude felt by patients receiving treatment meant that they did not like to complain. Other patients who were approaching the end of the two-year period on CPI treatment spoke about their worry about what, if anything, could or would be offered next and whether the cancer would return. Many patients experienced cyclical anxiety and spoke about the fear that they experienced prior to having a scan and attending clinic for the result, and the huge disappointment they experienced if the scan results were not favourable or relief if it was a positive outcome.
…"If they say, at some point, "You can't have it any more because it's doing you more harm than good", then quite what plan B will be, I don't know, and I don't really want to think about plan B until plan A is no longer an option" [0002]
Our case note review findings of 58% of patients experiencing any grade AEs and 19% serious AEs is similar to the findings of the Keynote-042 trial involving pembrolizumab, where 63% experienced any grade AE and 18% events of grade 3 or worse severity, mainly pneumonitis, severe skin reactions, and hepatitis [13].
This study, which supplements a case note review with detailed patient interviews, helps to understand where interventions should be targeted to improve the management pathways for irAEs. We found from our case note review that many 'minor' AEs are left unreported and clinic assessments prior to treatment provide patients the opportunity to relay Information. However, it is unclear whether these AEs would have ever been reported without prompting, or how many other AEs may often be left unreported. Findings from this mixed methods study were that patients were not accessing prompt management by delaying seeking help for their AEs; especially if they inferred them as either trivial or non-treatment related.
In many cases the timing of AE management may be insignificant; however, from our case note review we found examples of cases where minor AEs escalated to major ones and, in turn, required hospital admissions. This is similar to findings by Basch et al. [14] where symptom reporting in real time, in patients receiving chemotherapy rather than immunotherapy, led to reduced hospital admissions. Approximately one sixth of patients attended the emergency departments (ED), either directly or following guidance provided by the emergency helpline, because of an AE, highlighting the potential burden that these agents may add to the health system as their use expands. This figure may reduce with better management strategies, including prompt reporting. The current and future economic impact of this additional caseload on emergency departments is unknown.
In observing the variety of AEs seen, we noted the role of multiple specialisms, where input is essential to assure patient safety. Specialisms such as rheumatology and endocrinology are commonly called upon to provide specialist input. A recent cross-sectional study [15] using an algorithm-driven approach to characterize immune-related adverse events found that the diagnosis and characterization of immune-related adverse events are challenging. There was poor concordance of interrater agreement in the occurrence, severity, and timing of 8 common immune-related adverse events. Discordance was associated with longer durations of therapy and higher comorbidity burden in patients.
Interestingly, the themes we found from the interview data were remarkably concordant with the work of Scott et al. [16] in the early diagnosis of cancer setting. This model, known as Walter's model, considers the contribution of patients, providers/system and disease factors to four intervals: (Symptom) Appraisal, Help-seeking, Diagnostic and Pre-treatment. It is presented mainly as a linear sequence leading to diagnosis but acknowledges the possibility that patients move back and forth between intervals in consultation with healthcare professionals (HCPs). The theme of variability would feature in contributing factors; causality would represent the appraisal process and decision-making could be considered to be the appraisal and help seeking stage. We found there were delays by patients in appraisal as well as help-seeking. We believe this is the first study where AE management in cancer patients has been found to be remarkably similar to pathways for diagnosis of cancer, supporting use of this model to guide understanding around delays to treatment as others have done in the early diagnosis setting.
An area where the Walters model could be further tailored to toxicity management for newer treatments is in understanding the gratitude that patients feel when they receive new treatments. This finding came across many times in the interviews and should be explored further as the anxiety around treatment cessation may contribute to delaying the appraisal and help seeking phases. In addition, the complexity of patients' histories, diseases and concurrent medications can mean clinicians and patients experience difficulties in distinguishing disease or co-morbidity-related symptoms to those of an irAE and this may lead to delays in management.
Psychological 'side effects' such as anxiety and psychosomatic symptoms in relation to the disease itself cannot be ignored. This has similarities to the uncertainty described in a study examining the experiences of patients with metastatic melanoma undergoing pembrolizumab immunotherapy [17]. This observed that metastatic melanoma patients coped within a spectrum of uncertainty increasing before and during cycles of treatment, monitoring and investigations, then subsiding between, allowing patients to re-engage in their lives.
Suggestions for improving follow up
The most useful area for our organisation was the acknowledgement that delayed reporting is not only a delay in accessing advice but was also related to the patient's own lack of recognition that a symptom is actually related to treatment. This appraisal process by patients can be improved through more timely information and other educational support. We believe real-time reporting could be valuable but cannot be relied on solely. An eHealth intervention based on questions from the PRO-Common Terminology Criteria for Adverse Events (CTCAE) library was used and tested in a randomized clinical trial with patients receiving immunotherapy for malignant melanoma and clinicians at a hospital in Denmark [18]. The primary objective of this study was to examine patients' and clinicians' experiences with an eHealth intervention for weekly monitoring of side effects during treatment with immunotherapy. Overall, satisfaction with the eHealth intervention was high among patients and their treating clinicians. The tool was easy to use and contributed to greater symptom awareness and patient involvement.
As a result of the SARS-CoV-2 pandemic, patients are not being seen as frequently in clinic, and therefore it is even more important to assess regularly in the form of telephone or video consultations and we suggest that clinicians consider the following areas during these sessions:
Detailed probing of even minor symptoms
Attempt to understand what patients consider 'normal' for them or may be attributing to other things, such as prior treatments or side effects of other medications and co-morbidities
Remind patients regularly that AEs can occur at any point during or even after treatment.
Remind patients to report or seek advice as soon as possible and the benefits of treating early
Ask patients what medicines or creams they might have bought from pharmacies, including over the counter medicines or
Ask patients whether they have sought information on immunotherapy or advice about a particular side effect either on-line or from a colleague or friend/relative.
Our study was unique in that patient interviews explored reasons for delayed AE reporting, and we were able to find themes that might help with the development of interventions. We only examined data from one large single centre, which may limit the generalisability of some findings. We also acknowledge that the data extraction form needs to be tried out in larger studies in a variety of settings and further modified. However, we believe that many of the findings will be relevant to other centres and that this small study is an important step to obtaining patient outcome data in this new field. Additionally, many patients were not eligible to take part in our study as they were receiving treatment within a clinical trial, which limited the patient numbers. The retrospective nature of the case note review made it difficult to confirm the accuracy of reported grading. Despite thematic saturation being achieved we accept that our sample size was limited; however, our study complements findings from similar studies in this area, as well as broader toxicity management evaluations, which justifies the transferability of our findings. In fact, a recently published study [19] examined patients' experiences with immune checkpoint modulators, recruited from one organisation in Toronto, Canada, with a focus on their side effects and how these impacted on their daily life. They identified eight themes, characterising the complexity of these patients' lived experiences: major categories of side effects experienced and how they impacted patient well-being; the heterogeneous nature of side effects experienced, all of which were reflected in our category of 'variability'; living with uncertainty; reframing the meaning and severity of SEs; focus on survival, hope, and being positive; acceptance and adaptation; feeling supported; and faith in medical innovation, which correspond to our psychological impact categories.
Conclusions and recommendations for further research
This mixed methods study highlights key factors important to target in terms of prompt AE management. The most salient area from our work was that patients need to firstly understand that they are experiencing an AE and then promptly seek help from the relevant health care professional in real time. Implementation of existing research into real time monitoring could enable prompt management with fewer hospital admissions for this expanding group of patients.
The authors will make data available on request.
AE:
Checkpoint inhibitor
irAE:
immune related adverse event
UCLH:
University College London Hospitals NHS Foundation Trust
Rini BI, Powles T, Chen M, Puhlmann M, Atkins MB. Phase 3 KEYNOTE-426 trial: Pembrolizumab (pembro) plus axitinib versus sunitinib alone in treatment-naive advanced/metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2017;35(15_suppl):TPS4597.
Ramos-Casals M, Brahmer JR, Callahan MK, Flores-Chavez A, Keegan N, Khamashta MA, Lambotte O, Mariette X, Prat A, Suarez-Almazor ME. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020;6(1):38.
PubMed Article Google Scholar
Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R, Hollebecque A, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.
Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.
CAS PubMed Article Google Scholar
Wang PF, Chen Y, Song SY, Wang TJ, Ji WJ, Li SW, Liu N, Yan CX. Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front Pharmacol. 2017;8:730.
PubMed PubMed Central Article Google Scholar
Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015;13:211.
Wang Y, Zhou S, Yang F, Qi X, Wang X, Guan X, Shen C, Duma N, Vera Aguilera J, Chintakuntlawar A, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol. 2019;5(7):1008–19.
Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, Bergmann T, Bockmeyer CL, Eigentler T, Fluck M, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8(1):e53745.
CAS PubMed PubMed Central Article Google Scholar
Cavaille F, Peretti M, Garcia ME, Giorgi R, Ausias N, Vanelle P, Barlesi F, Montana M. Real-world efficacy and safety of pembrolizumab in patients with non-small cell lung cancer: a retrospective observational study. Tumori. 2020;300891620926244. https://doi.org/10.1177/0300891620926244.
Common Terminology Criteria for Adverse Events (CTCAE) version 5 2017 [https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50]. Accessed 1 Jan 2019.
Mekki A, Dercle L, Lichtenstein P, Marabelle A, Michot JM, Lambotte O, Le Pavec J, De Martin E, Balleyguier C, Champiat S, et al. Detection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1. Eur J Cancer. 2018;96:91–104.
Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K, Committee EG. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119–42.
Mok TSK, Wu Y-L, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G, Srimuninnimit V, Laktionov KK, Bondarenko I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819–30.
Basch E, Deal AM, Kris MG, Scher HI, Hudis CA, Sabbatini P, Rogak L, Bennett AV, Dueck AC, Atkinson TM, et al. Symptom monitoring with patient-reported outcomes during routine Cancer treatment: a randomized controlled trial. J Clin Oncol. 2016;34(6):557–65.
Hsiehchen D, Watters MK, Lu R, Xie Y, Gerber DE. Variation in the assessment of immune-related adverse event occurrence, grade, and timing in patients receiving immune checkpoint inhibitors. JAMA Netw Open. 2019;2(9):e1911519.
Scott SE, Walter FM, Webster A, Sutton S, Emery J. The model of pathways to treatment: conceptualization and integration with existing theory. Br J Health Psychol. 2013;18(1):45–65.
So AC, Board RE. Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. Melanoma Manag. 2018;5(1):MMT05.
Tolstrup LK, Pappot H, Bastholt L, Zwisler AD, Dieperink KB. Patient-reported outcomes during immunotherapy for metastatic melanoma: mixed methods study of Patients' and Clinicians' experiences. J Med Internet Res. 2020;22(4):e14896.
Ala-Leppilampi K, Baker NA, McKillop C, Butler MO, Siu LL, Spreafico A, Abdul Razak AR, Joshua AM, Hogg D, Bedard PL, et al. Cancer patients' experiences with immune checkpoint modulators: a qualitative study. Cancer Med. 2020;9(9):3015-22.
We would like to thank the patients who so generously gave their time to share their personal experiences in a 1:1 interview. MDF is is supported by the UCL/UCLH NIHR Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility supported by the UCL ECMC.
The research costs for the study were supported by a non-interventional study grant from Bristol-Myers Squibb (BMS). The funders did not have a role in the design of the study, data collection, analysis, interpretation of data nor in the writing the manuscript. Pinkie Chambers is a Doctoral Research Fellow funded by the NIHR Academy (Project reference DRF 2017–10-016). The views expressed are those of the authors and are not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
UCL School of Pharmacy / UCL/UCLH Centre for Medicines Optimisation Research and Education, 29-39, Brunswick Square, London, WC1N 1AX, UK
Liz Jamieson, Ian C. K. Wong & Pinkie Chambers
Department of Oncology, UCL Cancer Institute, 72 Huntley Street, London, WC1 6DD, UK
Martin D. Forster
NIHR UCLH Clinical Research Facility, 170 Tottenham Court Road, London, W1T 7HA, UK
Martin D. Forster, Kam Zaki & Sanjena Mithra
University College London Hospitals NHS Foundation Trust, 235 Euston Road, London, NW1 2BU, UK
Martin D. Forster, Heena Alli, Anne O'Connor, Apini Patel & Pinkie Chambers
Department of Pharmacology and Pharmacy, The University of Hong Kong, L02-56, 2/F, 21 Sassoon Road, Li Ka Shing Faculty of Medicine, Laboratory Block, Faculty of Medicine Building, Hong Kong, China
Ian C. K. Wong
Liz Jamieson
Kam Zaki
Sanjena Mithra
Heena Alli
Anne O'Connor
Apini Patel
Pinkie Chambers
LJ, PC, MDF and ICKW developed protocols for the whole study. PC, SM conducted data collection for the case note review. LJ, AOC, HA, MDF, KZ and AP were involved with recruitment and data-collection for the interview study. PC and LJ conducted analysis of both studies and were responsible for drafting the manuscript. All authors contributed to the writing and editing of this manuscript. All authors read and approved the final manuscript.
Correspondence to Pinkie Chambers.
The study was reviewed and approved by the East of England - Cambridgeshire and Hertfordshire Research Ethics Committee reference number 18/EE/0233. Written informed consent was obtained from all participants in the interview study.
All authors report the grant from Bristol Myers Squibb for the conduct of the study; MDF additionally reports grants and honoraria from Achilles, AstraZeneca, Bristol Myers Squibb, Celgene, Eli-Lilly, Merck, MSD, Nanobiotix, Novartis, Pfizer, PharmaMar, Roche and Takeda; outside the submitted work. PC reports research grants from Tessaro, and Janssen; outside the submitted work. Professor Wong reports research grants from Janssen; outside the submitted work.
Data extraction form for case note review.
Interview guide for semi-structured interviews and tables 2–5 themes of variability, causality, decision making and impact.
Jamieson, L., Forster, M.D., Zaki, K. et al. Immunotherapy and associated immune-related adverse events at a large UK centre: a mixed methods study. BMC Cancer 20, 743 (2020). https://doi.org/10.1186/s12885-020-07215-3
Immune checkpoint inhibitors
Immune-related adverse events
Survivorship, cancer burden and supportive therapy


