Prolonged Sequelae Research Articles

Damage to endothelial barriers and its contribution to long COVID.

The world continues to contend with COVID-19, fueled by the emergence of viral variants. At the same time, a subset of convalescent individuals continues to experience persistent and prolonged sequelae, known as long COVID. Clinical, autopsy, animal and in vitro studies all reveal endothelial injury in acute COVID-19 and convalescent patients. Endothelial dysfunction is now recognized as a central factor in COVID-19 progression and long COVID development. Different organs contain different types of endothelia, each with specific features, forming different endothelial barriers and executing different physiological functions. Endothelial injury results in contraction of cell margins (increased permeability), shedding of glycocalyx, extension of phosphatidylserine-rich filopods, and barrier damage. During acute SARS-CoV-2 infection, damaged endothelial cells promote diffuse microthrombi and destroy the endothelial (including blood-air, blood-brain, glomerular filtration and intestinal-blood) barriers, leading to multiple organ dysfunction. During the convalescence period, a subset of patients is unable to fully recover due to persistent endothelial dysfunction, contributing to long COVID. There is still an important knowledge gap between endothelial barrier damage in different organs and COVID-19 sequelae. In this article, we mainly focus on these endothelial barriers and their contribution to long COVID.

Association between serum ferritin level and decreased diffusion capacity 3 months after the onset of COVID-19 pneumonia.

Coronavirus disease 2019 (COVID-19) pneumonia can have prolonged sequelae and lead to respiratory dysfunction, mainly because of impaired diffusion capacity for carbon monoxide (DLCO). The clinical factors associated with DLCO impairment, including blood biochemistry test parameters, remain unclear. Patients with COVID-19 pneumonia who underwent inpatient treatment between April 2020 and August 2021 were included in this study. A pulmonary function test was performed 3 months after onset, and the sequelae symptoms were investigated. Clinical factors, including blood test parameters and abnormal chest shadows on computed tomography, of COVID-19 pneumonia associated with DLCO impairment were investigated. In total, 54 recovered patients participated in this study. Twenty-six patients (48%) and 12 patients (22%) had sequelae symptoms 2 and 3 months after, respectively. The main sequelae symptoms at 3 months were dyspnea and general malaise. Pulmonary function tests showed that 13 patients (24%) had both DLCO <80% predicted value (pred) and DLCO/alveolar volume (VA) <80% pred, and appeared to have DLCO impairment not attributable to an abnormal lung volume. Clinical factors associated with impaired DLCO were investigated in multivariable regression analysis. Ferritin level of >686.5 ng/mL (odds ratio: 11.08, 95% confidence interval [CI]: 1.84-66.59; p = 0.009) was most strongly associated with DLCO impairment. Decreased DLCO was the most common respiratory function impairment, and ferritin level was a significantly associated clinical factor. Serum ferritin level could be used as a predictor of DLCO impairment in cases of COVID-19 pneumonia.

The microbiome in post-acute infection syndrome (PAIS)

Post-Acute Infection Syndrome (PAIS) is a relatively new medical terminology that represents prolonged sequelae symptoms after acute infection by numerous pathogenic agents. Imposing a substantial public health burden worldwide, PASC (post-acute sequelae of COVID-19 infection) and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) are two of the most recognized and prevalent PAIS conditions. The presences of prior infections and similar symptom profiles in PAIS reflect a plausible common etiopathogenesis. The human microbiome is known to play an essential role in health and disease. In this review, we reviewed and summarized available research on oral and gut microbiota alterations in patients with different infections or PAIS conditions. We discussed key theories about the associations between microbiome dysbiosis and PAIS disease development, aiming to explore the mechanistic roles and potential functions the microbiome may have in the process. Additionally, we discuss the areas of knowledge gaps and propose the potential clinical applications of the microbiome for prevention and treatment of PAIS conditions.

