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Abstract Background The World Health Organization (WHO) declared the end of the COVID-19 (SARS-CoV-2) global public health emergency on May 5, 2023, but its long-term consequences have still been haunting the global population. Post-acute sequelae of COVID-19 (PASC) and long-term COVID-19 are serious concerns and present with various symptoms. Intranasal chlorpheniramine (iCPM) has been shown to decrease the viral burden of SARS-COV-2. iCPM uses decreased COVID-19 disease progression and severity in Accelerating COVID-19 Clinical Recovery in an Outpatient Setting (ACROSS)-I & III randomized control trials (RCT). Methods This prospective survey study included 259 participants in ACROSS I and III RCTs. We compared the effect of iCPM versus placebo on the reduction of PASC symptoms. A PASC questionnaire containing 17 questions regarding the most common PASC symptoms was used in this study. T-test and Pearson chi-square statistics were performed according to continuous and categorical data using STATA 17.0 Basic Edition software. Findings The iCPM cohort had a lower proportion of patients with fatigue or tiredness vs. placebo (0 Vs 17, 21, p

Abstract Background Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35–52% of patients and accounting for 20–40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD. Methods A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from − 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤ − 2.5 or ≥ + 2.5 with a standard deviation not crossing zero. Results Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants. Conclusions This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need.

Abstract Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real‐world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up‐titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross‐titration in an inpatient setting (median: 2 days) or gradual cross‐titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short‐term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

Rationale Nontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing on Mycobacterium avium complex (MAC), M. abscessus and M. kansasii. Methods Pulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to −5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or

Abstract Dual combination therapy with a phosphodiesterase‐5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate‐risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open‐ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from −5 (strongly disagree) to +5 (strongly agree) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus‐based recommendations may be helpful to clinicians and beneficial for patients when evidence‐based guidance is unavailable.

Abstract Background In patients with idiopathic pulmonary fibrosis (IPF) treated with pirfenidone (Esbriet®, Genentech USA, Inc. South San Francisco, CA.), effectively managing treatment-related adverse events (AEs) may improve adherence. Due to a lack of clinical evidence and expertise, managing these AEs can be challenging for patients and physicians alike. In the absence of evidence, consensus recommendations from physicians experienced in using pirfenidone to treat IPF are beneficial. Methods Using a modified Delphi process, expert recommendations were developed by a panel of physicians experienced with using pirfenidone for IPF. Over three iterations, panelists developed and refined a series of statements on the use of pirfenidone in IPF. Their agreement on each statement was ranked using a Likert scale. Results A panel of 12 physicians participated and developed a total of 286 statements on dosing and administration, special populations, drug-drug interactions, laboratory analysis, warnings and precautions, and AE management. Expert recommendations were achieved with regard to slower initial titrations and slower titrations for AEs, dosing with meal(s) or substantial meals, and adding other prescribed pharmacological agents for AEs. Conclusion Until there is further clinical evidence, the resulting consensus recommendations are intended to provide direction on the practical management of IPF with pirfenidone, by encompassing a broad experience from the real world to complement data gleaned from clinical trials.

Intravenous infusion of alpha-1 antitrypsin (AAT) was approved by the United States Food and Drug Administration (FDA) to treat emphysema associated with AAT deficiency (AATD) in 1987 and there are now several FDA-approved therapy products on the market, all of which are derived from pooled human plasma. Intravenous AAT therapy has proven clinical efficacy in slowing the decline of lung function associated with AATD progression; however, it is only recommended for individuals with the most severe forms of AATD as there is a lack of evidence that this treatment is effective in treating wild-type heterozygotes (e.g., PI*MS and PI*MZ genotypes), for which the prevalence may be much higher than previously thought. There are large numbers of individuals that are currently left untreated despite displaying symptoms of AATD. Furthermore, not all countries offer AAT augmentation therapy due to its expense and inconvenience for patients. More cost-effective treatments are now being sought that show efficacy for less severe forms of AATD and many new therapeutic technologies are being investigated, such as gene repair and other interference strategies, as well as the use of chemical chaperones. New sources of AAT are also being investigated to ensure there are enough supplies to meet future demand, and new methods of assessing response to treatment are being evaluated. There is currently extensive research into AATD and its treatment, and this chapter aims to highlight important emerging treatment strategies that aim to improve the lives of patients with AATD.

Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations. The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus. Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab. The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.

In patients treated with repository corticotrophin injection (RCI) for pulmonary sarcoidosis, effective management of adverse events may improve adherence. However, management of adverse events may be challenging due to limitations in real-world clinical experience with RCI and available published guidelines. We surveyed 12 physicians with a modified Delphi process using three questionnaires. Questionnaire 1 consisted of open-ended questions. Panellists' answers were developed into a series of statements for Questionnaires 2 and 3. In these, physicians rated their agreement with the statements using a Likert scale. Key consensus recommendations included a starting dose of 40 units twice a week for patients with less severe disease, continued at a maintenance dose for patients who responded, particularly those with chronic refractory sarcoidosis. Panellists reached consensus that concomitant steroids should be quickly tapered in patients receiving RCI, but that concomitant use of immunosuppressive medications should be continued. Panellists developed consensus recommendations for adverse event management, and reached consensus that RCI should be down-titrated or discontinued if other interventions for the adverse effects fail or if the adverse effect is severe. In the absence of clinical evidence, our Delphi consensus opinions may provide practical guidance to physicians on the management of RCI to treat pulmonary sarcoidosis.

A variety of phenotypic categorisations have been developed for sarcoidosis. Phenotyping has been used for genetics studies and to guide treatment selection. The authors participated in a Delphi expert consensus panel to develop a proposed phenotype categorisation and treatment recommendations for pulmonary sarcoidosis patients. Panellists reached consensus that asymptomatic patients with normal pulmonary function and adenopathy alone or normal chest imaging do not require therapy, while symptomatic patients with impaired pulmonary function or infiltrates should be treated. The panel did not reach consensus on asymptomatic patients with abnormal chest imaging or reduced pulmonary function, or symptomatic patients with normal chest imaging and pulmonary function. The proposed phenotype categories and associated treatment recommendations are asymptomatic (no therapy), acute (disease duration

Abstract Alpha-1 antitrypsin deficiency (AATD) is a common hereditary disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT; also known as alpha 1-proteinase inhibitor, A1-PI). An important function of A1-PI in the lung is to inhibit neutrophil elastase, one of various proteolytic enzymes released by activated neutrophils during inflammation. Absence or deficiency of A1-PI leads to an imbalance between elastase and anti-elastase activity, which results in progressive, irreversible destruction of lung tissue, and ultimately the development of chronic obstructive pulmonary disease with early-onset emphysema. AATD is under-diagnosed, patients can experience long delays before obtaining an accurate diagnosis, and the consequences of delayed diagnosis or misdiagnosis can be severe. Currently, A1-PI therapy is the only available treatment that addresses disease etiology in patients with AATD; however, demonstrating clinical efficacy of A1-PI therapy is challenging. In order to show therapeutic efficacy with traditional endpoints such as forced expiratory volume in one second and mortality, large sample sizes and longer duration trials are required. However, AATD is a rare, slow progressive disease, which can take decades to manifest clinically and recruiting sufficient numbers of patients into prolonged placebo-controlled trials remains a significant obstacle. Despite this, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1-Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, utilized quantitative chest computed tomography as a sensitive and specific measure of the extent of emphysema. Findings from the RAPID/RAPID Extension program definitively confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect of A1-PI therapy in patients with AATD. These findings suggest that the early introduction of treatment in patients with severe emphysema-related AATD may delay the time to death, lung transplantation or crippling respiratory complaints. In addition, there is now limited evidence that A1-PI therapy provides a gain of more than five life-years, supporting previous observations based on registry data. With the clinical efficacy of A1-PI therapy now demonstrated, further studies are required to assess long-term outcomes.

Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 (strongly disagree) to +5 (strongly agree) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable.