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chuyenmuctin
Ministry of Planning and Investment PortalCurrently selected
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Vietnam - Laos Investment Cooperation Conference (12/01/2023-17:40:00 PM) (MPI) - Within the framework of the Vietnamese Prime Minister's official visit to Laos, the Ministry of Planning and Investment of Vietnam coordinated with Lao side and relevant ministries to organise the two countries' investment cooperation conference in Vientiane on January 12.
Deputy Minister Nguyen Thi Bich Ngoc receives Chairman of the Semiconductor Industry Association (12/01/2023-16:09:00 PM) (MPI) - Deputy Minister of Planning and Investment Nguyen Thi Bich Ngoc received visiting Chairman of the Semiconductor Industry Association (SIA) John Neuffer in Hanoi on January 12.
The 45th session of the Vietnam-Laos Inter-Governmental Committee (12/01/2023-14:41:00 PM) (MPI) - The 45th session of the Vietnam-Laos Inter-Governmental Committee on bilateral cooperation was held under the co-chair of Prime Minister Pham Minh Chinh and his Lao counterpart Sonexay Siphandone in Vientiane on Jauary 12.
Deputy Minister Nguyen Thi Bich Ngoc meets Niigata Governor (12/01/2023-12:09:00 PM) (MPI) - Deputy Minister Nguyen Thi Bich Ngoc hosted a reception in Hanoi on January 12 for Hanazumi Hideyo, Governor of Japan's Niigata prefecture, during which she suggested that Vietnam and Japan in general, and Niigata prefecture and the Ministry of Planning and Investment (MPI) in particular promote investment cooperation in an effective manner.
Minister Nguyen Chi Dung receives the Guangdong-Hong Kong-Macau (China)'s business delegation (10/01/2023-16:13:00 PM) (MPI) - Minister of Planning and Investment Nguyen Chi Dung received a business delegation of the Guangdong-Hong Kong-Macau (China) of different sectors such as hi-tech, innovation, digital transformation, smart city, logistics, trade, real estate and service on January 10.
Senior official meeting within the framework of the 45th session of the Vietnam-Laos Intergovernmental Committee (10/01/2023-15:45:00 PM)
Vietnam and Hong Kong-Guangdong-Macao (China) partnership business forum (10/01/2023-13:45:00 PM)
National Master Plan concretises the socio-economic development orientations outlined by the Party and State (05/01/2023-18:56:00 PM)
Deputy Minister Nguyen Thi Bich Ngoc meets Governor of Japan's Tochigi prefecture (22/12/2022-11:13:00 AM)
Minister of Planning and Investment Nguyen Chi Dung meets Lao counterpart (21/12/2022-14:55:00 PM)
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MINISTRY OF PLANNING AND INVESTMENT PORTAL Copyright by Ministry of Planning and Investment Address: No. 6B, Hoang Dieu, Ba Dinh, Hanoi - Tel: (84-80)43485; (84-24)38455298 (Ministry Office); Fax: (84-24)38234453 (Ministry Office); Email: banbientap@mpi.gov.vn