Implementation of open-heart surgery in Dong Nai General Hospital: A preliminary result

Introduction: Implementation of open-heart surgery in local hospitals might be necessary to help economize the treatment, improve the quality of the local medical staff and unload central hospitals. Since 2018, Dong Nai General Hospital, such a program with the assistance from Cho Ray Hospital. After 4 years, a research was conducted to assess the efficacy of this program&#x0D; Methods: We retrospectively evaluated the efficacy of the cardiac surgery program in Dong Nai general hospital. Demographic characteristics, the preoperative cardiac lesions, comorbidities, early postoperative results, mid-term outcome were collected and analyzed.&#x0D; Results: From May 2018 to May 2022, a total of 62 patients underwent cardiac surgery at Dong Nai General Hospital. 33.9% were male, mean age was 45.6 ± 15.5. 47 cases were operated in the first phase and 15 underwent surgery in the second phase. The overall short-term mortality was 1.6% (1 patient), early complications rate was 9.7%. These complications did not lead to prolonged sequelae.&#x0D; Conclusion: Implementing cardiac surgery program in Dong Nai General Hospital under the assistance of Cho Ray hospital was proved safe and efficient in terms of short-term result. The success of this program should encourage other regional hospitals to start a new field and ameliorate the capacity of local healthcare system.

Predictive characteristics of prolonged symptoms and seroconversion in ambulatory patients recovering from SARS-CoV-2 infection

Introduction: As an increasing number of patients present for ambulatory care following acute COVID-19, we set out to characterize and identify clinical predictors of prolonged symptoms and antibody seroconversion. We hypothesized that patients who present with a high symptom burden are more likely have prolonged post-acute sequelae of COVID-19 (PASC). Methods: All adults with confirmed SARS-CoV-2 infection evaluated at a single ambulatory center between April and September 2020 were studied retrospectively using a logit model and ANOVA; the importance of variables associated with prolonged symptoms and seroconversion was determined using machine learning methodology. Results: The most common initial symptoms of 276 subjects were fatigue, dyspnea, cough, fever, and myalgia, with ~30% experiencing all five. Those with prolonged sequelae (&gt;4 weeks) reported higher initial symptom burden compared to those without PASC (mean 8.2 vs. 3.3 symptoms, p&lt;0.0001). Anosmia (odds ratio, OR 23.0), myalgia (OR 12.8), and dyspnea (OR 10.8) had highest predictive values for prolonged sequelae. Neither lung function, nor pre-existing lung disease correlated with PASC pulmonary symptoms (p=0.17, p=0.5, respectively). Natural post-COVID-19 seroconversion rate was 78%, with male gender having higher and corticosteroid treatment and elevated creatinine having lower likelihood of seroconversion. Conclusion: Ambulatory PASC patients display a broad range of symptoms. A high initial symptom burden correlates with prolonged sequelae. In unvaccinated individuals, antibody seroconversion may be influenced by gender, corticosteroid use, and renal function.

“Long COVID” results after hospitalization for SARS-CoV-2 infection

Long-term sequelae of symptomatic infection caused by SARS-CoV-2 are largely undiscovered. We performed a prospective cohort study on consecutively hospitalized Sars-CoV-2 patients (March–May 2020) for evaluating COVID-19 outcomes at 6 and 12 months. After hospital discharge, patients were addressed to two follow-up pathways based on respiratory support needed during hospitalization. Outcomes were assessed by telephone consultation or ambulatory visit. Among 471 patients, 80.9% received no respiratory support during hospitalization; 19.1% received non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV). 58 patients died during hospitalization, therefore 413 were enrolled for follow-up. At 6 months, among 355 patients, the 30.3% had any symptoms, 18.0% dyspnea, 6.2% neurological symptoms. Fifty-two out of 105 had major damages in interstitial computed tomography images. NIV/IMV patients had higher probability to suffer of symptoms (aOR = 4.00, 95%CI:1.99–8.05), dyspnea (aOR = 2.80, 95%CI:1.28–6.16), neurological symptoms (aOR = 9.72, 95%CI:2.78–34.00). At 12 months, among 344, the 25.3% suffered on any symptoms, 12.2% dyspnea, 10.1% neurological symptoms. Severe interstitial lesions were present in 37 out of 47 investigated patients. NIV/IMV patients in respect to no respiratory support, had higher probability of experiencing symptoms (aOR = 3.66, 95%CI:1.73–7.74), neurological symptoms (aOR = 8.96, 95%CI:3.22–24.90). COVID-19 patients showed prolonged sequelae up to 12 months, highlighting the need of follow-up pathways for post-COVID-19 syndrome.

Distinctive Evasion Mechanisms to Allow Persistence of Borrelia burgdorferi in Different Human Cell Lines.