A 76-year-old male Vietnam veteran with a medical history of OSA on CPAP, mild COPD, Parsonage-Turner syndrome (a rare neurologic syndrome manifesting with shoulder and arm pain), hypertension, gastroesophageal reflux, hiatal hernia, and prior endocarditis presented with 1 year duration progressive exertional dyspnea with minimal activity by referral from an outside pulmonologist. The patient reported possible exposure to Agent Orange during his service but was otherwise without significant occupational or environmental exposures. His exercise tolerance was well-maintained up until the last 12 months. Aside from marginal cigarette use, he denied any recreational drug use or any anorectic use. The patient provided records from a recent right heart catheterization (RHC) months earlier for review. [ABSTRACT FROM AUTHOR]

The advent of serial crystallography has rejuvenated and popularized room-temperature X-ray crystal structure determination. Structures determined at physiological temperature reveal protein flexibility and dynamics. In addition, challenging samples (e.g. large complexes, membrane proteins and viruses) form fragile crystals that are often difficult to harvest for cryo-crystallography. Moreover, a typical serial crystallography experiment requires a large number of microcrystals, mainly achievable through batch crystallization. Many medically relevant samples are expressed in mammalian cell lines, producing a meager quantity of protein that is incompatible with batch crystallization. This can limit the scope of serial crystallography approaches. Direct in situ data collection from a 96-well crystallization plate enables not only the identification of the best diffracting crystallization condition but also the possibility for structure determination under ambient conditions. Here, we describe an in situ serial crystallography (iSX) approach, facilitating direct measurement from crystallization plates mounted on a rapidly exchangeable universal plate holder deployed at a microfocus beamline, ID23-2, at the European Synchrotron Radiation Facility. We applied our iSX approach on a challenging project, autotaxin, a therapeutic target expressed in a stable human cell line, to determine the structure in the lowest-symmetry P1 space group at 3.0 Å resolution. Our in situ data collection strategy provided a complete dataset for structure determination while screening various crystallization conditions. Our data analysis reveals that the iSX approach is highly efficient at a microfocus beamline, improving throughput and demonstrating how crystallization plates can be routinely used as an alternative method of presenting samples for serial crystallography experiments at synchrotrons.

Abstract BackgroundStrong information systems are essential for safe and effective immunization programs. The COVID-19 vaccine rollout presented all immunization information systems (IIS) with challenging demands—requiring in-depth vaccine implementation data at all health system levels in real time. The system development approaches taken by countries were heterogeneous, with some countries opting to adapt existing systems and others implementing new ones. ObjectiveUsing data reported by Member States to the World Health Organization (WHO), we aim to develop a global understanding of (1) the types of IIS used to monitor COVID-19 vaccination implemented in 2021 and (2) the approaches taken by countries to develop these systems. MethodsWe conducted a descriptive analysis of data reported through a supplemental questionnaire of the WHO/United Nations Children's Emergency Fund (UNICEF) Joint Reporting Form on Immunization, collecting data for 2021 on (1) the use of and developmental approaches taken for 7 IIS functions (appointments, aggregate reporting, individual-level reporting, reminders, home-based records, safety surveillance, and stock management), and (2) modifications needed for digital health frameworks to permit COVID-19 vaccination monitoring. ResultsIn total, 188 of 194 WHO Member States responded to the supplemental questionnaire, with 155 reporting on the IIS-related questions. Among those reporting, for each of the 7 IIS functions explored, greater than 85% of responding countries reported that the system was in place for COVID-19 vaccines. Among responding countries, “aggregate reporting system” was the system most frequently reported as being in place (n=116, 98.3%), while “reminder system” was the least (n=77, 89%). Among the countries reporting using a system, whether an existing system was adapted for COVID-19 vaccines or a new one was developed varied by system. Additionally, two-thirds (n=127, 67.6%) of countries reported establishing at least one new system, ranging from 72% (n=42) in high-income countries (HICs) to 62% (n=16) in low-income countries. Concurrently, 55.3% (n=104) of countries reported adapting at least one system already in place for COVID-19 vaccines, with 62% (n=36) of HICs reporting this compared to about 53% for other income groups. Of those reporting developing new systems, for each of the systems explored, more than 85% of countries reported that they intended to keep new systems specific to COVID-19 vaccines. Further, 147 of the 188 (78.2%) Member States responding to the supplemental questionnaire responded to the digital health frameworks question. Lastly, 31% (n=46) of responding countries reported needing to adapt them for COVID-19 vaccination systems. HICs had a higher percentage. ConclusionsNearly all countries have adapted existing or developed new IIS to monitor COVID-19 vaccination. The approaches varied, notably by income group. Reflection is needed on how to sustain the investments made in IIS during the pandemic. Continued support for IIS is critical, given their essential role in program monitoring and performance.