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Masao Sato was living in Ofunato on Japans east coast the day the tsunami hit. He was one of the lucky ones who were quick enough to get to high ground in time to survive. He was featured in a Channel 4 documentary about the tsunami, and watched helplessly as people died right in front of him. He watched his house be washed away, along with everything he owned. Afterwards he said "We have nothing now, we receive relief supplies", "I do remember that I used to have this and that, but right now I don't think about specific items I want, I just think about things I need, day by day".
Many of us have our own personal tsunamis tear through our lives. They may not all be made of water, but the devastation is the same. When my first marriage broke up, my daughter was overnight ripped out of my life. I would never see her again before I set off for work, nor when I got home. I was obstructed from seeing her on birthdays, Christmas, Fathers Day, and not allowed to ring her up and talk on the phone. All the belongings I had worked for so long to acquire were suddenly no longer around me, they were in the family home I was still paying for, yet not allowed to go to, for fear I would upset the new guy my wife was trying to win over. For Claire when Rick was struck by Leukemia, overnight, nothing else mattered as she gave her all to being there for him and fight his cancer together.
We quickly learn in times of crisis, that 'things' do not matter. Belongings are just things you can do without. So many scurry around year after year in a panic, to own property, a shares portfolio, the latest mobile phone, designer labels, the latest model car, more property, taking out all sorts of insurances to feel safe. When we have to face reality, possessions aren't important. When our lives are ripped apart we suddenly realise we never really needed them anyway. We were conned by peer pressure, made to feel inferior for not having the biggest house, the newest car. We had paranoia pumped directly into our homes and minds by advertising telling us we were irresponsible if we didn't have insurance for our car, our home, our belongings, our jewellery, our flights, our holidays, for being sick, for our pets and for our lives.
These crises bring tectonic shifts to our outlook on life. The events are messengers reminding us what is really important, and what is not. It is up to us if we listen, or not. When we do we are changed forever, and for the better. We no longer care about 'things', possessions or belongings. Now we care about helping others, kindness, consideration, empathy, and Love. Those are the things that do matter. It just takes a tsunami for a lot of us to realise.