Lyme borreliosis is a multisystemic disease caused by the pleomorphic bacteria of the Borrelia burgdorferi sensu lato complex. The exact mechanisms for the infection to progress into a prolonged sequelae of the disease are currently unknown, although immune evasion and persistence of the bacteria in the host are thought to be major contributors. The current study investigated B. burgdorferi infection processes in two human cell lines, both non-immune and non-phagocytic, to further understand the mechanisms of infection of this bacterium. By utilizing light, confocal, helium ion, and transmission electron microscopy, borrelial infection of chondrosarcoma (SW1353) and dermal fibroblast (BJ) cells were examined from an early 30-min time point to a late 9-days post-infection. Host cell invasion, viability of both the host and B. burgdorferi, as well as, co-localization with lysosomes and the presence of different borrelial pleomorphic forms were analyzed. The results demonstrated differences of infection between the cell lines starting from early entry as B. burgdorferi invaded BJ cells in coiled forms with less pronounced host cell extensions, whereas in SW1353 cells, micropodial interactions with spirochetes were always seen. Moreover, infection of BJ cells increased in a dose dependent manner throughout the examined 9 days, while the percentage of infection, although dose dependent, decreased in SW1353 cells after reaching a peak at 48 h. Furthermore, blebs, round body and damaged B. burgdorferi forms, were mostly observed from the infected SW1353 cells, while spirochetes dominated in BJ cells. Both infected host cell lines grew and remained viable after 9 day post-infection. Although damaged forms were noticed in both cell lines, co-localization with lysosomes was low in both cell lines, especially in BJ cells. The invasion of non-phagocytic cells and the lack of cytopathic effects onto the host cells by B. burgdorferi indicated one mechanism of immune evasion for the bacteria. The differences in attachment, pleomorphic form expressions, and the lack of lysosomal involvement between the infected host cells likely explain the ability of a bacterium to adapt to different environments, as well as, a strategy for persistence inside a host.

Pulmonary Embolism as Post-COVID-19 Sequelae: Role of Lung Perfusion Scintigraphy.

We present the case of a 41-year-old male, suspected to have pulmonary thromboembolism with a history of coronavirus disease 2019 (COVID-19) infection 1 month ago. He presented with dyspnea and dry cough for 2 weeks. D-dimer was >776.70 mcg/L. Lung perfusion scan with Tc-99m macroaggregated albumin revealed multiple bilateral segmental perfusion defects with no mass lesion/consolidation on high-resolution computed tomography (CT) of lungs suggestive of pulmonary embolism (PE) present according to perfusion only modified PIOPED II criteria. CT pulmonary angiogram showed a large filling defect in the right pulmonary artery. The case emphasizes the prolonged sequelae following COVID-19 after recovery from the acute phase of the illness. Lung perfusion scintigraphy can play an important role in the screening of such patients who may be at risk for developing PE as post-COVID-19 sequelae.

Neonatal Pemphigus Vulgaris: A Case Report

: Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and mucous membranes. The transplacental passage of maternal immunoglobulin G (IgG) autoantibodies to desmoglein-3 (a transmembrane glycoprotein component in the skin) from the mother’s blood to the fetus can cause transient PV in the neonatal period. The duration of PV is short in the neonatal period, and the disease is improved with no prolonged sequelae. The similarity of skin lesions in PV to other skin conditions, such as infectious diseases caused by bacterial, viral, and fungal pathogens, or inherited bullous disorders, such as epidermolysis bullosa and incontinentia pigmenti, leads to misdiagnosis, inappropriate hospital admission, and poor antimicrobial treatment of patients. On the other hand, the maternal history of PV, besides laboratory examination, confirms the exact diagnosis. In this case report, we present a male term neonate with multiple pustules and blisters on the skin, developed within the first hours of life. The patient was admitted to the neonatal ward of our hospital for a sepsis workup and antibiotic treatment. Regarding the positive maternal history of PV in the second trimester of pregnancy and neonatal examinations skin biopsy confirmed the diagnosis of this disease.

Complications of Postoperative Epidural Analgesia For Oncologic Surgery: A Review of 18,895 Cases.