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Earlier this week it was announced that Mary Ann Hobbs would be returning to the BBC's airwaves, hosting 6Music's weekend breakfast show from January the 5th. While the 7-10am slot seems oddly early given her previous slots, she's one of my broadcasting heroes; so I thought I'd take the opportunity to toast her career.
For me, she'll always be synonymous with the show she started on the 17th of February 1997; The Breezeblock. For almost a decade it jumped around Radio 1's weeknight schedule, evolving into a repository for the best mixes from the most interesting electronic artists during a fine period in dance music history. In September 2006 the powers that be changed the name to the Experimental Show, and her penchant for breaking new talent had gotten a bit grime and dub-step heavy for my liking, but by then her legendary status was already well established.
Four year's later she finally left Radio 1, returning to her first station XFM and continuing her musical crusade, winning Best Specialist Show at the Sony and Arqiva Awards 2012. "For me, Music Is Life. I'm so excited to join a family with such depth and diversity of knowledge, pure passion and ingenuity. I look forward so much to the new challenge of creating a beautiful Weekend Breakfast Show which embodies the whole spirit of 6 Music, and allows me to explore some fascinating new radio terrain," she stated on Monday.
A former journalist with the NME and a fine DJ in her own right, she's pretty hot and has a voice as smooth as husky northern honey; what more could you want?
As with most Breezeblock sets, this mix was timed to coincide with a record release, in this case Damon Baxter's production pinnacle Deep Red. Predictably enough then, it draws heavily from that album, but like some of the other mixes below, that's no bad thing. One of the finest half hours of music you're likely to hear.
While he hasn't really done anything of note in quite a while, in 2001 Felix had just released his landmark album Kittenz and Thee Glitz, spearheading the electro-clash revolution with tracks like Silver Screen (Shower Scene) and The Rush. This mix feature both, as well as pretty much all the other essential tunes of the time.
One of several times the Beasties appeared on the show, this is probably the best, mixing the finest hip hop from Biz Markee, KRS-One, Tribe Called Quest and the Jungle Brothers with the last gasps of Brit pop a la Blur and Noel Gallagher.
Two of the finest house DJs of the era combine to create one of the best party mixes you're ever likely to hear. Zipping between the timeless – Blue Monday, Psycho Killer, Debaser – and the turn of the century's biggest tunes – Sandwiches, Dooms Night, Jacques Your Body – it's a lovely little nostalgia trip.
Not so much a mix as an education, as Tom+Ed take Hobbs through the records that influenced their early work. A really nice bit of radio, the duo chat away about the formation of the Brothers and what led them to producing the dance music they do.
Between this and their Essential Mix of around the same time, FC Kahuna laid out a blueprint for where house music would go in the next few years, eschewing the plodding prog of the day for an exciting electro-tinged vision that still sounds fresh over a decade later.
Much like the next mix, this is a great example of funky house in its pure, naive form, before the band wagon was jumped. Before everything exploded with the Big Beach gigs and Cook's career started to plateau, it's a joy to hear the man at the peak of his dance floor destroying powers.
Back when big beat was still a thing and mash-ups meant something completely different, the likes of Freddy Fresh were mixing hip hop, funk, house and breaks with delirious abandon. This bouncy, boisterous set is probably the most fun you can fit into 30 minutes.
This show saw Kid A era Radiohead make a 'sonic representation of their influences', according to Hobbs' intro. Basically Thom Yorke and Johnny Greenwood showing the length and breadth of their good taste.
I can't seem to find any evidence for this one online, but it's definitely up there with the greats. Much like the Avalanche's Breezebock session, it's basically a glorified album mix, but what an album (the Automator-produced So How's Your Girl? by Handsome Boy Modeling School) and what a mix; splicing the LP's brilliant tracks with plenty of fine old school hip hop.
Another mix to accompany another fantastic album, this time RJD2's Since We Last Spoke. Ramble John Krohn spices a hearty broth of his own productions with tasty bits of Massive Attack, Wagon Christ, Soulwax and Jethro Tull. A sweet, soulful journey.
One of the most weird and wonderful selections of music I've ever heard. Everyone's favourite Frenchman takes you on a journey through the more obscure recesses of his record collection. Worth a listen just for the yellow room bit alone.
A mix so brilliant that it went on to be released in its own right. This represents the original version of the now seminal Prodigy Dirthchamber Sessions, only with all the samples and songs he couldn't clear on the official mix.
Until they finally follow it up, Since I Left You remains The Avalanches' magnum opus, and this mix acted as a prelude to the album itself. Pre-dating 2ManyDJs eclecticism by a good few years, this is a blissfully entertaining romp through their own sample-heavy songs and a variety of otherwise incongruous classics.


Kevin, I agree. When I listen to the morning show on the radio it's for entertainment and news purposes. If I wanted to be preached to on the radio I can find that on one of the Christian radio stations.
A friend of mine at work just can't understand why I don't listen to Steve Harvey. I'm just not interested in listening to him on the radio.
I've been fortunate enough to listen to both Joyner and Harvey. In my humble opinion,…I'd rather have Mr. Joyner. I like Steve and his show is funny and informative. But if I want a sermon I'll seek one out through the proper means. Steve flat out tells you if you're not a religous person, as much as he is, your life means nothing. I'm happy Mr. Harvey has a strong faith but when I tune into his show I don't care to hear about it for the first 5 mins on air and all through out the morning program.
I don't feel this was a wise decison. Tom Joyner and Steve Harvey do not have the same listening audiences. I am fortunate to be able to listen to Tom Joyner on another station. I still listen to V103, but I do not listen to Steve Harvey. It is a shame that the two were put in the same category.


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Nikki Haley: Rex Tillerson and John Kelly Worked Against President Trump
By Staff Writer Last updated Nov 11, 2019
In her new book, former U.S. Ambassador to the United Nations Nikki Haley offers details about President Donald Trump's first two years in office…and the extraordinary efforts of his top staff to take the powers of the presidency away from him.
While Haley stops short of talking about the "25th Amendment" stuff that we've heard from other supposed insiders, she does reveal in her book that former Secretary of State Rex Tillerson and former White House Chief of Staff John Kelly tried to recruit her to help undermine Trump's agenda.
In "With All Due Respect," Haley says that Tillerson and Kelly often tried to justify their schemes to go around the president's back as doing what was right for America.
"Kelly and Tillerson confided in me that when they resisted the president, they weren't being insubordinate, they were trying to save the country," Haley wrote. "It was their decisions, not the president's, that were in the best interests of America, they said. The president didn't know what he was doing."
Haley wrote that Tillerson once told her that people would die if Trump's agenda wasn't kept in check.
According to the Washington Post, Haley provides only "glancing critiques" of President Trump in her book while insisting that it was the responsibility of Trump's Cabinet to carry out his agenda. He was, after all, the one voters put into the highest office in the land. And she was unapologetically supportive of many of Trump's decisions. In her book, she cites the withdrawal from the Iran nuclear agreement and the Paris Climate Agreement as two Trump moves she wholeheartedly backed.
Discussing the book with the Post, Haley was critical of Democrats' attempt to impeach President Trump, saying there was nothing even vaguely impeachable about the call with Ukrainian President Volodymyr Zelensky.
"There was no heavy demand insisting that something had to happen," Haley argued. "So it's hard for me to understand where the whole impeachment situation is coming from, because what everybody's up in arms about didn't happen.
"So, do I think it's not good practice to talk to foreign governments about investigating Americans? Yes. Do I think the president did something that warrants impeachment? No, because the aid flowed," she continued. "And, in turn, the Ukrainians didn't follow up with the investigation."
Republicans Demand That Bidens Appear as Impeachment Witnesses
Mo Brooks: Whistleblower is a "Spy for the Democratic Party"


There will be a new Women's Bible Study starting Friday, April 7th at 9 am at TVC. The study is, "Another Twelve Women of the Bible." The cost of the book is $8.00. See Norma if you have any questions.
Our next Women's IF Fellowship Gathering will be Sunday, March 24th, 4 pm to 6 pm at the Village Chapel. Please bring a main dish, salad or dessert to share. We look forward to this special time to get together! Please sign up at the Welcome Center. See you there!
Join us on Wednesday, April 3rd at 7 pm. Our prayer will be that God would bring a buyer for this building and prayer for our new building. Join us as we look forward to God's blessings.
We will have an Easter Sunrise Service at 6:30 am, and also an 8:30 am & 10:30 am service. There will be special pastries and fruit served at each service. Invite your family and friends! We are in need of volunteers for all services to sign up to help with set up, food prep and servers. Please sign up at the Welcome Center.
Join our new class to learn the foundation of our Christian faith. All are welcome to attend. It will be a 6-week course starting Sunday, April 7th from 9 am to10 am. Sign up at the Welcome Center.


One of the best buffet I have ever been to, I'm being bluntly selfish here because they had only the dishes that I like and it was totally like home cooked and extremely delicious. The ambience is different and catchy. It's totally a must try restaurant for anyone who enormously miss home food. They had limited drinks (soft drinks) i.e they just had two juices for drinks (which was unlimited but it was just like rasna and some weird blueberry juice). Except for that the others were were extra ordinary. The overall experience was tremendous and there were plenty of desserts which were hard to choose between and ice creams on the other hand sizzling the confusions within. Beef steak, spinach curry and panner was extra ordinary and pasta was just fine so if you're a pasta lover try one plate first then go for more if you liked it. Starters were superb and chicken was so soft and was getting dissolved as it reached the tongue so it's anti chewable you can say 😜. Never ever miss this restaurant, not under any circumstance. I personally recommend this restaurant and have rated 5.


We have no old photos of Balnahard available currently. You might like browse old photos of these nearby places.
Historic Maps of Balnahard and the local area.
We are busy preparing more old maps of Balnahard from other years.
Browse 1 photo books on Balnahard and the surrounding area.
Read and share your memories of Balnahard itself or of a particular photo of Balnahard.


The Chloe Frill detail skirt had a standard fitted waistband and front slant pockets. Skirt length sits on the knee.
Made in Australia from Viscose, Nylon, Spandex. Cold gentle machine wash with similar colours. Wash dark colours separately. Do not bleach. Do not wring. Do not tumble dry. Drip dry in shade. Cool iron, no steam. Dry with care (P).


ESC uses local native plant communities as a model for landscape designs and installations. After we analyze the environmental attributes of a site, we then create a list of appropriate plants to be used in our design.
It is important to understand environmental factors such as soil, moisture levels, sunlight, existing plants, and wildlife impacts on a site, as well as how these might change as a site is developed. With the client, decisions are made on such issues as whether to install an irrigation system, style preferences from more rustic to more formal, rockwork, budget, and functions such as shade for parking.
Diverse selections of species are planted in naturalistic arrangements that are attractive throughout the year. Although annuals are often planted to provide more color during the first year or two, the long term stability of the site depends on the right perennial flowers, shrubs, and trees. Informed maintenance is critical in both short term beauty and long term success, especially during the first two years.


Then I made the list of small tasks I have to work on in the coming months to reach the long term target of the year.
As I kept cutting down the yearly goal into small tasks, I felt relieved. The whole awareness narrowed down and pointed towards 'what I have to focus right now' !
It's been good to begin with simple and clear mind.


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Can Leftists Resuscitate Their 2020 Covid Litany of Lies?
By Christopher Adamo 6 months ago
Listening to all the artificial and overblown "hysteria" over vaccines, new "surges" in Wu-Flu cases, and dire prognostications over the fate of humanity if America doesn't enter into another "lock down," it is glaringly obvious that leftist Democrats are desperate to relive the 2020 "pandemic" glory days. Americans were dubious last year over the clear over-reaches of government, but without knowing the real extent of the threat, they were generally compliant. Predictably, the left severely overplayed its hand, and proved its motives to be entirely political. So a repeat of the fiasco is unlikely.
After the best economy in the history of the country was nearly driven to ruin, and the stage was set for the 2020 Presidential election to be stolen by an inept, corrupt, and highly unpopular leftist cabal, parading the hapless Joe Biden as its sock puppet, virtually every calamitous warning from the "medical" experts has proven to be grossly, if not deliberately, wrong. Mere incompetence cannot explain such a pattern, since its effects were universally beneficial to the political fortunes of the party of discord and chaos.
It is appalling, but very telling, that leftist Democrats believe they can once again shatter the well-being of Americans with their panicked warnings of yet more impending disaster. Ultimately, such leftist Democrat efforts to "cry wolf" in this manner reflect their abject contempt for Americans, whom they regard as fearful and gullible "sheep" to be stampeded in any direction at the whims of key Democrat players.
The latest inanities being spewed from the CDC, the creepy little Dr. Fauci, and their parakeets on the nightly Fake News are too numerous and too disjointed to be properly catalogued. But they bear one common thread. We all need to forfeit our liberties as free citizens, abandon the Constitution and the Bill of Rights, and just let power hungry leftists have complete and unquestioned control of the country if we are to survive this new wave of plague and death. Rings a bit hollow, doesn't it?
It would take an entire library to catalogue all of the lies, exaggerations, contradictions, and other unwarranted excesses that the left successfully perpetrated on America in 2020. But even a few examples ought to suffice as reminders of just how deceitful and malignant leftists are, the moment they see an opportunity to create havoc and suffering, in their fanatical quest to amass power.
For starters, when President Trump shut down travel to and from China, at the earliest signs of the virus, leftists went crazy with all their reflexive accusations of "bigotry and hate," with Nancy Pelosi grandstanding in Chinatown, claiming public gatherings were perfectly safe. Within a few weeks, she and other leftist squawk boxes were spewing new accusations that the President "ignored the danger" and hadn't acted quickly enough to stop it. On the heels of that, he was ultimately blamed for virtually every death attributed to the virus.
The Wu-Flu circus was underway. Initially, Church closures, business closures, and other lockdowns were ordered with the understanding that it might take two to three weeks before things could return to normal. That turned into two to three months, with leftists longing for it to eventually be two to three years. Nothing but objectivity and "following the science" here.
Then the whole mask lunacy ensued. Here again, early assurances of the total uselessness of masks were suddenly and completely contradicted. Before long, masks of any type, including those that were obviously porous, were nonetheless a life and death necessity, required in every public venue, and even stipulated in some leftist Democrat jurisdictions for members of the immediate family inside one's own home. Massive studies proving their total uselessness were venomously attacked and dismissed. The visual and emotional impact of an entire population under constant deadly threat was just too invaluable to leftists, and to their plans of thoroughly corrupting the 2020 Presidential Election.
In the midst of all this, some really astonishing results were observed from the use of Hydroxychloroquine, a readily available pharmaceutical, with a decades long track record of safe use. Amazingly, leftists declared open war on the treatment, mocking and deriding it, to the point of preventing its use by threats of legal action. When the dust settles, the needless deaths from its suppression will likely number in the tens or hundreds of thousands in America alone. At the same time, leftist Democrat Governors such as Andrew Cuomo of New York forced diseased patients into nursing homes, where the virus could quickly spread to other aged and vulnerable residents, causing enormous, wholly pointless suffering and death.
In neither case were such abominable decisions an accident. Those responsible for the misinformation and homicidal policy are absolutely guilty. Yet the DOJ has just announced that it sees no reason to pursue any of the blue-state governors who authored such appalling policy. Of course it is the same DOJ that declared Hillary "innocent" of trafficking in classified material on her personal computer. So those "dots" do connect.
While all of the previous insanity is difficult to grasp, it has since been totally eclipsed by "phase 2," which was the whole vaccine scam. In the real world, vaccines cause the human body to generate antibodies, which allow it to thwart any new attempts of the virus to invade. Yet we're now being told that Covid "vaccines" don't accomplish that, or that people who already have the antibodies must still get the vaccine. Furthermore, the totally useless and ineffective masks are being demanded once again, even for those who have had the disease and recovered from it, or have been vaccinated.
The lies and psychosis of the pro-pandemic crowd are mutating faster than any "delta variant," and always for the purpose of convincing Americans that we face imminent misery and death, unless we mindlessly follow the random and incoherent edicts of leftists at every level of government. But this time around, it finally looks like Americans have grown wise to the ruse and are ready to say a resounding "NO!" to all of it. Republican Governors are refusing to lock down, and even within blue state cesspools, city officials and county sheriffs are refusing to enforce lockdown edicts. The scope and intensity of threats and transparent attempts at psychological intimidation for those who refuse to comply with masks, lockdowns, or demands to get the "clot shot" are themselves evidence that a large number of Americans see through all the deception and are not having any of it.
Historically, whenever the alarmism of leftists exceeds rational thought and totally loses credibility, their reflexive reaction is to increase the shrillness and hysteria of their squalling. At that point, they reveal their true insincerity for all to see, and their sham effort collapses. They are currently teetering precariously on that precipice.
Christopher Adamo
Christopher G. Adamo is a lifelong conservative from the American Heartland. He has been involved in grassroots and state-level politics for years. His recently released book "Rules for Defeating Radicals," subtitled "Countering the Alinsky Strategy in Politics and Culture," is the "Go To" guide to effectively overcoming the dirty tricks of the political left. It is available at Amazon.
Previous VAERS and Forced Vaccination
Next Who's Calling The Shots? What Parents Must Know About Push To Mask & Inject Kids
1 thought on "Can Leftists Resuscitate Their 2020 Covid Litany of Lies?"
Armored Avenger says:
The old adle brained sock puppet, China Joe is nuttier than a truckload of fruit cakes. Americans need to stop behaving like a bunch of stampede Lemmings, running towards the suicide cliff's. A good friend of mine who writes for " News With Views " and I'm not intentionally trying to step on anyone's works here, recently wrote a masterpiece of research. Devvy Kidd has spent thousands of hours researching the COVID CRIME of the Century, and she's included so many links to back up her writing. I haven't yet traveled down the rabbit holes like she has, but this whole COVID CRIME thing is nothing but a " Weaponized Flu " virus, being crammed down our throats by the simple minded parrots of of the media and the Silicon Valley, Hot Tub soaking, Tree Hugging, Crystal Spinning Morons they are. The heads of the Tech companies are guilty of more crimes than I care to think. They've all set themselves up on remote islands or in foreign countries where they THINK they're safe from prosecution and punishment for their crimes. I can't wait for this fraudulent crime to come to an end. I want to see all these individuals caught, tried, punished and if the law allows, EXECUTED !!! I know it's bad karma to want a feeble minded old pervert crook, like China Joe, either swinging from a rope, ( and that rope doesn't need to be new, because an old rope is justifiable ), but I want all those connected to the theft of the election, along with the entire justice system, and numerous others who sold their soles to the chinese, and all who took part in the election theft and pushing the COVID agenda, paying a heavy price for the needless deaths of millions of humans.
Check out Devvy Kidds article, it will blow the top off the whole CIVID FARCE !!!!