The risks of epidural analgesia (EA) differ depending on the population studied. We describe our experience with postoperative EA for oncologic surgery. We searched our Acute Pain Medicine database for cases in which postoperative EA was used between 2003 and 2012. We used word search to identify and catalog cases of neurological changes, magnetic resonance imaging or computed tomography of the spine, electromyography studies, and neurologist or neurosurgeon consultations. Medical records of patients with documented persistent neurological deficits and patients who had spine imaging or neurology consultations were reviewed further. In addition, we cross-checked medical records with billing diagnosis codes for spinal epidural abscess or hematoma. We reviewed 18,895 cases in which postoperative EA was used. Complications included neurological symptoms in 2436 cases (12.9%), epidural insertion site abnormalities in 1062 cases (5.6%), complete epidural catheter migration in 829 cases (4.4%), epidural replacement in 619 cases (3.3%), and inadvertent dura puncture in 322 cases (1.7%). There were 6 cases of persistent deficits of uncertain etiology, 4 deep spinal infections (1:4724), and 2 cases of catheter tip shearing. No spinal epidural hematomas were identified (95% confidence interval, 0-0.0002). Our findings provide a contemporary review of some risks associated with the use of postoperative EA for patients undergoing oncologic surgery. Despite a not-uncommon incidence of neurological changes, serious complications resulting in prolonged sequelae were rare.

Image-guided tumour biopsies in a prospective molecular triage study (MOSCATO-01): What are the real risks?

PurposeTo evaluate efficacy, complications and preprocedural risk factors for percutaneous image-guided core needle biopsy of malignant tumours for genomic tumour analysis. Materials and methodsProcedural data for core biopsies performed at a single centre for the MOSCATO-01 clinical trial were prospectively recorded between December 2011 and March 2016. Data assessed included patient demographics, tumour characteristics, procedural outcomes and complications. ResultsA total of 877 biopsies were performed under computed tomography (38.4%) or ultrasound guidance (61.6%) for tumours in the liver (n = 363), lungs (n = 229), lymph nodes (n = 138), bones (n = 15) and other miscellaneous sites (n = 124). Each biopsy harvested a mean 4.4 samples [1–15], with adequate tumour yield for genomic analysis in 95.3% of cases. Procedural complications occurred in 89 cases (10.1%), with minor grade I complications in 59 (66.3%); grade II in 16 (18%) and grade III in 14 (15.7%). No grade IV complications and no procedure-related death occurred. The most common complications were pneumothorax (51/89, 57.3%), haemorrhage (24/89, 27%) and pain (8/89, 8.9%). Predictive factors for complications by univariate analysis included biopsied organ (lung vs other), sample number, prone position, lesion size, lesion depth and biopsy approach. By multivariate analysis, only pulmonary biopsy was a significant risk factor (odds ratio = 27.23 [4.93–242.76], p < 0.01). ConclusionPercutaneous image-guided core needle biopsy in cancer patients provides an effective method to obtain molecular screening samples, with an overall low complication rate. Lung mass biopsies present a higher risk of complication, although complications are manageable by minimally invasive techniques without prolonged sequelae.

Complications associated with intravenous midazolam and fentanyl sedation in patients undergoing minor oral surgery.

BackgroundAnxiety control remains an important concern in dental practice. We evaluated the incidence, nature, and sequelae of complications during and after minor oral surgeries performed under intravenous midazolam and fentanyl sedation using the titration technique.MethodsThe medical records of patients who had undergone minor oral surgeries under moderate intravenous midazolam and fentanyl sedation at our institution between January 1, 2015 and December 31, 2015 were retrospectively evaluated. Age, sex, body mass index, medical history, American Society of Anesthesiologists (ASA) classification, indications for sedation, amount of sedative used, surgical duration, and recovery time were evaluated for all patients.ResultsIn total, 107 patients aged 9–84 years were included. ASA class I and class II were observed for 56.1% and 43.9% patients, respectively. Complications associated with sedation occurred in 11 (10.2%) patients. There were no serious adverse events. Oxygen saturation reached 95% during the procedure in six patients; this was successfully managed by stimulating the patients to take a deep breath. Two patients exhibited deep sedation and one exhibited paradoxical excitement. After the procedure, one patient experienced nausea without vomiting and one exhibited a prolonged recovery time. The surgical procedures were completed in all patients. Obesity was found to be significantly associated with sedation-related complications.ConclusionsOur results suggest that complications associated with intravenous midazolam and fentanyl sedation using the titration technique for minor oral surgeries are mostly minor and can be successfully managed with no prolonged sequelae.