Abbey Springs is a unique golf course community located on the Southern shores of Lake Geneva in Fontana, Wisconsin. The breathtaking views are a spectacular backdrop for your wedding ceremony, reception, or other special celebrations. As one of the finest Lake Geneva, WI golf courses, Abbey Springs boasts a 4 ½ star rating from Golf Digest magazine. Abbey Springs can play host to your next round of golf or your group golf outing. Our Clubhouse has many wonderful casual and fine dining options from acclaimed Chef, Ben Janssen. We also have a fantastic work out facility, indoor and outdoor pool, and a wonderful tennis program. Abbey Springs offers resident and non-resident membership options for Golf, Dining, or Recreation.
Want to find out more on what these memberships at Abbey springs can offer you?


Luxury safari kitchens are not gastronomic temples, nor do they try to be one. You are in a remote natural environment and the focus is on the wildlife, not wild thyme. Still, the food is admirable - and clearly superior to what is prepared at sub-luxury safari lodges and camps.
It's important to recognize that safari chefs (including those in luxury venues) face some culinary handicaps that few restaurants suffer. Your lodge or camp is in the middle of nowhere, distant from the nearest town. All the food has to be trucked in through the wilderness over rough dirt roads.
Much of the food shipped to the lodges and camps has to be frozen and stockpiled in bulk in freezers (just in case the dirt roads become muddy and impassable for days).


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Hollywoodworth
How Much Is Rally Driver Ken Block Net Worth Before Death? Cause of Death in Detail
By : Deepesh
Ken Block (Image Source: NPR)
One of the founders of DC Shoes, Ken Block, is no more in the world. The whole world is mourning the death of Ken Block, who passed away at the age of 55. Ken encountered a snowmobile accident in Woodland, Utah, which led to his death. The late rally driver competed in many action sports events, such as skateboarding, snowboarding, and motocross.
The news of Ken's death was announced on Monday, January 2, which left everyone devasted. His cause of death was due to an accident. After meeting the accident, he was announced the death at the scene. He was married to Lucy Block, with whom he tied the knot on July 10, 2004. His wife is also a rally racer, and they had also raced together. The couple lived together for 15 years. Ken and Lucy had three kids, including a daughter named Lia Block.
Ken was close to his family members, and all of them lived a low-key life. The whole family is devastated by the death of their loved one. His daughter, Lia, posted a heartfelt statement to Instagram late Tuesday night, saying,
"Yesterday I didn't just lose my father, I lost my best friend," Lia Block wrote. "He was truly my whole world and the only person I ever looked up to. No matter what I did he was always there to support me. I can't believe how fast he was taken from all of us. No words can describe of how much of an amazing human my dad was, he lived so many lives, accomplished more in 55 years than most people could in 10 lifetimes, and lived his life to the absolute fullest every single day."
"He always did what he loved no matter what, right up to the last second, and always was there for me and my siblings and my mom whenever we did what we loved. He never said no to something we wanted to try, never pushed us to like what he liked, just opened the door for us to explore. He never missed an opportunity to help us grow as good people, he always told me that he wanted us to be even more amazing, caring, happy, selfless, humans than him and my mom. He always helped others and opened doors for so many other people. I can only hope to do half as many amazing things he did."
"I grew up, knowing in the back of my head, that I wanted to be just like dad. He was one of the most amazing people in the world, not to mention the best dad I could have ever asked for. I will strive every single day to make you proud. I love you to the moon and back kenny boi."
Many of Ken's closest friends and collaborators commented in response. Likewise, fans were left emotional by that statement, and they left some comforting messages in the comment section. While the world is devasted by the death news, some people are also eager to know about Ken's earnings and income.
See This: What Is The British Net Worth of Author Douglas Murray? Here Are His Income and Earning Sources
Ken Block Had a Net Worth of $100 Milion
According to Celebrity Net Worth, Ken Block had an impressive net worth of over $100 million, but some sources say it was around $200 million. Contributing to his high income are the two renowned companies he founded, the skating fashion brand DC Shoes and Hoonigan Industries, a motor apparel brand.
Ken launched DC Shoes in 1994 with his business partner Damon Way who he met during a community college class. They started a series of start-ups, including Blunt Magazine, Type A Snowboards, Droors Clothing, and Eightball Clothing. Meanwhile, Ken needed $10,000 to create the sports brand and had to convince his parents to lend him the amount. So, their input paid off, and in the first year of business, DC shoes generated $1.5 million in revenue.
Ken Block was a rally race driver ( Source: Road and Track )
The revenue increased by 2003, as the brand was making $100 million each year, as Hot Cars reports. Quicksilver later acquired DC Shoes for $87 million in 2004. However, Ken remained Brand Vision Leader for the company. After DC Shoes was sold, Ken launched Hoonigan Industries. Until his death, he served as the co-owner and "Head Hoonigan In Charge" at the company.
Furthermore, the company made clothing and apparel for petrolheads and operated Block's racing team in partnership with Ford until 2021. In the same way, Ken raced in every rally season from his 2005 debut until 2015, winning 15 Rally America races. He also won six Global RallyCross races in his decade-long career. So, due to his career as a rally driver, he has racked up a massive fortune.
Similarly, Ken was featured in a few video games like Colin McRae: Dirt 2. Ken's Gymkhana videos on YouTube were also the plus point behind his increasing earnings every year. Once, his car Ford Fiesta appeared in one of his Gymkhana videos. That video received more than seven million views, and again, in July 2012, that received about five million views. Due to that, his income peaked.
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Electro, Pop
Psychedelic, neo-hippie, dream pop
Tame Impala, Garbanotas Bosistas, Grizzly Bear
Psychedelia combined with electronics, indie and dream pop, so 60s defined anew.
by Hubert Grupa
The 60s successfully returned to the festival stages around the world. Of course we are talking about psychedelia, in which you can also find influences of indie, experimental music or dream pop, thanks to bands like Tame Impala or MGMT. At a time when it seems that young bands are grabbing less analogue instruments, there are projects heavily inspired by music from half a century ago. One of them is NiXes, which does not wander blindly into the realm of the original psychedelia, but redefines it in its own way, with great sensitivity.
NiXes is made up of vocalist Ania Rusowicz, her husband Hubert Gasiul and Kuba Galinski. It is the figure of Rusowicz who stands out in the first place when listeners meet NiXes. The vocalist already gained considerable popularity due to her solo project, to which she stylistically referred as "the big beat and blues". An important role in the artistic route that Rusowicz chose was played by her parents. Ada Rusowicz, her mother, was a talented vocalist, and Wojciech Korda, her father, is well-known Polish guitarist and composer.
In 2017, Rusowicz decided to start a new project. NiXes is not only inspired by the past, it is a fresh and refined sound, in which echoes of the 60s are strong, but they are not the most important here. The incredible catchiness of all 10 compositions included on the band's debut album is something that has not been present in Polish guitar music for a long time. The melodiousness of the songs is combined with a noncommittal lightness that makes the music of NiXes seem to suit every circumstance. Listening to this album makes you feel like leaving the house and run, no matter where to.
The debut album of NiXes has been well received by critics, but the band itself, despite of the popular singer in a crew, is still unknown. One of the reasons for this situation is the niche in which the band is on the Polish music market. This makes NiXes not only an interesting surprise, but also a band that can not be mistaken for any other since their debut.
The work of NiXes is not limited to music from the past. You can easily hear electronic inspirations ("Don't You Wanna", "Galaxy Sounds") or dream pop ("Circles") on the band's first album. Let's hope that NiXes will become more and more popular. Their music deserves to reach the largest audience possible.
More about Nixes
Electro / Portugal
Electro / Sweden
Play! Warsaw Calling


Our in-depth course is designed to better prepare sophomores, juniors and seniors to take the SAT, ACT, and PSAT. Covered in this 18-hour class are general test taking techniques and the verbal and math strategies needed to help improve your scores for the newly revised SAT exam. Students will take a sample SAT math exam and be given helpful approaches to the various kinds of math problems found on the exam. Students will then take a sample SAT verbal exam, be given test strategies to improve scores, be given step-by-step procedures for solving analogy problems, learn the importance of a good vocabulary in scoring well on the exam, and discover shortcuts to vocabulary improvement. Also learn techniques for improving reading speed and comprehension. Morning is the writing & critical reading section, afternoon is the math section of the class.
Please read: Plus $12 material fee, payable to Instructor. Please bring notebook paper, #2 pencil, a pen and highlighter to class.


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Failure of Alefacept in the Treatment of Vitiligo
February 2013 | Volume 12 | Issue 2 | Original Article | 159 | Copyright © February 2013
Salman Bin Dayel MDa and Khalid AlGhamdi MDb
aDepartment of Dermatology, Salman Bin Abdulaziz University, Alkarj, Saudi Arabia bDepartment of Dermatology, King Saud University, Riyadh, Saudi Arabia
Background: Vitiligo is a common acquired pigmentary disorder with a profound psychosocial impact. The exact pathogenesis of vitiligo is not fully understood; however, vitiligo appears to be an autoimmune disease involving T-cell-mediated melanocyte destruction. Recently, complete clearance of coexisting vitiligo without recurrence over 2 years was reported in 2 psoriasis patients treated with alefacept.
Objective: To evaluate the safety and efficacy of alefacept in the treatment of vitiligo.
Methods: After providing informed written consent, 4 adult patients with widespread vitiligo (covering a body surface area ≥5%) were treated with weekly intramuscular injections of 15 mg alefacept for 12 weeks. All patients were monitored clinically, by laboratory investigation, and by digital image analysis. All patients were followed up with for 24 weeks.
Results: All patients tolerated alefacept well, without any adverse events. None of the patients showed any repigmentation. However, 1 patient developed new depigmented patches during treatment with alefacept.
Limitations: A pilot study with a small number of patients.
Conclusion: Alefacept as a monotherapy for vitiligo treatment did not result in any patient improvement, and further evaluation in larger studies may be required.
J Drugs Dermatol. 2013;12(2):159-161.
Vitiligo is a common acquired pigmentary disorder with a profound psychological impact. It has been reported to affect approximately 1% of the population worldwide, irrespective of skin color or ethnic origin.1 Vitiligo can be cosmetically and psychologically devastating, resulting in low self-esteem, poor body image, and difficulties in sexual relationships. 2-4 Because the disease is not well understood, several theories have been proposed to explain the loss of epidermal melanocytes in this disorder, including autoimmune, biochemical, oxidant–antioxidant, neural, and viral mechanisms.5 An autoimmune hypothesis for vitiligo pathogenesis has been supported by both experimental data and clinical association with autoimmune diseases.6-8 Because the disorder is not fully understood, a plethora of different treatments are available, with variable results. Vitiligo improvement was reported in 2 patients who were treated with alefacept because of coexisting psoriasis.9 The aim of this pilot study is to evaluate the efficacy and safety of alefacept in the treatment of widespread vitiligo.
Four adult patients with widespread vitiligo (covering a body surface area of ≥5%) were recruited from our dermatology clinic. All patients had nonstable vitiligo and had not received any treatment for vitiligo for the past 6 months. All patients gave their written informed consent. This pilot study had been approved by the Research Ethics Committee, Vitiligo Research Chair, King Saud University.
Patient data and treatment results are summarized in Table 1.
Treatment With Alefacept
Baseline complete blood counts, differential leukocyte counts, liver function test, renal function test, thyroid function test, fasting blood sugar, antinuclear antibodies, and chest radiographs were all within normal limits for all patients. CD4 counts were monitored before and biweekly during treatment with alefacept and were within normal limits throughout the treatment. Alefacept was administered to all patients as 15-mg weekly intramuscular injections for 12 weeks. The response was assessed by investigators through visual comparison of photos obtained by digital camera at baseline and at 6, 12, and 24 weeks. All patients completed the treatment plan and were followed up with for 24 weeks.
Alefacept was well tolerated during the treatment period, and none of the patients reported any adverse events. All digital images were compared before, during, and after treatment. In all patients, there was no repigmentation of the affected areas. One patient (patient 2) developed new depigmented patches during treatment period, but vitiligo was stable in the other 3 patients (Figures 1 and 2).
Vitiligo is an acquired dyschromia of the skin in which there is a loss of epidermal melanocytes. Although the precise pathogenesis is not fully understood, vitiligo appears to be an autoimmune disease involving the T-cell–mediated destruction of melanocytes.10,11 Although the triggers and specific nature of the autoimmune response remain unknown, circulating autoantibodies to melanocytes and various melanocytic protein