Treatment of compound tibial fracture with free osteomuscular latissimus dorsi scapula flap.

Compound tibial fractures with extensive comminution and soft tissue defects are limb-threatening reconstructive challenges. The purpose of this study was to assess the long-term outcomes and the reliability of the latissimus dorsi scapula flap for this indication. The hospital records of 26 compound tibial fracture patients treated with the latissimus dorsi scapula flap were reviewed. An overall assessment was performed in several steps based on a preinformation and two function-related questionnaires together with radiographs, clinical overviews, and functional tests. In 85% of the cases, the fractures had resulted from high-energy trauma and had extensive zone of injury. The mean follow-up time was 6.2 years. Nine patients required reconstruction because of prolonged sequelae after infection, nonunion, or tissue deficiency. One flap loss occurred leading to amputation. Six patients required an additional operation to enhance bony union. Full weight-bearing was allowed in 3 months and the mean time to bony union was 10 months. Overall, 90% returned to their pretrauma occupation. Overall 11 patients were lost to follow-up. A total of 14 patients answered the questionnaires whereas 12 outpatients attended the clinical assessment. The main finding after evaluating the results of the functional tests and reviewing the questionnaires was the limitation in ankle movement while the donor site performed well. This study confirms that osteomuscular latissimus dorsi scapula flap reconstruction is a suitable alternative for compound and comminuted tibia fractures especially in the case of extensive soft tissue injury with bony loss or significant comminution and with high probability of amputation.

Endoscopic lumen restoration for obstructive aphagia: outcomes of a 25-year experience

After chemoradiation therapy for head/neck cancer, some patients develop strictures that progress to complete pharyngoesophageal occlusion. Total lumen occlusion is less often due to other conditions. Enteral access (enterostomy tube) and good nutritional status tend to minimize the significance of dysphagia and therefore may mask recognition of impending complete lumen occlusion. Review outcomes of a 25-year experience with endoscopic lumen restoration (ELR) in 30 patients. Retrospective, case review study. Two tertiary-care referral centers. This study involved 30 consecutive patients referred for obstructive aphagia due to complete lumen occlusion, primarily after chemoradiation therapy for head/neck cancer. Antegrade and retrograde endoscopy with tri-plane fluoroscopy for penetrating the occluded segment, serial retrograde and antegrade dilations, plus swallowing rehabilitation therapy. Restoration of lumen patency, swallowing function, and removal of enteral feeding tube. ELR was successful in 30 patients in 31 of 33 attempts (93%). Return to soft to regular diet was achieved in 15 of 30 patients (50%), and fluids to pureed food with partial percutaneous endoscopic gastrostomy nutrition was achieved in 5 of 30 patients (17%). Ten of 30 patients (33%) were considered unsafe for oral feeding because of oropharyngeal neuromotor deficits. Complications occurred in 5 of 30 patients (17%), with no prolonged sequelae, deaths, or surgery, but two stents were placed for anastomotic fistulas. The median duration of follow-up was 22.75 months. Retrospective, case review study. ELR by using tri-plane fluoroscopic guidance with antegrade and retrograde endoscopy and serial dilations allows lumen restoration and swallowing to some degree in a majority of patients. Engagement of a core team of specialists can provide optimal restoration of swallowing function.

Adverse skin and joint reactions associated with oral antibiotics in children: The role of cefaclor in serum sickness‐like reactions

To review presentations to Princess Margaret Hospital Emergency Department (PMH ED) with adverse joint and skin reactions associated with the use of oral antibiotics, to describe the clinical course of children with cefaclor-related serum sickness-like reactions (cefaclor SSLR) and compare these with cases reported to the Adverse Drug Reactions Advisory Committee (ADRAC). Twelve-month retrospective review of presentations to a tertiary paediatric ED (42,000 visits annually) via an ED computer database search and review of medical charts of children presenting with joint or skin reactions. Telephone interviews were conducted with the caregivers of children with cefaclor SSLR. Adverse skin or joint reactions occurred in 150 children; 70 after cefaclor alone, 10 after cefaclor in combination with other antibiotics and 70 after other antibiotic courses. SSLR occurred in 44 children; 32 after cefaclor alone, five after cefaclor in combination with other antibiotics and seven after other single antibiotics. In children with cefaclor SSLR, otitis media was the most common indication (59.4%), another 18.8% had viral illnesses. Prolonged sequelae occurred in four children, a situation not previously reported. Sixty reports of paediatric cefaclor SSLR were made to ADRAC during the study period, none originated from PMH ED. Cefaclor was associated with 53.3% of oral antibiotic related skin and joint adverse reactions and 84.1% of SSLR. The indications for its use in paediatric illness require careful reconsideration. ADRAC data under-represents the incidence of cefaclor SSLR.

Carbon Monoxide Exposure in the Home Environment and the Evaluation of Risks to Health - A UK Perspective

The causes and effects of exposure to high levels of car bon monoxide (CO) are well documented, and many countries maintain records of annual deaths arising from CO poisoning incidents. Many such incidents are associ ated with the use of badly installed, poorly maintained or malfunctioning domestic combustion appliances or with the use of such appliances in poorly ventilated rooms. However, the prolonged sequelae of acute CO poisoning and the chronic effects of long-term exposure to lower levels of CO are not well understood. The home environ ment is particularly important because of the possibility of unrecognised long-term, low-level exposure to CO. Furthermore, the common problem of missed or mis diagnosis of CO poisoning can result in exposed individ uals being given inappropriate treatment and being re turned to a hazardous situation.

Neuropsychological Functioning and Recovery after Mild Head Injury in Collegiate Athletes

This study prospectively examined neuropsychological functioning in 2300 collegiate football players from 10 National Collegiate Athletic Association Division A universities. The study was designed to determine the presence and duration of neuropsychological symptoms after mild head injury. A nonequivalent repeated measures control group design was used to compare the neuropsychological test scores and symptoms of injured players (n = 183) with those of gender, age, and education matched controls. A number of neuropsychological tests, including the Paced Auditory Serial Addition Test, the Digit Symbol Test, and the Trail Making Test, as well as a symptom checklist were used. Players and controls were assessed before engaging in game activity and 24 hours, 5 days, and 10 days after injury, using the standardized test battery and symptom checklist. Players with head injuries displayed impaired performance and increased symptoms in comparison to controls, but this impairment resolved within 5 days in most players. Players with head injuries showed significant improvement between 24 hours and 5 days, as well as between 5 and 10 days. Although single, uncomplicated mild head injuries do cause limited neuropsychological impairment, injured players generally experience rapid resolution of symptoms with minimal prolonged sequelae.

Q fever in Plymouth, 1972–88: A review with particular reference to neurological manifestations

Between 1972 and 1988 we have serologically confirmed 103 Coxiella burnetii infections: 46 were acute, 5 were chronic, 52 represented past infections. Details of 61 cases are presented. Of acute cases 80% had respiratory involvement; at least 63% had pneumonias. The incidence (22%) of neurological complications was of particular interest; 40% of these patients had prolonged sequelae. One acutely ill patient died of fulminating hepatitis. Patients with pre-existing pathology or immunosuppression were especially susceptible to C. burnetii. In the absence of acute sera, the complement fixation test alone provided inadequate differentiation between recent and past Q fever: phase II titres persisted at greater than or equal to 80 for more than 1 year after the acute infection in 15 cases; maximum duration of persistence was 14 years. Three patients acquired high phase I titres. Only 5% of cases had chronic Q fever, but in view of the diverse sequelae observed in this series, we suggest that long-term serological and clinical follow-up of all cases of Q fever is fully justified.

Chlordane contamination of a municipal water system

On March 24, 1976, a section of the public water system of Chattanooga, Tennessee, supplying 105 people was contaminated with chlordane, a chlorinated hydrocarbon pesticide. In a door-to-door health survey of the 71 residents affected, 13 (18%) were noted to have symptoms or signs compatible with mild acute chlordane toxicity. Serum levels of chlordane metabolites measured shortly after the incident did not correlate with the recorded symptomatology. Retesting of the symptomatic residents 2 months later revealed a possible rise in oxychlordane levels, suggestive of an acute exposure in the past. None of the residents have had prolonged sequelae from chlordane exposure; further followup is recommended.