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Ad litem (ad = "zum, für den"; lis, litis = "Streit, Prozess") ist eine lateinische Wendung, die im Recht in unterschiedlichen Sachzusammenhängen verwendet wird:

 Ad-litem-Richter, ein etwa aufgrund seiner Sachkenntnis oder Fachkompetenz einem Richterkollegium für einen bestimmten Prozess zugeordneter Richter. Dies ist regelmäßig der Fall beim Internationalen Strafgerichtshof (IStGH) in Den Haag sowie bei den Ad-hoc-Strafgerichtshöfen der UN für Ruanda und das ehemalige Jugoslawien.

 Administrator ad litem (lat. administrator = "Verwalter"), ein Nachlassverwalter zur Fortführung eines Rechtsstreits.

 Guardian ad litem (lat. guardianus = "Wächter, Hüter"), ein – insbesondere im angloamerikanischen Raum – einem Minderjährigen oder Unmündigen für die Dauer eines entsprechenden Prozesses zugeordneter Vormund und Rechtsbeistand. In Deutschland entspricht dieser zum Teil dem Verfahrenspfleger, der in familiengerichtlichen Auseinandersetzungen um das Umgangs- und Sorgerecht von Kindern (gemäß  Gesetz über das Verfahren in Familiensachen und in den Angelegenheiten der freiwilligen Gerichtsbarkeit – FamFG) bzw. in Unterbringungssachen (gemäß  FamFG) bestellt werden kann.

 Mediator ad litem (lat. mediator = "Mittler"), ein in einem einstweilen ausgesetzten Verfahren tätig werdender Mediator, der die Parteien berät und zu einer einvernehmlichen Lösung führt (vgl.  FamFG).

Siehe auch
 Latein im Recht

Lateinische Phrase
Rechtssprache
Prozessrecht (Deutschland)

redpajama_set_name: RedPajamaWikipedia


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Gomphidia maclachlani is een libellensoort uit de familie van de rombouten (Gomphidae), onderorde echte libellen (Anisoptera).

De wetenschappelijke naam van de soort is voor het eerst geldig gepubliceerd in 1873 door Selys.

Rombouten


Funny that a stadium named after Arthur Ashe, one of the most collected players to ever hold a racket, has become known as the place to rage against the tennis machine.
What will Serena Williams do in New York this summer? Yes, there is great interest in whether Williams, the Wimbledon champion and Olympic gold medallist, can keep that success going on her home side of the Atlantic by winning the final slam of the year. But you just know there will be almost as much scrutiny of the other run she's on, having growled at officialdom the past couple of times she has played at the US Open. Perhaps Williams does both, crushing the field and effing as she goes, so confirming her status as the greatest, most watchable, player of her generation. New York City tends to bring out the best and worst in her.
To truly shock Flushing Meadows this summer, Williams could go quietly, minding her Ps and Qs. Unlikely. Even Williams thinks "something will happen" this year. If that 'something' is on the same scale as events in 2009 and 2011 – she missed 2010 because of injury – the tournament director ought to schedule all her matches late at night, after America's children have gone to bed. The worst of the two incidents came during a semi-final against Kim Clijsters at the 2009 tournament when, furious with a lineswoman for calling her for a double-fault, she threatened to stuff a tennis ball down her throat. Then, on the way to defeat to Sam Stosur in last summer's final, after a hindrance call for crying out "C'mon" during a rally, she spent the next changeover accusing the umpire of being "a hater" who was "unattractive inside". Ask the casual tennis fan about the women's tournament at last year's US Open and they might be able to quote Serena at you; less likely that they can tell you who won the title. That was a pity for Stosur, but there's no getting around the fact that Serena commands attention at the US Open.
Though Williams's first slam title came at Flushing Meadows, some 13 years ago in 1999, she has not had been as dominant in New York as she has been in Melbourne or London. She has won the Australian Open and the Wimbledon Championships five times each, and the US Open on three occasions, the last of those being in 2008. For Williams to win the US Open for a fourth time, does she need to learn to count to ten to control her temper? More of the internal dialogue, less of the external cursing.
Serena's draw is ridiculously easy. All of the competition is on the other side. Fix is in.


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Obituary of Joan Schulte
Joan Schulte, 88, of Hilton Head Island passed away May 5th, 2021 surrounded by family.
Joan was born January 21, 1933 in Clarksburg, WV, the daughter of Frank G. Maybury and Olive Katherine Calkins. She was a graduate of St. Mary's High School in Clarksburg, WV. Joan worked in the financial industry before meeting and marrying her husband of 61 years, Patrick Schulte. They moved from Fairmont, WV to Hilton Head Island in retirement 28 years ago. Joan was an active volunteer at St. Francis Thrift Shop for many years.
Joan is survived by her son and daughter-in-law Mark and Angela Schulte, her grandsons Bryan and Zachary Schulte and brothers Joseph Maybury and Robert Maybury. She was preceded in death by her loving husband Patrick Schulte, son James Patrick Schulte and brothers-in-law Joseph, James and Paul Schulte.
A Mass of Christian Burial will be celebrated Friday, May 14 at 10 am at St. Francis by the Sea Catholic Church. In lieu of flowers, please donate in Joan's memory to the American Heart Association at heart.org.
St. Francis by the Sea Catholic Church
Hilton Head Island, South Carolina, United States
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